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Incorporating genetic and environmental risk factors in to risk prediction for colorectal cancer


Cancer Epidemiology HomeFrom: Incorporating non-genetic risk factors and behavioural modifications into risk prediction models for colorectal cancer

Yarnall, Crouch & Lewis (Division of Genetics and Molecular Medicine, King’s College London, United Kingdom.). Cancer Epidemiology 2013 Jan 29

Abstract

Background: Epidemiological studies have identified potentially modifiable risks for colorectal cancer, including alcohol intake, diet and a sedentary lifestyle. Modelling these environmental factors alongside genetic risk is critical in obtaining accurate estimates of disease risk and improving our understanding of behavioural modifications. Methods: 14 independent single nucleotide polymorphisms identified though GWAS studies and reported on by the international consortium COGENT were used to model genetic disease risk at a population level. Six well validated environmental risks were selected for modelling together with the genetic risk factors (alcohol intake; smoking; exercise levels; BMI; fibre intake and consumption of red and processed meat). Through a simulation study using risk modelling software, we assessed the potential impact of behavioural modifications on disease risk. Results: Modelling the genetic data alone leads to 24% of the population being classified as reduced risk; 60% average risk; 10% elevated risk and 6% high risk for colorectal cancer. Adding alcohol consumption to the model reduced the elevated and high risk categories to 9% and 5% respectively. The simulation study suggests that a substantial proportion of individuals could reduce their disease risk profile by altering their behaviour, including reclassification of over 62% of heavy drinkers. Conclusion: Modelling lifestyle factors alongside genetic risk can provide useful strategies to select individuals for screening for colorectal cancer risk. Impact: Quantifying the impact of moderating behaviour, particularly related to alcohol intake and obesity levels, is beneficial for informing health campaigns and tailoring prevention strategies.

Risk factors

Low risk (Green), average risk (blue), moderate risk (yellow) and high risk (red)using combined genetic and environmental risk factors

Discussion

Over the last 30 years the lifetime risk of colorectal cancer (CRC) for men has almost doubled, from 3.5% to 6.9% in the UK in 2008. For women the increase is more than a quarter, rising from 3.9% to 5.4%.  Since both genetic and environmental factors contribute to the susceptibility to colorectal cancer, this trend may be due to a change in the dietary and lifestyle factors of the general population leading to higher levels of obesity and more sedentary pastimes.

The major risk factor for colorectal cancer is age and over 85% of colorectal cancer occurs in people over the age of 60.  Other risk factors include the presence of polyps and people having an Ashkenazi Jewish genetic heritage. The use of non-steroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy and aspirin use have also been associated with disease risk. However, it is estimated that between 52 and 57% of colorectal cancers are associated with lifestyle and environmental factors.  Many risk factors for colorectal cancer may be modified by intervention, ranging from known risks, such as increased risk from a sedentary lifestyle and dietary changes. The evidence for dietary factors indicates possible increased risk from diets low in fibre, garlic, calcium, fruit, vegetables and fish and high in red and processed meat. In addition to alcohol, BMI, smoking and exercise, we chose to model the most consistent and well validated dietary findings, which suggest that low levels of fibre and high levels of red and processed meat are both significant risk factors.

The international consortium COGENT (COlorectal cancer GENeTics) have identified many of the known genetic variants that predispose to CRC with the 14 single nucleotide polymorphisms (SNPs) found to be convincingly associated with CRC risk from GWA studies summarized in Houlston et al.’s recent update.  Of these 14 SNPs, the mean odds ratio per allele is 1.14, with the highest odds ratio reported for SNP rs16892766 near the EIF3H gene (OR 1.28).

The identification of SNPs that contribute to susceptibility for CRC has raised the prospect of genetic screening. Companies such as DeCODEme and 24andme include panels of SNPs for CRC in their genetic testing panels, yet research suggests that the genetic risk prediction alone is of questionable utility.  In this research study, we combined the known genetic risk with data on the environmental risks for CRC, enabling more complete risk prediction. We applied a statistical risk model and to determine the impact of modelling environmental factors alongside the 14 genetic susceptibility loci identified by the COGENT consortium.

Early screening for colorectal cancer can be extremely helpful in identifying individuals with polyps and nonpolypoid lesions and preventing the development of cancer. Regular faecal occult blood tests (FOBT) in the over 50 s for example have been found to reduce the number of deaths due to CRC by 15–33%.  In the UK, screening is offered to all men and women aged between 60 and 69 at a cost of £77.3 million and this will be extended to 74 year olds. However, it has been suggested that if individuals are provided with a personalized disease risk assessment from their combined genetic and environmental profile, they are likely to be more motivated to alter their lifestyle as a preventative measure, which would increase the effectiveness of health campaigns. In this study we develop predictions of CRC risk in different sub populations and assess the impact of modifying lifestyle factors on risk levels. By providing predictions of disease risk both before and after a lifestyle change for a given genetic profile, the study illustrates the potential benefits for both selection of candidates for screening programmes and the tailored promotion of healthier lifestyle choices, in high risk groups.

There are several modifiable risk factors for colorectal cancer and building predictive models encompassing both genetic and environmental factors enables us to move in the direction of a complete assessment of disease risk. This paper describes a predictive model which takes account of the known genetic contribution as well as the modifiable risks. There is considerable evidence to suggest that detecting polyps in the early stages can reduce mortality rates for colorectal cancer and whilst the interactions between the genetic and environmental elements are undeniably complex, separating out the inherited risk from the lifestyle factors using this model helps to illustrate the potential gains from modifying lifestyle behaviour and could usefully inform healthy lifestyle campaigns.

