There has been quite a backlash to the recent news that many cancers are due to “bad luck” of random mutations, which was proclaimed in headlines around the world, and based on a report published in the January 2 issue of Science.
The International Agency for Research on Cancer (IARC), the World Health Organization’s specialized cancer agency, put out a press release to say that it “strongly disagrees with the conclusion,” and warning that the message could harm cancer research and public health.
“We already knew that for an individual to develop a certain cancer there is an element of chance, yet this has little to say about the level of cancer risk in a population,” explained IARC director Christopher Wild, PhD. “Concluding that ‘bad luck’ is the major cause of cancer would be misleading and may detract from efforts to identify the causes of the disease and effectively prevent it.”
As previously reported by Medscape Medical News, the researchers, from Johns Hopkins University in Baltimore, reported that in about two-thirds (22 of the 31) of cancer tissue types they had investigated, the cancer could be largely explained by the bad luck of random mutations that arise during DNA replication in normal noncancerous stem cells.
However, many of the news stories reported a distorting simplification of the findings, and stated that two-thirds of all cancers are due to bad luck.
There has been fierce criticism of the way that the media reported the story, but an expert argues that journalists were misled.
The Science report was accomapnied by an editorial entitled “The Bad Luck of Cancer,” and the subheading added: “Analysis suggests most cases can’t be prevented.”
But the data do not support either of these ideas, noted George Davey-Smith, MD, a clinical epidemiologist at Bristol University, United Kingdom, in a BBC News report. He also noted that “in the press release [from the Johns Hopkins School of Medicine], the authors say they’ve come up with a method to quantify the contribution of these stochastic or chance factors, which their method doesn’t,” he adds.
“It’s both in the journal and in the press release so it’s just not fair to attribute the mis-reporting of this to journalists,” Dr Davey-Smith commented.
In reaction to the huge media uptake of the story, the study authors issued further comments in a Johns Hopkins University statement, which also included the press release that had been “ammended for clarity.” The public relations officer for Johns Hopkins University, Vanessa Wasta, MBA, noted that the press release was updated to change reference from “incidence” to “risk” as a clarification in the first paragraph, but pointed out to Medscape Medical News that the original news release contained no reference to “cases” or “all” cancers, but referred to “risk” many times.
Science ran a follow-up piece, entitled “A Science Reporter’s Reflections on a Controversial Story,” in which the author returned to the researchers for clarification. “We did not claim that two-thirds of cancer cases are due to bad luck,” said lead author Christian Tomasetti, PhD, an assistant professor of oncology at the Johns Hopkins School of Medicine and the Bloomberg School of Public Health. What the study argued, he explained, was that two-thirds of the variation in cancer rates in different tissues could be explained by random bad luck.
Dr Tomasetti also said that many scientists and statisticians had also needed clarification, and that the team is now working on a technical report with additional details.
Our briefing highlights the lack of surveillance screening for younger people at higher risk of bowel cancer.
Genetic factors contribute up to 30% of bowel cancer cases, an estimated 8,000-12,000 cases each year.
Genetic factors mean a strong family history of bowel cancer, or genetic conditions such as familial adenomatous polyposis (FAP) or Lynch syndrome. People with long-term inflammatory bowel disease are also at higher risk.
People in higher risk groups are likely to develop bowel cancer much younger than the general population. Clinical guidance recommends that people in high-risk groups should be in a surveillance screening programme, which is proven to reduce deaths in these groups.
Recent evidence shows that:
Our briefing, “Never too young: Supporting people at higher risk of bowel cancer”, has five recommendations to improve services for people in high risk groups:
Full details of our findings and recommendations are in our full report available here.
Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis is manifested as colonic polyposis caused by mutations in the APC gene and is also inherited in an autosomal dominant manner. Finally, MYH-associated polyposis is caused by mutations in the MUTYH gene and is inherited in an autosomal recessive manner but may or may not be associated with polyps. There are variants of both familial adenomatous polyposis (Gardner syndrome—with extracolonic features—and Turcot syndrome, which features medulloblastoma) and Lynch syndrome (Muir–Torre syndrome features sebaceous skin carcinomas, and Turcot syndrome features glioblastomas). Although a clinical diagnosis of familial adenomatous polyposis can be made using colonoscopy, genetic testing is needed to inform at-risk relatives. Because of the overlapping phenotypes between attenuated familial adenomatous polyposis, MYH-associated polyposis, and Lynch syndrome, genetic testing is needed to distinguish among these conditions. This distinction is important, especially for women with Lynch syndrome, who are at increased risk for gynecological cancers. Clinical testing for these genes has progressed rapidly in the past few years with advances in technologies and the lower cost of reagents, especially for sequencing. To assist clinical laboratories in developing and validating testing for this group of inherited colorectal cancers, the American College of Medical Genetics and Genomics has developed the following technical standards and guidelines. An algorithm for testing is also proposed.
A history of polyposis and familial colorectal cancer
(Link to full article can be found here)
On the 25 September 2012 a meeting was held in Central London, convened by the History of Modern Biomedicine Research Group of Queen Mary, University of London, and funded by the Wellcome Trust. Assembled were many of the men and women whose research was at the forefront of the breakthroughs that led to the identification of genes for familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) (Lynch Syndrome) in the 1990s.
One of the most significant locations for early research into hereditary bowel cancer was St Mark’s Hospital in London, where surgeon John Percy Lockhart-Mummery (1875–1957) and pathologist Dr Cuthbert Dukes (1890–1977) were based. As Ms Kay Neale explained: ‘St Mark’s Polyposis Registry started in 1924 as a result of John Percy Lockhart-Mummery having an interest in family diseases and Dr Dukes having an interest in polyps turning into cancer.’ The Registry’s success was helped enormously by the work of Dick (later Dr) Bussey, who, aged just 17, started a meticulous system for recording patients with FAP, a condition that had first been noted in the medical literature as early as 1882. Neale elaborated on the spread of the Registry’s impact beyond the UK: ‘Dukes, of course, would lecture and publish in the journals of the day and so people would send pathological slides or descriptions of cases of polyposis from all over the world, and Dr Bussey would record them all and catalogue them.’ Fast forward to the 1980s when Sir Walter Bodmer became Director of Research at the Imperial Cancer Research Fund (ICRF) and, during the meeting, he recalled how in 1984 he established a St Mark’s Unit at the ICRF for all aspects of colorectal cancer, as research in familial cancer began to take more shape. The context for this growth in familial cancer research during the 1980s is discussed by Professor Tim Bishop in his introduction to the publication, along with several seminar participants who reflect on the work of the UK’s Cancer Family Study Group.
Representing a transatlantic viewpoint, Professor Jane Green from Canada moved the story into the 1990s and to HNPCC. A world away from the research lab, she tried to find familial links amongst cancer patients: ‘I spent many hours on roads in Newfoundland going to different small communities and talking to people in their homes. Every time somebody said, I’ll speak to my grandmother because she knows more of the history,’ or ‘You need to know about that other part of the family’ and they would contact them … As I put the pedigrees together they were very, very interesting.’ Her informal conversations revealed linkages, the understanding of which would be critical to the international effort that identified the MSH2 and MLH1 HNPCC-related genes in 1993. Like Jane Green’s families, patients from St Mark’s Polyposis Register were critical in providing DNA samples that helped identify APC, the gene for polyposis in 1991.
These and many other stories from the scientists, clinicians and others involved in this significant research can be read in more depth in the published, annotated transcript of this Witness Seminar. This volume is free to download from the Group’s website as a PDF document.
Emma M Jones, Alan YabsleyHistory of Modern Biomedicine Research Group Queen Mary, University of London Mile End Road London E1 4NS United Kindom
TRIPLER ARMY MEDICAL CENTER, Hawaii, USA – Daniel Shockley, a retired Sailor living on Oahu, meets with Lt. Col. Ronald Gagliano, chief, Colon and Rectal Surgery and director, Surgical Research, TAMC, to discuss recovery and post-operative…
Due to his hectic work schedule, Shockley rescheduled the screening a couple times and it wasn’t until May 8, 2012, when he got the colonoscopy.
“They usually schedule colonoscopies for 1-hour blocks of time, but they found so much wrong during mine that he had to spend a lot of time documenting and taking pictures,” Shockley explained. “What they found was approximately 100 polyps embedded throughout my colon, rectum and anus. And at the traverse colon, the junction between the large and small intestine, they found a large tumor that was creating an 80 percent blockage.”
