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Diet & bowel cancer risk in Lynch syndrome


coverAnalysis from a recent study has found that loading up on snack foods may increase cancer risk in individuals with an inborn susceptibility to colorectal and other cancers. Published early online in Cancer, a peer-reviewed journal of the American Cancer Society, the study suggests that an eating pattern low in snack foods could help these individuals — who have a condition called Lynch syndrome — lower their risk.

Lynch syndrome is an inherited condition characterized by a high risk of developing colorectal cancer, endometrial cancer, and other cancers at an early age. The syndrome is caused by mutations in genes involved with repairing DNA within cells.

Numerous studies have investigated associations between certain foods and colorectal cancer, and now there is general agreement that red and processed meats and alcohol consumption can increase individuals’ risk. Only a few studies have evaluated lifestyle factors and colorectal cancer in patients with Lynch syndrome, though. To investigate, Akke Botma, PhD, MSc, of the Wageningen University in the Netherlands, and her colleagues collected dietary information from 486 individuals with Lynch syndrome. During an average follow-up of 20 months, colorectal polyps (precancerous lesions) were detected in 58 people in the study.

“We saw that Lynch syndrome patients who had an eating pattern with higher intakes of snack foods — like fast food snacks, chips, or fried snacks — were twice as likely to develop these polyps as Lynch syndrome patients having a pattern with lower intakes of snack foods,” said Dr. Botma.

The findings suggest that certain dietary patterns have an influence on the development of polyps in individuals with Lynch syndrome. “Unfortunately, this does not mean that eating a diet low in snack foods will prevent any polyps from developing, but it might mean that those Lynch syndrome patients who eat a lot of snack foods might have more polyps than if they ate less snack foods,” said Dr. Botma. Because the study is observational, other studies are needed to confirm the results.

Previous work from the group revealed that smoking and obesity may also increase the risk of developing colorectal polyps among individuals with Lynch Syndrome. Thus, even though they may have inherited a very high risk of developing cancer, it may be possible to affect this risk by adopting a healthy lifestyle, including a healthy diet.

Akke Botma, Hans F. A. Vasen, Fränzel J. B. van Duijnhoven, Jan H. Kleibeuker, Fokko M. Nagengast and Ellen Kampman. Dietary patterns and colorectal adenomas in Lynch syndrome : The GEOLynch Cohort Study. Cancer, 2012; DOI: 10.1002/cncr.27726

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Lynch Syndrome in Ireland: An opportunity for cancer prevention?


English: The island of Ireland, showing intern...Lynch Syndrome is an inherited cancer syndrome which causes up to 1 in 20 cases of bowel cancer in Ireland, that is equivalent to over 100 cases annually in the Republic of Ireland alone.  It is also an important cause of multiple cancers outside the bowel including endometrial, ovarian, and urinary tract cancers.

Prevention of cancer in people at high risk depends on the accurate identification of families with this condition. However it is estimated that over 90% of families remain unidentified. Currently there are two clinical genetics centres in Ireland, in Dublin and Belfast. Unfortunately there is only limited access to genetic testing particularly in the Republic of Ireland where testing for Lynch Syndrome may only be requested from within the genetics department in Dublin.  Thus it may be argued that much more could be done to improve the management of this condition in Ireland.

Some published data indicates that Lynch Syndrome may account for up to 5% of colorectal cancer in Ireland, thus this has a highly clinically significant impact.

Resources

1. Irish Cancer Society Factsheet

2. National Centre for Medical Genetics Information

A series of published abstracts from international medical conferences have been reproduced below which summarise the available academic work on Lynch Syndrome in Ireland.

Screening an Irish cohort with colorectal cancer for Lynch Syndrome using immunohistochemistry for mismatch repair proteins