Our findings indicate that that cessation of alcohol consumption and reducing obesity levels lead to the most significant changes to the proportion of the population reducing their disease risk category. Whilst this could have been predicted to some extent by the higher odds ratios for these factors, it is the combination of relative risk, together with the prevalence of the factor within the population that determines the overall impact. In addition, being able to create personalized risk predictions in this way, has the potential to motivate greater behavioural change, showing for example, that it is possible to significantly reduce disease risk by moving from a high risk category to an average risk category though increasing fibre levels; cessation of alcohol consumption or weight management, given a particular genetic profile. Further research is required to increase understanding of how individuals respond to risk assessment based on genetic information.  This may increases their motivation since the results are personal, or decrease their motivation because they consider that their genetic risk cannot be modified.

Our focus has been on risk categorization, and not on the absolute level of risk estimated from the combination of genetic and environmental risk factors, which is modest for most categories. There are two advantages to this strategy. Firstly it moves away from the strategy used, for example, by direct-to-consumer genetic testing companies such as 23andme and deCODEme (who provide a single figure of risk with no confidence intervals) towards the strategy deployed in genetic counselling of using a qualitative risk level, which can be more easily interpreted for the purpose of risk prediction. Secondly, it puts a stronger statistical framework on the risk model: an assignment to elevated risk implies that the risk is statistically distinct from the risk of the average, baseline, individual, given the uncertainty of the parameters used in the model.

There are several limitations of the model. Firstly, the model is built from estimates in the literature extracted from different studies. This enables researchers to select the best study to capture information on each risk factor, but assumes that information is directly comparable between studies. This limits the precision with which risk estimates can be calculated. A further limitation is that the model assumes all risk factors entered are independent. For known gene and environment interactions, this can be overcome by either modelling the interaction explicitly as an environmental risk factor, or by omitting known genetic loci to prevent over-representation of a risk factor (such as SNPs on the FTO gene which are associated with BMI). Within the genetic component, linkage disequilibrium between SNPs can be tested to confirm no correlation at a population level; few interactions of risk between genetic loci have been identified, so the assumption of independence should not be a major problem. For the environmental component, assumptions of independence are more difficult to assess. Lack of independence may lead to inaccuracies in the population frequencies estimated, but the contribution of environmental factors to the model is based on relative risks that are estimated in the presence of relevant covariates, so levels of risk should not be inflated. Increasing our understanding of the association between lifestyle factors, as well as between genes and the environment, will be important in obtaining more accurate assessments of risk. In addition, the accuracy could be further improved by more specific modelling of the population being targeted. Applying data with relative risks by sex, by population group, or for individuals with a first degree relative with CRC for example, would provide more accurate estimations of disease risk specific to those populations.

Colorectal cancer screening programmes are widespread, but are age-targeted and look for signs of cancer in early development. In contrast, the methods described here can be used to target lifestyle factors, and are relevant for younger age-groups. The approach could encourage behavioural changes and help to reduce CRC rates. Although the model indicates that certain individuals can reduce their CRC risk by changing their behaviour, the time taken for changes in environmental risk factors to have an effect on risk is unknown, and will differ by factor. Additional research is needed to further elucidate the genetic and environmental contributions to disease risk and to measure the longer term impact of behavioural change on disease outcomes.

A dedicated service for the Management of Hereditary Colorectal Cancer Improves Adherence with Molecular Testing for Lynch Syndrome


A DEDICATED SERVICE FOR THE MANAGEMENT OF HEREDITARY COLORECTAL CANCER IMPROVES ADHERENCE WITH MOLECULAR TESTING FOR LYNCH SYNDROME

UEGW Amsterdam 2012

Leon Sergot, Sophie Stevens Poster, Fiona Turkes, Jason Smith, Kevin J. Monahan

The Family History of Bowel Cancer Clinic, West Middlesex University Hospital, London, United Kingdom

INTRODUCTION/OBJECTIVES:

Lynch Syndrome (LS) is responsible for 2-3% of colorectal cancer (CRC) which equates to ~1000 cases of CRC in the United Kingdom annually. Previous studies have demonstrated that in current practise less than 10% of these cases are identified as LS due to lack of appropriate testing. The international Bethesda guidelines were devised in 2002 to help identify such cases for tumour testing for the molecular features of LS, such as immunohistochemistry (IHC) for MLH1, MSH2, MSH6 and PMS2 expression, or DNA microsatellite instability analysis (MSI). These criteria include all individuals diagnosed

AIMS & METHODS:

We identified all new cases of CRC over 1 year before and after the establishment of a dedicated ‘Family History of Bowel Cancer Service’ in our hospital in March 2011. Adherence to the Bethesda guidelines was determined by examination of medical records and UK National Bowel Cancer Audit Programme (NBOCAP) data. Pathology reports were studied in patients aged 50-59 years at diagnosis for features consistent with MSI-type histology.

RESULTS:

In total, 198 cases of CRC were discussed at the CRC multidisciplinary meeting over a 2 year period. 12 individuals were diagnosed under the age of 50 years (~6%) consistent with Office of National Statistics (ONS) data. 31 patients were diagnosed between 50-59 years, of which 4 patients had MSI-type histology. A further 25 patients had a significant family history of CRC or a LS-related cancer diagnosed under 50 years. Therefore in total 41 patients fulfilled Bethesda criteria (20.7%). Between March 2010-March 2011 there were 18 such cases with only 1 patient’s tumour tested for the molecular features of LS (5.6%) compared to 19/23 cases tested in the subsequent year (82.6%), p value = 9.7e-7 (Chi=23.9956).  Six out of 20 (30%) cases tested demonstrated these molecular features with MSI and abnormal IHC, and are undergoing germline genetic testing.

CONCLUSION:

The establishment of a dedicated family history of bowel cancer service resulted in a significant improvement in testing individuals diagnosed with CRC with a possible diagnosis of LS. We recommend that this service be applied to identify such families throughout the United Kingdom to improve clinical pathways for these patients.

via Abstract View.

EGAPP™ Recommendation Statement: Genetic testing for Lynch Syndrome


EGAPP™ Recommendation Statement

EGAPP™ Recommendation Statement Adobe PDF file [PDF 219 KB]External Web Site Icon

“The Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer (CRC) to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.”