Shockley was referred to Tripler Army Medical Center’s general surgery clinic, and the week following the screening, he met with Susan Donlon, a certified genetic counselor at Tripler.
Donlon performed DNA tests on Shockley and within three weeks the tests had come back confirming that Shockley has a gene mutation known as Adenomatous Polyposis Coli, which increases a person’s risk of developing colorectal cancer. As a result of the mutation, Shockley was diagnosed with Attenuated Familial Adenomatous Polyposis, a condition in which numerous polyps form mainly in the large intestine.
“I knew surgery was inevitable and I was willing to accept the worst case scenario the whole time,” Shockley said.
On July 13, Shockley underwent a total proctocolectomy with ileostomy surgery, which removed portions of his large intestine to include the entire colon, rectum and anus.
Shockley spent about two weeks in Tripler’s general inpatient surgery ward recovering before he was able to go home. It was nine weeks before he was able to go back to work.
Lt. Col. Ronald Gagliano, chief, Colon and Rectal Surgery and director, Surgical Research, TAMC, performed Shockley’s surgery and has followed up with him to ensure he is not only well-informed, but also well-educated.
“He knew nothing of his disease and its many facets before we met and our team (at Tripler) began his personal education in order to promote effective counseling regarding his diagnostic and therapeutic options,” Gagliano explained. “Finally we educated him regarding his genetic situation so that he could choose (how to best) inform his family. By giving him great care, we essentially treat an entire family cohort.”
“(Dr. Gagliano and his team) have passion for what they do, and my care was phenomenal,” Shockley expressed. “I cannot say enough good things about my stay and the care they provided.”
Gagliano is very pleased with Shockley’s recovery thus far and attributes it to his attitude.
“I tend not to think about things I can’t control,” Shockley explained. “Medical issues are not something I can control, but what I can control is my attitude and after 51 years on God’s green earth my positive attitude has gotten me this far and I am not going to change it.”
Because of Shockley’s surgeries, he now has an ostomy pouching system, a prosthetic medical device that provides a means for the collection of waste. Nina Lum, certified wound, ostomy and continence nurse, TAMC, who helped care for Shockley throughout his recovery, echoed Gagliano’s remarks.
“Shockley’s resilience in the face of challenges including his tremendous enthusiasm for life, regardless of setbacks, certainly played a huge role in his recovery,” Lum said. “He has always maintained a positive outlook, been fully engaged in his care from the beginning, reached out to the ostomy community not only for support, but also to offer support and advise based on his personal experience.
“He is selfless in trying to reach out to others,” Lum added.
Shockley has embraced his diagnosis and challenged it from the start. He acts as a patient advocate and an ambassador for colon cancer awareness.
“(I want to) share my story with others on behalf of those patients that have gone before me and who were unable to share their story,” Shockley explained. “My catchphrase is ‘AFAP-Seize the disease!'”
Shockley wants to spread the information about his diagnosis and experience so he can inspire others to get the screening and be aware of the condition. Additionally, there is not a lot of information about AFAP available, so he hopes that talking about his diagnosis will help the medical community.
“By maintaining a positive attitude, the opportunity for a success story is much higher,” Shockley said. “This in turn allows me a better chance of overcoming adversities I am faced with during my lifetime.”
Grover S, Kastrinos F, Steyerberg EW, et al
Familial adenomatous polyposis (FAP) is caused by mutations in the APC gene and 2 different, or biallelic mutations, in the MUTYH gene. However, not all patients with colorectal polyposis are found to carry mutations on these genes. In addition, it is unclear how the extent of polyp burden or the age at development of the first adenoma corresponds to the likelihood of finding mutations in either of these 2 genes.
In an effort to better characterize the mutation frequency in patients with multiple colorectal adenomas, this study tested for APC and MUTYH mutations in 8676 individuals over 8 years. Each person’s cancer history, adenoma count, and family history of cancer or colorectal adenomas was reported by clinicians ordering the genetic testing.
The study found that patients with classic polyposis were very likely to carry an APC mutation: 80% of those with ≥ 1000 colorectal adenomas and 56% of those with 100-999 adenomas carried an APC mutation. APC mutations were prevalent even in individuals with fewer than 100 adenomas, with mutations seen in 10% of those with 20-99 adenomas and in 5% of those with 10-19 adenomas.