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 10547 © 2007 American Society of Clinical Oncology. D. G. Power, M. P. Farrell, C. B. Muldoon, E. Fitzpatrick, C. Stuart, D. Flannery, M. J. Kennedy, R. B. Stephens and P. A. Daly St James’s Hospital, Dublin, Ireland Background: Large-scale screening for germ-line mutations that lead to the onset of disease in adulthood is possible owing to recent technical advances. The care of those with inherited predisposition to breast and ovarian cancer is now becoming a mainstream component of medical care. It is more difficult to identify those with Lynch Syndrome (LS) as various criteria (Amsterdam and Bethesda) have not proved definitive. An important development is the examination of tumor tissue to detect mismatch repair (MMR) protein loss using immunohistochemical (IHC) techniques. When coupled with family history those at risk of harbouring a mutation for LS can be identified. Once a mutation is identified predictive testing can be offered to family members, risk-reduction measures applied and mortality from colorectal cancer reduced. Methods: Screening for MMR protein expression (MLH1, MSH2, MSH6, PMS2) was planned on all colorectal cancer (CRC) cases using IHC on formalin-fixed tumor tissue from January 1st 2002. Local ethics committee approval was obtained and then written informed-consent from patients. Family history data was gathered from the index case or an appropriate relative. An aliquot of blood was stored from index cases for subsequent genetic screening if indicated by IHC analysis and genetic counseling. Results: 108 cases with CRC (62 male, 46 female, median age 59 years) from a potential total of 612 have been screened for MMR protein expression by a gastrointestinal pathologist and independently validated. Turn-around time for IHC analysis was 9 weeks. 5 patients (4.6%) had loss of MMR proteins, MSH2/MSH6- 2 cases, MSH6 alone- 1 case and MLH1/PMS2- 2 cases. All 5 have opted for genetic counselling and sequencing of relevant genes. Conclusion: These early results in an Irish cohort with CRC showing MMR loss in 4–5% of cases is consistent with other population findings. Microsatellite instability analysis is difficult, expensive and relatively unavailable. IHC, however, is an established technique in pathology departments and can be the cheapest and most reproducible approach to identify LS cases. IHC results along with robust family data can guide the genetic counseling process towards preventing deaths from CRC and other LS-associated cancers. Published on Meeting Library (http://meetinglibrary.asco.org)

Investigating parent of origin effects (POE) and anticipation in Irish Lynch syndrome kindreds. 

J Clin Oncol 30: 2012 (suppl 34; abstr 431) Author(s): Michael P. Farrell, David J. Hughes, Jasmin Schmid, Philip S. Boonstra, Bhramar Mukherjee, Margaret B. Walshe, Padraic M. Mac Mathuna, David J. Gallagher; Mater Private and Mater Misericordiae University Hospital, Dublin, Ireland; Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Biostatistics, University of Michigan, Ann Arbor, MI; High Risk Colorectal Family Clinic, Mater Misericordiae University Hospital, Dublin, Ireland; Mater Private Hospital and Mater Misericordiae University Hospital, Dublin, Ireland

Background: Genetic diseases associated with dynamic mutations often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Genetic anticipation describes the progressively earlier onset and increased severity of disease in successive generations of a family. Previous studies have provided limited evidence for and against both POE effect and anticipation in Lynch syndrome. We sought evidence for a specific POE effect and anticipation in Irish Lynch syndrome families. Methods: Affected parent-child pairs (APCPs) (N = 53) were evaluated from kindreds (N = 20) from two hospital-based registries of MMR mutation carriers. POE were investigated by studying the ages at diagnosis in the offspring of affected parent-child pairs. Anticipation was assessed using the bivariate Huang and Vieland model. Results: Paired t-test revealed anticipation with children developing cancer mean 11.8 years earlier than parents, and 12.7 years using the Veiland and Huang bivariate model (p < 0.001). Conclusions: These data demonstrate a similar age at diagnosis among all offspring of affected mothers that was indistinguishable from affected fathers. Affected sons of affected mothers were diagnosed with cancer almost 3 years younger than female offspring; however, this finding failed to reach statistical significance. Genetic anticipation was present in this cohort of LS families, emphasizing the importance of early-onset screening. An additional 60 LS kindreds are under review and updated data will be presented at the meeting. POE effect: comparison in age at diagnosis in 53 affected parent-child pairs with Lynch syndrome associated malignancies. Affected mothers Affected fathers P value Unique parent N = 14 N = 13 0.28 Mean = 48.8 Mean = 53.6 Range = 27-73 Range = 36-85 All offspring N = 24 N = 30 0.67 Mean = 40.4 Mean = 41.6 Range = 23-72 Range = 23-60 Female offspring N = 6 N = 15 0.75 Mean = 42.5 Mean = 41.06 Range = 31-64 Range = 27-58 Male offspring N = 18 N = 15 0.94 Mean = 39.77 Mean = 40.07 Range 23-72 Range = 20-60 P value female vs male offspring 0.604 0.95 ________________________________________ Source URL: http://meetinglibrary.asco.org/content/106059-133 Published on Meeting Library (http://meetinglibrary.asco.org) Home > 88749-115 ________________________________________ 88749-115

Breast cancer in Irish families with Lynch syndrome.