Summary of Findings on Genetic Testing for Lynch Syndrome for the General Public

General Public:
Genetic Testing for Lynch Syndrome

In 2009, the independent, non-federal Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) Working GroupExternal Web Site Icon reviewed the scientific evidence for genetic testing for Lynch syndrome (hereditary colorectal cancer) and developed a recommendation statement about the appropriate use of this testing. This brief summary of the EGAPP™ recommendation statement can help the general public understand what is intended by the EGAPP™ recommendation and where to find more information.

This information may be helpful for people with a recent diagnosis of colorectal cancer (cancer of the colon or rectum) and their close family members.

  • What is the purpose of genetic testing for Lynch syndrome for people newly diagnosed with colorectal cancer?

    Genetic testing is used to find out if a person’s colorectal cancer is hereditary (caused by an inherited gene change), so that family members can learn if they are also at increased risk.  This could help to protect them from getting this disease.

  • What is Lynch syndrome?

    About 3% of colorectal cancer cases are due to an inherited condition known as Lynch syndrome (sometimes referred to as hereditary nonpolyposis colorectal cancer or HNPCC).  People with this condition have a greatly increased chance to develop colorectal cancer, especially at a young age (younger than 50 years).  Children, sisters, and brothers of people with Lynch syndrome have a 50% chance to inherit the condition. Parents and other blood relatives such as grandparents, aunts, uncles, nieces and nephews are also at increased risk to have Lynch syndrome.

  • Who developed this recommendation?

    The EGAPP™ Working Group is a group of scientists and health care experts who review available research and evidence to make recommendations about the use of genetic tests.  This independent, non-government body includes representatives from universities, industry, clinical practice, insurance companies, and public health.

  • Did EGAPP™ recommend the use of genetic testing for newly diagnosed colorectal cancer patients?
    • YES:  The EGAPP™ Working GroupExternal Web Site Iconfound good scientific evidence to show that if individuals with colorectal cancer are found to have Lynch syndrome by genetic testing, their family members can benefit by:
      • undergoing genetic testing to learn if they are also at increased genetic risk.
      • if positive for the gene change, having earlier and more frequent screening which can prevent colorectal cancer.
    • They concluded that all people with a new diagnosis of colorectal cancer should be offered counseling and educational materials about genetic testing for Lynch syndrome.

 

Other Information

  • Are there other people the test might help?
    Although the EGAPP recommendation did not address use of testing in other situations, people with colorectal cancer diagnosed in the past (especially under age 50), and/or people with several family members with colorectal and/or uterine cancer may also benefit from genetic evaluation for Lynch syndrome.
  • How do I find out more about the condition/test?
    In addition to talking with your health care provider, the Web sites below provide additional information on colorectal cancer, Lynch syndrome, cancer genetic testing, and access to genetic counseling services.

    Health Professionals:
    More About the EGAPP™ Lynch Syndrome Recommendation

    This page contains more information about the EGAPP Lynch syndrome recommendation for health professionals.

    For more information about genetic testing for Lynch syndrome that is not part of the EGAPP recommendation, see More About Genetic Testing for Lynch Syndrome.

    EGAPP™ Evidence Review at a Glance

    Testing Approach Application Quality of Evidence
    Adequacy of information to address:
    Overall Recommendation*
    Analytic Validity Clinical Validity Clinical Utility
    DNA analysis of mismatch repair (MMR) genes: (MLH1, MSH2, MSH6, PMS2) Diagnostic Testing Adequate Convincing Adequate Sufficient evidence to recommend use for the benefit of relatives
    Microsatellite Instability (MSI) Preliminary (Screening) Test Convincing / Adequate
    Immunohisto-chemistry (IHC) Preliminary (Screening) Test Convincing / Adequate
    Methylation Status (BRAF V600E mutation) Preliminary (Screening) Test (Supplemental to IHC) Adequate

    *Overall recommendation was decided on the basis of a) evidence indicating moderate level of net health benefits to relatives, and b) contextual factors.


    EGAPP™ Recommendation Statement Adobe PDF file [PDF 219 KB]External Web Site Icon

    “The Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer (CRC) to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.”

    Considerations for Practice

    Note: See Contextual Factors Identified by EGAPP™ for more information.

    • All patients with a new diagnosis of colorectal cancer (regardless of age or family history) should be offered counseling and educational materials regarding genetic testing for Lynch syndrome.
      • The primary benefit will be the identification of relatives who also carry a gene mutation for Lynch syndrome. Affected relatives can be offered appropriate screening beginning at age 20-25.
    • Colonoscopy every one to two years is recommended for these patients and their relatives who test positive for Lynch syndrome beginning at age 20-25 years. Although there is not enough research to indicate that colorectal cancer due to Lynch syndrome should be treated differently than non-Lynch related colorectal cancer, individuals with Lynch syndrome are at increased risk for additional cancers and second primary colon tumors.
    • Individuals with colorectal cancer should be offered genetic testing even if there are no other family members with Lynch syndrome cancers. This is because family history was found to be less useful as a first step than strategies involving tumor testing in identifying Lynch syndrome in individuals with colorectal cancer. However, family history may still be an important decision tool for identifying individuals in the general population for referral to genetic counseling services to evaluate risk for hereditary colorectal cancer.

    See More Considerations for Practice for additional information that is not part of the EGAPP™ recommendation.


    Testing Approaches

    Several testing approaches are potentially effective for identifying Lynch syndrome. DNA analysis has the highest sensitivity and specificity, but is also the most expensive. Most protocols directed at screening unselected colon cancers begin with preliminary testing of tumor tissue by MSI and/or IHC (with or without BRAF mutation).