With regard to MUTYH mutations, the frequency was low in individuals with≥ 1000 adenomas (2%) but was fairly consistent in those with 10 colonic adenomas, those who present with multiple adenomas at an unusually young age, or those who have a family history consistent with FAP. The findings of the current study support testing in these individuals and demonstrate that the greater the number of polyps, the greater the likelihood of identifying a mutation.
However, multiple factors can complicate the value of genetic testing in clinical practice. The clinical phenotype of biallelic MUTYH mutations is quite varied; reports show that some mutation carriers can have hundreds of polyps, whereas others with colon cancer have no reported polyps. Also, overlap among the clinical phenotypes of Lynch syndrome, MUTYH-associated disease, and attenuated FAP or other polyposis conditions may require clinical expertise for appropriate diagnosis and management. Finally, some controversy remains with regard to risk (if any) for colon cancer in persons with only 1 MUTYH mutation, and management in these patients is uncertain.
At the same time, not all individuals manifesting colonic polyposis harbor a mutation in APC or MUTYH, and management is not straightforward in patients with polyposis but no identified mutation. Clearly, there are cases of unknown etiology, and there are probably as-yet unidentified genes that may predispose to adenomatosis. But changing technologies and testing standards can also affect interpretation of genetic test results. For example, polyposis testing was once only pursued in persons with > 20 polyps, whereas guidelines now recommend that testing be done in all patients who have ≥ 10 adenomas, so historically “negative” tests may need to be revisited in the future.
Similarly, individuals tested before the availability of APC deletion/duplication analysis and MUTYH testing must be reassessed. Indeed, in the past few months, new and more efficient molecular testing modalities, so-called next-generation sequencing, have allowed the commercial launch of several cost-efficient gene panels that can test multiple genes at once for polyposis and nonpolyposis mutations. This may prove particularly helpful in evaluating patients with low polyp counts.
Current recommendations note that individuals with multiple adenomas or a family history of colon cancer be referred for genetic counseling. However, a lack of family history does not exclude the possibility of FAP, because an individual can harbor a de novo mutation; genetic testing for a hereditary cancer syndrome can thus be pursued on the basis of age, polyp count, and family history. In the absence of an identified mutation, family history as well as clinical presentation can be used to determine whether the individual may be at increased risk for other syndromes, and an empiric screening and prevention protocol can be established.
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.
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.
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].
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.
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].
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  [II, B].
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].
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.
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.
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%.
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.
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].
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.
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].
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.
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].
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].
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.
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.
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
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
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
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:
2 relatives 10–99 adenomas (>30 years of age)
1 relative of CRC patient with 10–99 adenomas (>30 years of age)
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.
Multiple polyp patients are a clinically heterogeneous group. Classical familial adenomatous polyposis (FAP; OMIM 175100) is caused by a germline mutation of the APC gene (at the locus 5q22-21) which activates the Wnt pathway (Bodmer et al. 1987; Groden et al. 1991; Clevers 2006). APC is also somatically mutated in approximately 70% of sporadic colorectal cancer. However these cases are not caused by inherited mutations in the gene.
Polyposis (carpeting the rectum 20 years following a previous ileorectal anastamosis)
FAP is characterised by over a hundred colonic adenomas, and a high penetrance of colorectal cancer with an average age of cancer presentation of 39 years. There are also extra-colonic manifestations including intra-abdominal desmoids, duodenal adenomas and congenital hypertrophy of the retinal pigment epithelium(CHRPE).
In classical FAP, the risk of developing colorectal cancer exceeds 90% by age 70 years without prophylactic surgery. The risk of gastroduodenal cancer is about 7%. Around 25% of all cases are due to new mutations in the APC gene and so there is no previous family history. Nonetheless, children of individuals with a new mutation are at 50% risk of inheriting the condition.
The population prevalence of FAP is estimated at 1:14 000. Owing to highly effective surgical prophylaxis, FAP accounts for only 0.07% of incident colorectal cancers in modern practice. As registries and genetic services improve detection of at-risk family members, the proportion of colorectal cancer cases due to FAP should reduce, limited only by the proportion due to new mutations, which account for 25% of cases.