J Clin Oncol 30, 2012 (suppl 4; abstr 413) Author(s): E. J. Jordan, M. P. Farrell, R. M. Clarke, M. R. Kell, J. A. McCaffrey, E. M. Connolly, T. Boyle, M. J. Kennedy, P. J. Morrison, D. J. Gallagher; Mater University Hospital, Dublin, Ireland; St. James Hospital, Dublin, Ireland; Mater University Hospital , Dublin , Ireland; Belfast City Hospital HSCTrust, Belfast, Northern Ireland Background: Breast cancer is not a recognised malignant manifestation of Lynch Syndrome which includes colorectal, endometrial, gastric, ovarian and upper urinary tract tumours. In this study we report the prevalence of breast cancer in Irish Lynch Syndrome families and determine immunohistochemical expression of mismatch repair proteins (MMR) in available breast cancer tissue. Methods: Breast cancer prevalence was determined among Lynch Syndrome kindreds from two institutions in Ireland, and a genotype phenotype correlation was investigated. One kindred was omitted due to the presence of a biallelic MMR and BRCA1 mutation. The clinicopathological data that was collected on breast cancer cases included age of onset, morphology, and hormone receptor status. Immunohistochemical staining was performed for MLH1, MSH2, MSH6, and PMS2 on all available breast cancer tissue from affected individuals. Results: The distribution of MMR mutations seen in 16 pedigrees was as follows; MLH1 (n=5), MSH2 (7), MSH6 (3), PMS2 (1). Sixty cases of colorectal cancer and 14 cases of endometrial cancer were seen. Seven breast cancers (5 invasive ductal and 2 invasive lobular cancers) and 1 case of ductal carcinoma in situ were reported in 7 pedigrees. This compared with 4 cases of prostate cancer. Six MSH2 mutations and 1 MSH6 mutation were identified in the 7 Lynch syndrome kindreds. Median age of breast cancer diagnosis was 49 years (range 38-57). Hormone receptor status is available on 3 breast cancer cases at time of abstract submission; all were ER positive and HER 2 negative. All cases had grade 2 or 3 tumours. Final results of immunohistochemistry for mismatch repair protein expression on breast cancer samples are pending and will be reported at the meeting. One breast cancer has been tested to date and demonstrated loss of MSH2 protein expression in an individual carrying an MSH2 mutation. Conclusions: Breast cancer occurred at an early age and was more common than prostate cancer in Irish Lynch Syndrome pedigrees. All reported breast cancer cases were in kindreds with MSH2 or MSH6 mutations. Enhanced breast cancer screening may be warranted in certain Lynch Syndrome kindreds. ________________________________________ Source URL: http://meetinglibrary.asco.org/content/88749-115

Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome.

Fam Cancer. 2012 Sep;11(3):509-18. doi: 10.1007/s10689-012-9544-4.Farrell MP, Hughes DJ, Berry IR, Gallagher DJ, Glogowski EA, Payne SJ, Kennedy MJ, Clarke RM, White SA, Muldoon CB, Macdonald F, Rehal P, Crompton D, Roring S, Duke ST, McDevitt T, Barton DE, Hodgson SV, Green AJ, Daly PA. Source Department of Cancer Genetics, Mater Private Hospital, Dublin 7, Ireland. farrelm7@tcd.ie

Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic. PMID: 22773173 [PubMed – indexed for MEDLINE]

Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than Hereditary Non Polyposis Colorectal Cancer cohorts

Ulster Med J. 2008 January; 77(1): 25–30. PMCID: PMC2397009 Lisa A Devlin,1 Colin A Graham,1 John H Price,2 and Patrick J Morrison1

Objective To determine and compare the prevalence of MSH6 (a mismatch repair gene) mutations in a cohort of families with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), and in an unselected cohort of endometrial cancer patients (EC). Design Two patient cohorts participated in the study. A cohort of HNPCC families who were known to the Regional Medical Genetics department, and an unselected cohort of patients with a history of EC. All participants received genetic counselling on the implications of molecular testing, and blood was taken for DNA extraction with consent. All samples underwent sequencing and Multiple Ligation probe analysis (MLPA) for mutations in MSH6. Populations DNA from one hundred and forty-three probands from HNPCC families and 125 patients with EC were included in the study. Methods Molecular analysis of DNA in all participants from both cohorts for mutations in MSH6. Outcome measures Prevalence of pathogenic mutations in MSH6. Results A truncating mutation in MSH6 was identified in 3.8% (95% CI 1.0–9.5%) of patients in the endometrial cancer cohort, and 2.6% (95% CI 0.5–7.4%) of patients in the HNPCC cohort. A missense mutation was identified in 2.9% and 4.4% of the same cohorts respectively. No genomic rearrangements in MSH6 were identified. Conclusion MSH6 mutations are more common in EC patients than HNPCC families. Genomic rearrangements do not contribute to a significant proportion of mutations in MSH6, but missense variants are relatively common and their pathogenicity can be uncertain. HNPCC families may be ascertained through an individual presenting with EC, and recognition of these families is important so that appropriate cancer surveillance can be put in place. Keywords: Endometrial, Cancer, MSH6, HNPCC

The InSiGHT database: utilizing 100 years of insights into Lynch Syndrome genetic variants.