    • Diagnostic testing: Typically performed on blood; identifies an inherited mutation in one of the Lynch syndrome genes.
      • DNA analysis (gene sequencing, deletion/duplication testing) for the mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2.
    • Preliminary (Screening) Tests: Performed on tumor tissue; does not identify Lynch (MMR) gene mutations, but is used to guide subsequent diagnostic testing via DNA analysis.
      • MSI testing of tumor tissue: those with high instability either proceed to DNA analysis for MLH1, MSH2, MSH6, and PMS2 or to IHC testing.
      • IHC testing of tumor tissue: those with negative staining would proceed to DNA analysis of the gene/genes indicated.
      • Modification of Strategy 3, such that tumor tissue of patients with negative staining for MLH1 on IHC is tested for the BRAF V600E mutation to determine methylation status.  If the BRAF mutation is not found, the individual continues on for MLH1 DNA analysis.

    For more information about genetic testing approaches for Lynch syndrome, please see the National Library of Medicine, GeneReviews Web siteExternal Web Site Icon. (Note: This Web site does not necessarily reflect the opinions or recommendations of the Centers for Disease Control and Prevention or the EGAPP Working Group.)


    Contextual Factors Identified by EGAPP

    • Due to limited benefit to the colorectal cancer (CRC) patient, informed consent before microsatellite instability (MSI) or immunohistochemistry (IHC) testing is recommended.
    • There is no substantial evidence to show that identifying Lynch syndrome through routine genetic testing would lead to adverse psychological outcomes.
    • Evidence shows that there are relatively high levels of counseling and testing uptake among relatives and adherence to screening if patient is mutation positive.Top of Page

    Research Gaps Identified by EGAPP

    The EGAPP™ working group identified the need for research to address the following:

    • Better quality research regarding analytical validity of testing and laboratory proficiency testing;
    • Better quality studies evaluating clinical validity of various testing strategies;
    • Higher quality studies assessing clinical outcomes/clinical utility, effectiveness of screening;
    • Cost-effectiveness analyses to address testing strategies and impact on relatives
      (see More Considerations for Practice for additional information that is not part of the EGAPP™ recommendation);
    • Studies to assess whether the clinical care and screening of CRC patients with Lynch syndrome should be altered.

    For more information about genetic testing for Lynch syndrome that is not part of the EGAPP recommendation, see More About Genetic Testing for Lynch Syndrome.

 

JAMA: Identification of Lynch Syndrome Among Patients With Colorectal Cancer


Identification of individuals at increased risk of hereditary cancer allows for the possibility of screening and early cancer detection, possibly resulting in decreased disease-specific mortality, and is the justification for germline genetic testing for specific cancer risk alleles. However, factors of prevalence and age-specific penetrance, effectiveness and invasiveness of screening procedures, and efficacy of early detection influence the potential benefit of such an approach.

For one of the most common hereditary cancer syndromes, Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), various sets of clinical criteria, combined with pathologic phenotypic characteristics of tumor tissues in probands, have been used to identify individuals at risk in whom it is important to consider germline genetic testing for deleterious mutations in 1 of 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2). Lynch syndrome was originally defined by the “Amsterdam” clinical criteria as a history of at least 3 family members with histologically confirmed colorectal cancer (CRC) involving 2 generations with at least 1 person diagnosed before age 50 years.1 Although this approach is fairly specific in identifying families with highly penetrant LS, it is also overly restrictive and does not consider the possibility of later-onset variants of the disease, the implications of extracolonic tumors, or the limitations imposed by small family size.

Many families with known LS do not meet the original Amsterdam criteria, and this approach misses many families because of poor sensitivity. Therefore, it has been suggested, given the availability of an immunohistochemistry-based screening test for mismatch repair that closely mimics phenotypic microsatellite instability, that testing all colorectal (and perhaps endometrial) cancers for loss of proteins associated with mismatch DNA repair deficiency, or all cancers below some age cutoff, may overcome the limitations of selective criteria. However, the effectiveness of such a “universal” approach to screening for LS has not been tested in a population-based manner.

In this issue of JAMA, Moreira and colleagues2 address this question by performing a pooled-data analysis of a large set of population-based patient cohorts from around the world to determine the sensitivity and efficiency of several different strategies for LS screening, including the “universal” approach. Using more than 10 000 CRC samples, the authors found overall that universal tumor testing for mismatch repair deficiency was superior in sensitivity to the Bethesda guidelines, which incorporate personal and family history information, and which have been reported to be more accurate than the Amsterdam criteria,3 or an approach using an age cut-off of 70 years old, but that a hybrid of testing all tumors in individuals 70 years or younger and in older patients who meet Bethesda guidelines provides a reasonable compromise that may result in substantial cost savings.

The study by Moreira et al2 confirms that the prevalence of LS is high enough among patients with CRC, 3.1% in the whole series, that screening should be considered. However, in the EPICOLON cohort, consisting of patients newly diagnosed with CRC in 20 community hospitals in Spain,3 the prevalence was only 0.9% compared with 2.9% to 3.5% in the other 3 cohorts analyzed. The current study does not address possible explanations for this difference. Some patients in the study by Moreira et al were not drawn from a population-based registry but were excluded from analyses on the performance characteristics of screening strategies. Because most germline tests were driven by abnormal tumor testing results and not all patients underwent “gold-standard” (germline) testing, the high sensitivity estimates for screening strategies are probably somewhat optimistic. In addition, the PMS2 gene was not tested in many patients, so some persons with PMS2 mutations were probably missed. In this study, microsatellite instability testing added little to immunohistochemistry, but not all previous studies have found similar results. Selective BRAF mutation testing or promoter methylation testing to identify sporadic CRC were not performed, but the focus of the study was on the sensitivity of screening strategies, not specificity.

These results highlight the limitations of various clinical criteria to identify persons with LS, particularly those with mutations in the MSH6 or PMS2 genes. The study results should remind clinicians that simply asking about a family history of CRC in a first-degree relative will miss the majority of patients with LS: only 43% of patients with LS had such a family history—approximately 50% of those with MLH1 and MSH2 gene mutations and less than 20% of those with MSH6 and PMS2 gene mutations. Furthermore, although the mean age at CRC diagnosis was 48 years in LS patients, only 45% were diagnosed with CRC at 50 years or younger.