In attenuated FAP (AFAP) there is a later age of onset of colorectal cancer with a lower penetrance. The polyps number 10-100 in affected individuals. This arbitrary distinction is based on clinical characteristics, merely representing different ends of the same phenotypic spectrum of FAP. Germline mutations in APC account for up to 15% of patients with 5–100 adenomas and can be categorised AFAP.
English: CHRPE – congenital hypertrophy of the retinal pigment epithelium (Photo credit: Wikipedia)
With regard to APC mutations, the most important functional domains of the APC gene appear to be the first serine alanine methionine proline (SAMP) (axin binding) repeat at codon 1580(Smits et al. 1999) and the first, second and third 20-amino acid repeats (20AARs) involved in ß-catenin binding and degradation. The great majority of pathogenic APC mutations truncate the protein before the first SAMP repeat and leave a stable, truncated protein that encodes 0-3 20AARs.
The ‘just-right’ model. The figure shows the multiple domains of the APC protein and the correlation between the position of the germline mutation and that of the somatic mutation. (a) Germline mutations between the first and the second 20AAR are associated with LOH. (b) Germline mutations before the first 20AAR are associated with somatic mutations between the second and third 20AAR. (c) Germline mutations after the second 20AAR are associated with somatic mutations before the first 20AAR(Segditsas and Tomlinson 2006).
APC is a classic tumour suppressor gene, requiring two hits for inactivation (Knudson 1971). In colorectal tumours from FAP patients, the germline wild-type allele either undergoes loss of heterozygosity (LOH) or acquires a protein-truncating mutation. Most somatic mutations occur in a restricted region of the gene, the mutation cluster region (MCR) (Miyoshi, Nagase et al. 1992). The reason for the MCR and relatively low frequency of LOH at APC was discovered from studies of FAP (Lamlum et al. 1999). It was found that LOH is strongly associated with germline mutations between the first and second 20AAR (codons 1285-1379). Germline mutations before codon 1280 are associated with somatic mutations between the second and third 20AAR (codons 1400 and 1495); and germline mutations after codon 1400 are associated with somatic mutations before codon 1280 (Lamlum, Ilyas et al. 1999; Albuquerque et al. 2002; Crabtree et al. 2003), Most tumours end up with APC alleles that encode a total of two 20AARs(Figure 1‑4). Similar associations exist for sporadic colorectal cancers. This association has been proposed to cause an optimal level of Wnt signalling/ß-catenin activation (Lamlum, Ilyas et al. 1999; Albuquerque, Breukel et al. 2002). Whatever the case, it is clear that selective constraints act on colorectal tumours such that some combinations of APC mutations provide a superior growth advantage for the tumour cell. This is known as the ‘just right’ hypothesis.
There is a genotype-phenotype relationship determined by the precise location of the APC mutation. AFAP is associated with germline mutations in three regions of APC: 5’ (codon 1580); and the alternatively spliced region of exon 9 (Knudsen et al. 2003). Mutations close to codon 1300 are the most commonly found and are associated with a severe phenotype, typically producing over 2000 polyps and earlier-onset colorectal cancer (Nugent et al. 1994; Debinski et al. 1996). De novo mutations of APC occur in approximately 20% of FAP. In a small study de novo mutations of APC were found to be more commonly of paternal origin (Aretz 2004).
Figure 1. Wnt doesn’t bind to the receptor. Axin, GSK and APC form a “destruction complex,” and β-Cat is destroyed. Compare to Figure 2. See the article main text for details. (Photo credit: Wikipedia)
The Wnt signalling pathway is activated in approximately 75% of colorectal cancer, and is one of the key signalling pathways in cancer, regulating cell growth, motility and differentiation. APC binds to the ß-catenin protein which functions in cell adhesion andas a downstream transcriptional activator in the Wnt signallingpathway (Wong and Pignatelli 2002). Somatic mutations in ß-CATENIN usually delete the whole of exon 3 or target individual serine or threonine residues encoded by this exon (Ilyas et al. 1997; Morin et al.). These residues are phosphorylated by the degradation complex that contains APC, and hence their mutation causes ß-catenin to escape from proteosomal degradation. These mutations are particularly associated with HNPCC tumours (but not sporadic MSI tumours) (Johnson et al. 2005). However, less than 5% of all sporadic colorectal cancer has mutation in ß-CATENIN. In addition somatic mutations have been reported in AXIN1 (Webster et al. 2000) and AXIN2 (Suraweera et al. 2006), the importance of which is uncertain.