Familial CancerThis article provides a historical overview of the online database (www.insight-group.org/mutations) maintained by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT). The focus is on the mismatch repair genes which are mutated in Lynch Syndrome. APC, MUTYH and other genes are also an important part of the database, but are not covered here. Over time, as the understanding of the genetics of Lynch Syndrome increased, databases were created to centralise and share the variants which were being detected in ever greater numbers. These databases were eventually merged into the InSiGHT database, a comprehensive repository of gene variant and disease phenotype information, serving as a starting point for important endeavours including variant interpretation, research, diagnostics and enhanced global collection. Pivotal to its success has been the collaborative spirit in which it has been developed, its association with the Human Variome Project, the appointment of a full time curator and its governance stemming from the well established organizational structure of InSiGHT.

The InSiGHT colorectal cancer hereditary mutation database can be found here

 

Making Universal Screening for Lynch Syndrome a Reality: The Lynch Syndrome Screening Network


Centers for Disease Control and Prevention CDC 24/7: Saving Lives. Protecting People.™

Making Universal Screening for Lynch Syndrome a Reality: The Lynch Syndrome Screening Network

March 22nd, 2012 11:35 am ET – From CDC

Deb Duquette, MS, CGC, Sarah Mange, MPH- Michigan Department of Community Health, Cecelia Bellcross, PhD, MS- Emory University, Heather Hampel, MS, CGC- The Ohio State University, Kory Jasperson, MS, CGC- Huntsman Cancer Institute

Authors are all from the Lynch Syndrome Screening Network (LSSN) Founding Board of Directors

flow chart individualEvery day, about 400 people in the United States are diagnosed with colorectal cancerExternal Web Site Icon. Approximately twelve of them have Lynch syndrome, a hereditary condition that increases the risk of colorectal cancer and other cancers. Identifying people with Lynch syndrome could have substantial health benefits for them, their families, and communitiesExternal Web Site Icon.

Lynch syndrome is the most common hereditary cause of colorectal and endometrial cancer; it also leads to increased risks of ovarian, pancreatic, and several other cancers, which often occur at a younger than average age. Lynch syndrome occurs among men and women in all ethnic groups in the United States. A diagnosis of Lynch syndrome offers an opportunity to 1) enhance cancer prevention and screening measures for patients and families, 2) prevent cancer or detect it earlier, and 3) save lives and is cost-effectiveExternal Web Site Icon.

In 2009, the Evaluation of Genomic Applications in Practice and Prevention Working Group published an evidence-based recommendationExternal Web Site Icon that every person newly diagnosed colorectal cancer should be offered screening for Lynch syndrome to identify opportunities to reduce morbidity and mortality in their relatives.

Lynch syndrome screening is performed by analyzing tissue from the person with colorectal cancer for specific pathologic features. If the results suggest the possibility of Lynch syndrome, the affected person is offered genetic counseling and additional testing. Offering screening to all newly diagnosed colorectal cancer patients—regardless of age, ethnicity or family history—is termed “universal screening.” This approach supports an objective of Healthy People 2020, which is to:

‘Increase the number of newly diagnosed colorectal cancer patients who are screened for Lynch syndromeExternal Web Site Icon’

In September 2011, a group of 37 dedicated people from leading cancer institutions created the Lynch Syndrome Screening Network (LSSN)External Web Site Icon, with the goal of reducing the cancer burden associated with Lynch syndrome. LSSN has already received more than 80 institutional applications for membership. More than half of the applicant institutions have already implemented universal Lynch syndrome screening and the others are either interested or in the process. The LSSN will facilitate implementation of universal Lynch syndrome screening by promoting sharing of resources, protocols, and data. LSSN Founding members have already gathered existing educational resources and created a new database to monitor progress toward achieving the Healthy People 2020 objective for Lynch syndrome.