The potential for individualized preventive medicine provides the rationale for screening for LS. In deciding whether to establish widespread screening for LS in selected subgroups, the same considerations that govern screening for CRC in the general population could be applied. The target condition must be common enough to justify screening. A long asymptomatic period must allow for effective interventions. The potential benefits must outweigh the risks. The aggregate costs of screening and its consequences must be acceptable.

Moreira et al2 confirm that a variety of strategies can identify a significant number of persons with LS among patients with CRC. The benefits of intensive CRC and adenoma screening and prophylactic hysterectomy-oophorectomy in LS are well established.4 – 7 This raises several questions. What is the balance between the potential benefits and harms of screening? Are the economic costs acceptable? Which screening strategies are preferred?

Several studies have addressed the potential psychological harms of testing for LS. These studies include select populations and are observational. Patients considering genetic testing can develop short-term increases in anxiety, distress, and fear of cancer or death, especially among mutation carriers.8 – 10 Generally, a person’s psychological state returns to baseline after several months. Longer follow-up has demonstrated no major adverse psychological consequences for either mutation carriers or noncarriers after 1 and 3 years.8 – 9 ,11 However, some groups, such as younger men affected by cancer, may be at higher risk for adverse psychological effects.12 Patients may express fear concerning discrimination in employment or health insurance. In the United States, patients may be counseled that such discrimination is illegal under the Genetic Information Nondiscrimination Act.13

In the absence of controlled studies evaluating the long-term consequences of different screening strategies for LS, computerized decision analytic modeling can be used to explore critical questions. Several modeling studies with long-term time horizons have suggested that screening for LS among persons with CRC is likely to be cost-effective.14 – 17 The same may apply to women with endometrial cancer.18 One study that incorporated the potential short-term adverse effects LS testing can have on quality of life19 found that the long-term gains in life expectancy are likely to outweigh any short-term decreases in quality of life, at acceptable costs.20

Key issues raised by the results of Moreira et al2 were explored in a modeling study.17 Moreira et al found a relatively small incremental yield of universal tumor screening vs a highly sensitive selection strategy based on clinical criteria. The modeling study suggested that tumor testing strategies are likely to be costly compared with clinical criteria strategies when both are implemented optimally.17 However, in the model, when the clinical criteria strategies failed to be implemented in as few as 15% of patients, tumor testing strategies became cost-effective. In clinical practice, routine testing of tumors in pathology laboratories may be more feasible than ensuring widespread application of clinical criteria.

Moreira et al2 address the important issue of age at CRC diagnosis as a factor to inform screening strategies. The modeling study17 estimated that immunohistochemistry-based tumor testing in all persons vs only in those 70 years and younger could be considered cost-effective depending on society’s willingness to pay for preventive services. Using the actual age distribution at CRC diagnosis in the study of Moreira et al, instead of the model’s original assumptions, would result in enhanced cost-effectiveness for the “universal” approach.

Lynch syndrome affects families, not only individuals. Patients often identify the potential benefits to their family, especially their children, as a motivating force driving acceptance of genetic testing.21 However, the published uptake rates for genetic testing among relatives at risk have varied from 34% to 52%.22 – 23 The number of relatives unaffected by cancer but at risk for LS who undergo genetic testing is a key determinant of the cost-effectiveness of any screening strategy.16 – 17 Future public health efforts must address this critical factor.

A recent survey of US hospitals reported that routine tumor testing with immunohistochemistry, microsatellite instability, or both is currently performed at 71% of National Cancer Institute comprehensive cancer centers, 36% of American College of Surgeons–accredited community hospital comprehensive cancer programs, but only 15% of community hospital cancer programs.24 Routine tumor testing with immunohistochemistry or microsatellite instability does not require written consent. The authors suggested that this approach to testing may reflect an emerging standard of care. Routine tumor testing programs require mechanisms to track results, contact patients in ways patients will accept, and facilitate consultation with genetics professionals. Those dealing with results must understand complicating factors, including variants of uncertain significance, and must handle difficult cases, such as patients with classic family pedigrees in whom no mutation is found by current methods.

In the not too distant future, advances in genomic sequencing will challenge current genetic testing approaches. Commercial panels of “cancer genes” are already emerging. With the anticipated further reductions in the costs of DNA sequencing, up-front germline testing at the time of CRC diagnosis could become the most cost-effective strategy to screen for LS.17 Such testing would require written informed consent. Population-based genomic profiling could revolutionize the approach to identifying persons with LS.

The majority of patients with CRC do not have LS. But in the haystack of patients with CRC, those with LS are more like large knitting needles than tiny sewing needles—and a systematic search can find them. The investments of effort and resources required for this search can be rewarded by reductions in cancer incidence and mortality that are possible among patients and their unsuspecting relatives.

Abstract

Context Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear.

Objective To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands.

Design, Setting, and Patients Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10 206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data.

Main Outcome Measures Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening).

Results Of 10 206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach.

Conclusion Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.

via JAMA Network | JAMA: The Journal of the American Medical Association | Identification of Lynch Syndrome Among Patients With Colorectal CancerLynch Syndrome and Colorectal Cancer.

Preoperative Testing For Lynch Syndrome Yields ‘Huge’ Benefit


Preoperative Testing For Lynch Syndrome Yields ‘Huge’ Benefit

Vancouver, British Columbia—Mayo Clinic researchers are calling for all young patients with colorectal cancer (CRC) to undergo preoperative testing for Lynch syndrome as the results can significantly alter surgical management.

“The benefit of this testing to the patient and their family is huge,” said Rajesh Pendlimari, MBBS, a research fellow at Mayo Clinic in Rochester, Minn., and a study investigator.

“If they have Lynch syndrome and will, therefore, be more prone to getting cancer, they can get screened more regularly. The knowledge gleaned can change the course of surgical treatment.”

At the 2011 annual meeting of the American Society of Colon and Rectal Surgeons, the Mayo team presented two studies examining the benefit of pre- and postoperative microsatellite instability (MSI) testing for Lynch syndrome.