Screening and Managment of FAP
Establishment of FAP registries
Families with FAP should be referred to the regional clinical genetics service or other specialist service that can facilitate risk assessment, genetic testing and screening of family members. Some regional services have specific FAP registers that facilitate regular follow-up. FAP registries have been shown to improve outcomes by systematic and structured delivery of management, monitoring interventions and surveillance, as well as serving as a focus for audit.
Large bowel surveillance for FAP family members Annual flexible sigmoidoscopy and alternating colonoscopy should be offered to mutation carriers from diagnosis until polyp load indicates a need for surgery.198 In a small minority of families where no mutation can be identified and genetic linkage analysis is not possible, family members at 50% risk should have annual surveillance from age 13e15 until age 30 years, and every 3–5 years thereafter until age 60. Surveillance might also be offered as a temporary measure for people with documented APC gene mutations and a significant polyp load but who wish to defer prophylactic surgery for personal reasons. Such individuals should be offered 6-monthly flexible sigmoidoscopy and annual colonoscopy. As in Lynch syndrome, chromoendoscopy or narrow band endoscopy may have a place in surveillance for attenuated FAP, but the utility of these techniques merits further appraisal and must not replace conventional endoscopic approaches. Surgery can be deferred if careful follow-up is instigated and the patient is fully aware of the risks of cancer. This is especially the case for attenuated FAP but can also be useful in the management of classical FAP for individuals who have a low polyp burden in terms of size, multiplicity and degree of dysplasia. The cancer risk increases substantially after 25 years, and so surgery should be undertaken before then unless polyps are sparse and there is no high-grade dysplasia. If colectomy and ileorectal anastomosis are performed, the rectum must be kept under review annually for life because the risk of cancer in the retained rectum is 12–29%.The anorectal cuff after restorative proctocolectomy should also be kept under annual review for life.
Prophylactic colorectal surgery
Patients with typical FAP should be advised to undergo prophylactic surgery between the ages of 16 and 25 years, but the exact timing of surgery should be guided by polyp numbers, size and dysplasia and fully informed patient choice influenced by educational and child-bearing issues. Surgical options include proctocolectomy and ileoanal pouch or a colectomy with ileorectal anastomosis.
People with proven FAP require prophylactic surgery to remove the majority of at-risk large bowel epithelium. Colectomy and ileorectal anastomosis is associated with a 12–29% risk of cancer in the retained rectum, whereas restorative proctocolectomy is associated with a very low risk of cancer in the pouch or in the retained mucosa at anorectum. Ileoanal pouch construction may be associated with impaired fertility. It is clear that case identification and prophylactic surgery have markedly improved survival in FAP.
Upper gastrointestinal surveillance in FAP
Because of the substantial risk of upper gastrointestinal malignancy in FAP, surveillance of this tract is recommended. While gastroduodenal polyposis is well recognised in FAP and surveillance practice is established practice in the overall management, there is limited evidence on which to gauge the potential benefit of surveillance. However, the approach seems reasonable, and 3-yearly upper gastrointestinal endoscopy is recommended from age 30 years with the aim of detecting early curable cancers. Patients with large numbers of duodenal polyps should undergo annual surveillance.
Gastroduodenal and periampullary malignancies account for a small, but appreciable, number of deaths in patients with FAP. Duodenal polyposis occurs in approximately 90% of FAP patients and the overall lifetime risk of periampullary cancer is 3–5%.Advancing age and mutation location within the APC gene appear to have an effect on duodenal carcinoma risk. Almost all FAP patients have some abnormality on inspection and biopsy of the duodenum by age 40. The degree of duodenal polyposis can be assessed using an endoscopic/histological scoring system (Spigelman classification143), which can be helpful in predicting the risk of duodenal cancer. The worst stage (IV) has a 10-year risk of 36% and stage 0 negligible risk.207 Hence, it seems reasonable to offer 3-yearly upper gastrointestinal surveillance from age 30 years and more frequently if there is extensive polyposis. However, it should be noted that the effectiveness of this intervention in reducing mortality is unknown, especially since duodenal polypectomy is unsatisfactory208 and prophylactic duodenectomy is a major undertaking with substantial attendant morbidity and mortality.