Each first-degree relative (parent, sibling, or child) of a person with Lynch syndrome has a 50% risk of carrying the gene mutation and should be offered genetic counseling and testing. Relatives of a person with Lynch syndrome who are not found to have the gene mutation for Lynch syndrome will typically have the same risk for colorectal cancer as the general population, and their children will not be at risk for Lynch syndrome. Family members who are found to have the gene mutation for Lynch syndrome can be offered earlier and more frequent screening for colorectal and other cancers. Because these people can pass the gene mutation on to their children, the children should also be offered testing after reaching adulthood.

Genetic testing in family members of persons with a Lynch syndrome gene mutation is called “cascade testing.” Cascade testing will allow the Healthy People 2020 objective to achieve population health impact by preventing additional cancers in family members.

March is National Colorectal Cancer Awareness month. This month, increasing awareness of Lynch syndrome is especially timely, as the importance of collecting and sharing information regarding family history of colorectal cancer is being promoted throughout the United States (Colon Cancer AllianceExternal Web Site Icon ; Family PLZExternal Web Site Icon). People with an immediate family member diagnosed with colorectal cancer should share this information with their health care providers, so that screening for Lynch syndrome can be considered.

Lynch Syndrome International is promoting March 22, 2012, as LYNCH SYNDROME PUBLIC AWARENESS DAY. To learn more, please visit Lynch Syndrome International Home pageExternal Web Site Icon ( or the Lynch Syndrome Hereditary Cancers Public Awareness pageExternal Web Site Icon or LSI on FacebookExternal Web Site Icon)

via CDC – Blogs – Genomics and Health Impact Blog – Making Universal Screening for Lynch Syndrome a Reality: The Lynch Syndrome Screening Network.

Awareness of symptoms could eliminate 5600 late cancer diagnoses in England each year


BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7669 (Published 13 November 2012)

Cite this as: BMJ 2012;345:e7669

by Zosia Kmietowicz

Age, sex, and income as well as the type of cancer influence the stage at which patients’ cancer is diagnosed, a study has found.

Eliminating these demographic inequalities would help improve the chances of a cure for up to 5600 patients in England with seven common cancers each year, the researchers have estimated.

For the study, published in the Annals of Oncology, researchers from the University of Cambridge and the Eastern Cancer Registration and Information Centre examined data on the stage at diagnosis of nearly 100 000 patients with any of 10 different cancers, including the five most common (lung, breast, prostate, colon, and rectal cancers) and also bladder, kidney, ovarian, and endometrial cancers and melanoma.1

They found that melanoma and prostate, endometrial, and breast cancers in patients in the most deprived socioeconomic groups were more likely than those in the least deprived to be diagnosed in advanced stages. The increase in risk of late diagnosis according to deprivation ranged from more than double for melanoma (odds ratio 2.24 (1.66 to 3.03) to a third more for breast cancer (1.31 (1.15 to 1.49)).

For other cancers age and sex were important determinants of late diagnosis. Men with melanoma and those with lung cancer were more likely to have their cancer diagnosed at an advanced stage than were women with the same cancer.

The researchers also found that for melanoma and breast, prostate, and endometrial cancers older patients were more likely to be given a diagnosis at an advanced stage. But for lung, bladder, and renal cancers the opposite was true, with diagnosis at an advanced stage being less likely among older patients. This may be because older patients had more tests than younger patients, say the researchers.

During the study period, 2006-10, there were no notable social inequalities in the risk of diagnosis at an advanced stage among patients with bowel cancer and among women with ovarian cancer.

Because melanoma and breast and endometrial cancers are easy to diagnose, delays in detecting these cancers are probably because of patients’ lack of awareness of symptoms, say the researchers.

The lead author, Georgios Lyratzopoulos, a researcher at the University of Cambridge, said, “We know that earlier stage diagnosis of cancer is important: it dramatically improves the effectiveness of treatment and survival for many cancers. This study documents the importance of awareness of cancer symptoms and signs by patients of all social groups. It provides clear evidence about which patient groups would benefit most from targeted campaigns to raise awareness of different cancers.”

The findings could help target publicity about cancer at groups at high risk of late diagnosis, say the researchers. For example, older men from deprived groups would benefit from information about melanoma, while older women could be targeted with material on breast and endometrial cancers.

Notes

Cite this as: BMJ 2012;345:e7669

References

Lyratzopoulos G, Abel GA, Brown CH, Rous BA, Vernon SA, Roland M, et al. Socio-demographic inequalities in stage of cancer diagnosis: evidence from patients with female breast, lung, colon, rectal, prostate, renal, bladder, melanoma, ovarian and endometrial cancer. Ann Oncol2012, doi:10.1093/annonc/mds526.

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