In the first study, 210 of 258 newly diagnosed patients younger than age 50 years who underwent colorectal surgery at Mayo Clinic had MSI testing between 2003 and 2008. Of these, 82 underwent testing postoperatively, according to the hospital’s protocol requiring pathologists to complete MSI testing on operative specimens for all young patients who did not have the tests done prior to surgery. Overall, 13% of patients were found to have high levels of MSI and 33% of these would have been missed without the testing protocol.

The second, complementary paper retrospectively compared the surgical management of 210 patients who were tested pre- and postoperatively for MSI (n=103, n=107, respectively). (The number of patients in the postoperative group differs in the two studies: It is listed as 82 in the first study and 107 in the second because 25 patients underwent preoperative testing on the day of surgery; their results were not available to surgeons before operating.)

Results showed that the MSI test results significantly influenced surgical recommendations for total colectomy. Of patients with positive preoperative MSI tests (MSI-H), 94% underwent total colectomy, compared with 8% of patients whose status was not known until after surgery (P<0.0001). Moreover, there appears to be an increased rate of hysterectomy among women with MSI-H. Eight of 10 MSI-H women had a hysterectomy. There was only one female patient who was tested postoperatively and she did not have a hysterectomy.

“Probably the most significant result of this research is that it has stimulated our multidisciplinary team of geneticists, pathologists, gastroenterologists and surgeons to develop new clinical pathways that will direct patients at risk to providers experienced with management of Lynch syndrome,” said Eric Dozois, MD, professor of surgery at Mayo Clinic and lead researcher on the project.

Other gastroenterologists and surgeons applauded the paper, saying that preoperative testing for Lynch syndrome is easy to do and can dramatically affect surgical treatment.

“Virtually everybody [who] gets an operation for colorectal cancer has a colonoscopy or biopsy of the tumor before they go on to surgery. In my opinion, that is a golden opportunity, since you are taking a biopsy anyway, to get the cascade of evaluation going for the possible presence of HNPCC [hereditary nonpolyposis colorectal cancer],” said Patrick Lynch, MD, professor of medicine in the Department of Gastroenterology, Hepatology and Nutrition at the University of Texas MD Anderson Cancer Center in Houston.

He added that endoscopists should not skip the opportunity for testing during colonoscopic biopsy.

“It doesn’t take that much material, it’s easy to do and you’re doing it at the front end of a window of opportunity that exists between that time and when the patient goes to surgery. The surgeon and the patient can use that information to decide if they want to expand the surgery from a simple segmental resection to a subtotal colectomy.”

Preoperative testing could improve treatment for younger patients, a group that is showing increased incidence of CRC, said Michael Stamos, MD, professor and chair of surgery at the University of California, Irvine, where surgeons and gastroenterologists routinely do immunohistochemistry (IHC) staining testing prior to surgery.

The Mayo Clinic team has developed a new clinical pathway (Figure) for testing and treatment of patients at high risk for CRC. The protocol requires all high-risk patients to undergo either MSI or IHC to test for Lynch syndrome prior to surgery.

It’s still unclear which test is best to start with. Although MSI is the gold standard test for the DNA mismatch repair, it does have some disadvantages such as a slow turnaround time and it requires an advanced and experienced lab as well as more testing than IHC. Individuals with positive results still need to undergo IHC. On the other hand, IHC requires an experienced pathologist and detects abnormalities of only four major genes.

The best test depends on the local expertise, said Dr. Stamos.

Of every 35 patients with CRC, one has Lynch syndrome, the most common hereditary cause of colorectal and endometrial cancers.

The last guideline on screening was the 2004 Revised Bethesda Guideline, which calls for MSI screening for anyone with young-onset (<50 years old) CRC, synchronous or metachronous CRC or HNPCC-associated cancer at any age, CRC in a patient under age 60 years with tumor-infiltrating T lymphocytes, mucinous/signet ring differentiation or Crohn’s-like lymphocytic reaction, or for patients of any age with a first-degree relative with an HNPCC-related tumor before age 50, or two first- or second-degree relatives with HNPCC tumors at any age.

“Since those guidelines, we’ve discovered a new gene,” said Dr. Pendlimari. “Our understanding of this disease is changing considerably.”

ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making


English: Original Logo of the Society

English: Original Logo of the Society (Photo credit: Wikipedia)

Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.

3 Diagnosis, management and counselling of hereditary colorectal cancer

All patients with CRC should have a collection of family history regarding polyps and any type of cancer (at least first and second-degree relatives) [V, A]. About 5% of CRC are of hereditary origin. If a clinical suspicion of polyposis or Lynch syndrome is made, the patient should be referred to a specialist in human genetics [V, C]. Average-risk populations should have an organized access to population-CRC screening, if resources are available at national level [V, A]. Methodology and choice of screening modality is a matter of discussion. An overview of management of hereditary CRC syndromes is summarized in Table 2.

View this table:

Table 2.

Management of hereditary colorectal cancer

3.1 Lynch syndrome

Clinical suspicion is based on fulfilment of clinical criteria (Amsterdam, Bethesda) or on an altered molecular screening [microsatellite instability (MSI) and/or immunohistochemistry (IHC) for mismatch repair proteins (MMR)] in the context of a suggestive personal or family history [III, B].

3.1.1 Detection of mutation

Germline genetic testing will be performed according to the results of molecular screening (MSI and/or IHC of MMR). If a tumour block is not available, the gene-specific prediction models may help to guide a genetic strategy [III, B].

If loss of MLH1 expression is observed (especially in non-familial cases), somatic hypermethylation of the MLH1 promoter should be considered, which can be ruled out by testing the somatic BRAF V600E mutation or analysis of hypermethylation of the MLH1 promoter [III, B].

Full germline genetic testing should include DNA sequencing and large rearrangement analysis of the MMR genes [I, A]. Adequate pre- and post-test genetic counselling should always be performed.