The Family History of Bowel Cancer Registry was founded in 2010. It has been a useful resource for hereditary and non-hereditary colorectal cancer research conducted at West Middlesex University Hospital. Our clinicians and researchers have utilised the information our registry provides for research on the causes of colorectal cancer. It helps to link our patients with their screening and surveillance programmes, and also in to local and national research projects such as the Cancer Research UK study CORGI (COloRectal Gene Identification Study). The registry also provides services to families, community health professionals, and the general public, including educational materials and programs on hereditary colorectal cancer syndromes, cancer genetics, and current research.
Family History of Bowel Cancer Registry;
Conditions and Syndromes;
Colorectal cancer is diagnosed in approximately 35,000 people in the United Kingdom each year, the third most commonly diagnosed cancer after breast and lung cancer (NICR 2005; ONS 2005, ISD_Online, 2005 #540). With 16,148 deaths in 2004 it was the second most common-cause of cancer death. This is also true in other Caucasian populations (Jemal et al. 2007).
Colorectal cancer, however,is not equally common throughout the world (Boyle and Langman 2000). In the ‘westernised’countries colorectal cancerrepresents ~13.4% of all incident cases compared to ~7.8% elsewhere.
The occurrence of colorectal cancer is strongly related to age, with 93% occurring after the age of 50 years (ONS 2005). Before this age there are equal numbers of males and females diagnosed, although after males predominate, with an eventual overall male to female ratio of 1.2:1. Using data for England and Wales the overall lifetime risk of colorectal cancer is 1 in 18 for men and 1 in 20 for women (CRUK. 2006). Sixty two percent of cancers are situated in the colon and the remainder in the rectum (ONS 2005). Seventy percent are left-sided and the remainder right-sided (Toms 2004).
More than 90% of colorectal cancers are adenocarcinomas arising from benign precursor adenomas. A small proportion may arise from other types of polyps including hyperplastic and serrated polyps (Young et al. 2007). The remainder of colorectal malignant tumours include carcinoids and lymphomas. The National Polyp Study showed that endoscopic removal of adenomas prevents colorectal cancer (Winawer et al. 1993). Endoscopic surveillance and polyp removal is a vital tool making colorectal cancer also one of the most preventable cancers as polyps removed at an early stage can prevent the cancer ever occurring. Of course the endoscopic procedure performed must be technically perfect, performed at the correct stage in cancer development and in appropriate groups, e.g. for age, risk etc. The resources are not available to perform colonoscopy on whole populations. Identifying individuals at high risk due to genetic or environmental factors will help us undertake these preventative measures with the highest levels of efficacy and efficiency.
The concordance rates of cancer in monozygous and dizygous twins suggest that about one-third of the variation in cancer risk might typically be ascribed to genetic factors (Lichtenstein et al. 2000). Highly penetrant (Mendelian) genetic syndromes account for 5–10% (Cannon-Albright et al. 1988) (Houlston et al. 1992) (Johns and Houlston 2001). These include Familial Adenomatous Polyposis (FAP), due to germline mutations in the tumour suppressor gene APC, and Hereditary Non-Polyposis Colorectal cancer (HNPCC), due to germline mutations DNA mismatch repair enzymes MLH1, MSH2, PMS2 and MSH6. HNPCC accounts for 1-4% of colorectal cancer and is characterised by cancers with DNA microsatellite instability (MSI). There is good evidence that endoscopic surveillance of patients with high-risk genetic predisposition also prevents cancer (Jarvinen et al. 2000; Dove-Edwin et al. 2005; Dove-Edwin et al. 2006).