3.1.2 Surveillance for healthy mutation carriers

For individuals with Lynch syndrome carrying an MLH1 or MSH2 mutation, colonoscopy should start at the age of 20–25 years and should be repeated every 1–2 years [II, A].

No specific upper limit for surveillance endoscopies is established and it should be based on the individual’s health status.

For healthy individuals with Lynch syndrome carrying an MSH6 or PMS2 mutation, colonoscopy should start at the age of 30 years and be repeated every 1–2 years. Again, no specific upper limit is established [II, A].

Endometrial and ovarian cancer screening may be performed on a yearly basis starting at the age of 30–35 years with gynaecological examination, pelvic ultrasound, analysis of CA125 and aspiration biopsy [IV, C]. Pros and cons should be adequately discussed with the individual subject at risk given the evidence of benefit only from observational studies.

Surveillance for other Lynch-associated cancers is recommended on the basis of the family history and may include upper endoscopy, abdominal ultrasound and urine cytology from the age of 30–35 years in a 1–2-year interval [IV, C].

3.1.3 Chemoprevention

Neither specific chemoprevention nor specific dietary interventions is being recommended at the current time in individuals with Lynch syndrome to prevent CRC, although data are emerging supporting the use of aspirin [7] [II, B].

3.1.4 Risk reduction: prophylactic surgical options

Prophylactic colectomy in healthy mutation carriers is not recommended. Prophylactic gynaecological surgery might be an option in female carriers from the age of 35 onwards and after childbearing is completed [IV, C].

3.1.5 Cancer treatment

The need for intensive surveillance after surgery versus the option of an extended colectomy should be discussed at the time of diagnosis of an advanced adenoma or CRC, especially in young patients [IV, C]. For female CRC patients with good prognosis, surveillance/surgical options for gynecological cancer should also be discussed. Chemotherapy regimens are the same as those for sporadic CRC.

3.2 Familial colorectal cancer × syndrome

Relatives of individuals with CRC who fulfil the Amsterdam criteria and who do not exhibit MMR deficiency have a moderate risk of CRC. Surveillance would include colonoscopy at a 3–5-year interval, starting 5–10 years before the youngest case in the family. Surveillance of extra-colonic cancers is not recommended.

3.3 FAP

Clinical diagnosis of classical familial adenomatous polyposis (FAP) is based on the identification of >100 colorectal adenomas. Lifetime risk of development of CRC is 100%.

3.3.1 Attenuated FAP

Clinical diagnosis of attenuated FAP is based on the following criteria:

  • at least two patients with 10–99 adenomas at age >30 years; or

  • one patient with 10–99 adenomas at age >30 years, a first-degree relative with CRC and few adenomas and no family members with >100 adenomas before the age of 30 years.

3.3.2 Genetics

Genetic testing (germline adenomatous-polyposis-coli (APC) mutation) should start by investigating the affected individual. If the causative mutation is detected, pre-symptomatic diagnosis can be offered to at-risk family members. When the causative mutation is not identified, all at-risk family members should undergo colorectal endoscopic screening [V, C].

3.3.3 Colorectal screening

In families with classic FAP, flexible sigmoidoscopy is an adequate technique and it should be performed every 2 years, starting at the age of 12–14 years, and continued lifelong in mutation carriers [V, C]. If adenomas are found, colonoscopy should be done annually until colectomy.

In families without an identified APC mutation, surveillance should be performed every 2 years until the age of 40, and be repeated every 3–5 years between 40 and 50 years and may continue with general screening at age 50 if no polyposis has developed [V, C]. When an attenuated form is suspected, total colonoscopy is needed. In this setting, examination should be performed every 2 years until polyposis is diagnosed. Screening should be started at the age of 18–20 years and continued lifelong.

3.3.4 Screening for extra-colonic manifestations

It should start when colorectal polyposis is diagnosed or at the age of 25–30 years, whichever comes first [V, C].

Gastroduodenal endoscopy should be performed every 5 years until adenomas are detected [V, C]. Screening for thyroid cancer should be performed by annual sonography of the neck [V, C]. Regular physical examination and if indicated abdominal CT should be performed in search for desmoid tumours [V, C]. Screening for other extra-colonic manifestations is not justified because of their low prevalence and/or limited clinical impact. Since gastrointestinal adenomas may also develop in the jejunum and ileum, it has been suggested that regular screening by barium contrast series or wireless capsule endoscopy could be performed [V, C].

3.3.5 Treatment

Surgical resection is the standard of care in patients with classical FAP [IV, A]. It can be considered in some patients with an attenuated form. Surgical resection includes either total colectomy with ileoanal pouch anastomosis or subtotal colectomy with ileorectal anastomosis, once adenomas are detected [IV, C]. Duodenal adenomas are managed with endoscopic polypectomy, and in Spigelman stage IV (see below), duodenal–pancreatectomy may be considered. Because of the high recurrence rate of desmoid tumours, surgical resection should be delayed unless complications occur. The first-line treatment in patients with large or growing intra-abdominal or abdominal wall desmoid tumours is based on, e.g COX 2 inhibitors, tamoxifen and tyrosine kinase inhibitors.

3.3.6 Surveillance for healthy mutation carriers

Colon-rectum

Regular endoscopic surveillance every 6–12 months after subtotal colectomy is recommended to detect rectal adenoma recurrence [V, C]. When total colectomy is performed, surveillance of the pouch can be repeated every 1–2 years. In patients with attenuated FAP conservative management with endoscopic polypectomy, examination of the entire colon and rectum should be performed annually [V, C].

Duodenum

Surveillance of duodenal manifestation will depend on its extension. When it corresponds to Spigelman stage I or II, upper endoscopy should be performed every 5 or 3 years, respectively, and every 1–2 years in stage III or every 6 months in stage IV [IV, C].

3.4 MUTYH-associated polyposis

MUTYH-associated polyposis (MAP) is inherited as an autosomal recessive trait with high penetrance. Clinically, MAP resembles the attenuated form of FAP syndrome, with an average age of onset around the mid-50s with often <100 adenomas and, accordingly, patient management is very similar.

3.4.1 Screening for family members

Individuals should undergo total colonoscopy every 2 years, starting at the age of 18–20 years and continuing lifelong [V, C]. Genetic testing allows the most cost-effective screening to be performed by focussing colorectal examinations only on gene carriers. However, when the causative mutation is not identified, all at-risk family members should undergo colorectal screening.

3.4.2 Treatment for healthy gene carriers

Colorectal management is similar to that proposed for patients with attenuated FAP.

ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making

Table 2.

Management of hereditary colorectal cancer

Syndrome Diagnosis of index case (with cancer) Management of the affected individual (with cancer) Management of individuals at high risk (healthy mutation carriers or individuals at 50% risk of being mutation carrier)
Clinical Molecular screening (tumour tissue) Germline genetic testing (blood) Treatment Follow-up Cancer risk Surveillance Germline genetic testing (blood)
Lynch Amsterdam, Bethesda MSI and/or IHC for MMR proteins MLH1, MSH2
MSH6, PMS2
  • Tumour resection

  • Discuss colectomy, especially in young patients

Yearly endoscopy of the remnant colon or rectum High
  • Colonoscopy q 1–2 years, starting age 25 (30 years in case of MSH6 or PMS2 mutations)

  • Annual pelvic examinations, transvaginal ultrasound, ca125, endometrial biopsy in females, starting age 30–35 years

Direct genetic testing of the mutation identified in the family
Familial CRC X Amsterdam, Bethesda No MMR deficiency Unknown As average population As average population Moderate only CRC
  • Colonoscopy 1 3–5 years, starting 5–10 years before youngest case in the family.

None
FAP Colonoscopy: >100 adenomas none APC
  • Total or subtotal colectomy when adenomas occur

  • Endoscopic removal of duodenal adenomas

  • After subtotal colectomy: rectal examination q 6–12 m

  • After total colectomy: pouch exam. q 1–2 years

  • Duodenoscopy from 6 months to 5 years according to Spigelman stage

  • Thyroid examination yearly

100%
  • Flexible sigmoidoscopy q 2 years, starting age 12–14 years until diagnosis of adenomas

  • If no mutation identified in the family: Flexible sigmoidoscopy q 2 years until 40 years, then q 3–5 years until 50, then general population screening

APC
Attenuated FAP (aFAP) Colonoscopy:

  1. 2 relatives 10–99 adenomas (>30 years of age)

  2. 1 relative of CRC patient with 10–99 adenomas (>30 years of age)

APC
  • Total or subtotal colectomy when adenomas occur.

  • Endoscopic removal of duodenal adenomas

As above High
  • Colonoscopy q 2 years, starting age 18–20 years, lifelong in mutation carriers.

APC
MAP As aFAP MUTYH As aFAP As aFAP High As aFAP MUTYH
  • APC, adenomatous-polyposis-coli; MSI, microsatellite instability; MMR, mismatch repair proteins; CRC, colorectal cancer; FAP, familial adenomatous polyposis; aFAP, attenuated FAP; MAP, MUTYH-associated polyposis.

via ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making.

Much Of The Population Genetic Risk Of Colorectal Cancer Is Likely To Be Mediated Through Susceptibility To Adenomas


Gastroenterology (journal)

Gastroenterology (journal) (Photo credit: Wikipedia)

Several single nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) susceptibility. Most CRCs arise from adenomas, and SNPs might therefore affect predisposition to CRC by increasing adenoma risk. We found that 8 of 18 known CRC-associated SNPs (rs10936599, rs6983267, rs10795668, rs3802842, rs4444235, rs1957636, rs4939827, and rs961253) were over-represented in CRC-free patients with adenomas, compared with controls. Ten other CRC-associated SNPs (rs6691170, rs6687758, rs16892766, rs7136702, rs11169552, rs4779584, rs9929218, rs10411210, rs4813802, and rs4925386) were not significantly associated with adenoma risk. Genetic susceptibility to CRC in the general population is likely to be mediated in part by predisposition to adenomas.

ScienceDirect.com – Gastroenterology – Much Of The Population Genetic Risk Of Colorectal Cancer Is Likely To Be Mediated Through Susceptibility To Adenomas. Carvajal-Carmona et al In Press September 2012

Metachronous colorectal cancer risk in patients with a moderate family history – Colorectal Disease – Wiley Online Library


Metachronous colorectal cancer risk in patients with a moderate family history – Colorectal Disease

In Press August 2012

Abstract:

Aim:  Life-time risk of a metachronous colorectal cancer (CRC) is 0.6%-3% following sporadic CRC and 15-26% in Lynch syndrome (LS). The life-time incidence of CRC in individuals with moderate familial risk is 8-17%. Risk of metachronous CRC (mCRC) is unknown.

Method:  A retrospective longitudinal study of the Regional Familial CRC Registry was performed. Patients who had at least one CRC were categorised as follows: moderate risk (n=383), LS (n=528) and population risk (n=409). Kaplan-Meier estimate (1-KM) and cumulative incidence function (CI) were used to calculate the risk of mCRC. 1-KM gives the risk for individuals remaining at risk (alive) at a given time point thus is useful for counselling. CI gives the risk for the whole population.

Results:  1-KM and CI demonstrated that the risk of mCRC was significantly higher in moderate risk patients compared with population risk (1-KM p= 0.008, CI p= 0.00097). Both were lower than LS. Moderate risk 1-KM was 2.7%, 6.3% and 23.5% at 5,10 and 20 years. Population risk 1-KM was 1.3%, 3.1% and 7.0% at 5, 10 and 20 years and CI was 0.3%, 0.6% and 2.4%.

Conclusion:  These data indicate that the risk of mCRC is significantly higher in patients with a moderate family history than in those at population risk. This justifies pro-active life-long surveillance.

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