Environmental factors such as physical activity, obesity, diet and other exogenous factors also contribute to the aetiology of colorectal cancer (Linseisen et al. 2002; Bingham et al. 2003; Ferrari et al. 2007). Diet and lifestyle has been found to modify risk across the cancer spectrum e.g., smoking and lung cancer (Doll and Hill 1950). However, there are difficulties studying the effects of ‘five pieces of fruit a day’ in population studies due to analytical challenges with accurate food monitoring, variation in the fruit types and other confounding variables such as smoking, BMI, etc, and results of studies of environmental factors often vary widely. Large international studies such as the European Prospective Investigation into Cancer and Nutrition (EPIC) are attempting to unravel the evidence of sometimes contradictory epidemiological studies (Gonzalez 2006). Genetic predisposition alleles with a low penetrance may be more susceptible to environmental influences which modify an individual’s risk of colorectal neoplasia. There have been very few studies that clearly address the mechanisms of mutational induction by the environment in colorectal cancer. Although the contribution of individual environmental factors is uncertain, they play an important role in the multifactorial aetiology of colorectal cancer.
The normal large bowel
The large bowel is embryologically derived from midgut and hindgut which in have their junction at the splenic flexure. The vascular supply and lymphatic drainage of the large bowel is similarly divided, and this junction is sometimes taken to separate the ‘right’ and ‘left’ colorectum. In adults, the large bowel lumen is continuous with nine anatomical regions: The caecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon and the rectum. The mucosa lies over a basement membrane, underneath is the muscularis mucosa, lamina propria and muscularis propria (Figure 1‑1).
The Wnt, and to a lesser extent the TGF-ß, BMP, Notch, and Par polarity pathways are the major players in homeostatic control of the adult epithelium (Sancho et al. 2004). The surface of the colon is covered by an epithelium composed of four differentiated cell types (enterocytes, enteroendocrine,goblet and Paneth cells) that invaginates at regular intervalsto form crypts. The bottom of the crypts is occupied by a few stem cells that give rise to actively dividing precursorcells that populate the bottom two-thirds of the crypts. The epithelial cell precursors migrate upward in an ordered fashion, which isalso controlled by Wnt factors, and they stop proliferating when they reach the top third of the crypt, possibly because they are too far from the Wnt source. Meanwhile, they continue their migration and colonise the surface of the colon.After about a week, epithelial cells undergo apoptosis and areshed in the lumen of the gut. The Paneth cells constitute anexception, as they migrate downward and occupy the very bottomof the crypt (van Es et al. 2005).
Thus, the epithelium of the colon is under perpetual renewal. Wnt growth factors activate a cascade of intracellular events, which is known as the canonical Wnt pathway that ultimately leads to the expression of a genetic program controlling the co-ordinated expansion, fate and sorting of the epithelial cell population (Figure 1‑2).
The canonical Wnt signalling cascade controls cell behaviour by activating the transcriptional properties of DNA-binding proteins of the T-cell factor(TCF)/lymphoid enhancer factor-1 family (Clevers 2006). Wnt induces stabilisation of cytosolic ß-catenin, which is transported to the nucleus and associates with TCFs, leading to the expression of specific target genes (McDonald et al. 2006). In the absence of Wnt signalling, ß-catenin is targeted for degradation in proteosomes, and TCFs block expression of Wnt target genes. Thus activation of the pathway may be demonstrated by nuclear localisation of ß-catenin. In colorectal cancer mutations in components of the Wnt pathway mimic the effect of a permanent Wnt stimulation, causing epithelial cells to proliferate inappropriately.
Wnt factors can also trigger the activation of at least twoother, ß-catenin-independent, non-canonical pathways. They are referredto as non-canonical signalling and their implication in colorectal cancer, if any, is not yet elucidated. The list of genes targeted by the Wnt pathway is very long (http://www.stanford.edu/%7ernusse/pathways/targets.html), indicating its wide range of roles in cellular homeostasis.
The transforming growth factor-ß (TGF-ß) superfamily comprises a large number of structurally related polypeptide growth factors and each of these is capable of regulating a complex array of cellular processes (Hata et al. 1998). In normal epithelial cells including intestinal epithelium, TGF-ß has a major inhibitory role and a substantial body of evidence suggests a role as tumour suppressor. Neoplastic transformation results in loss of normal growth inhibitory responses to TGF-ß (Kurokowa et al. 1987). Inhibition of intestinal cell proliferation by TGF-ß treatment results in cell cycle arrest from mid-to-late G1 (Ko et al. 1998). To date, some of the most important contributors to the growth response seen on TGF-ß exposure appear to involve cell cycle regulatory genes, including C-MYC, CDC25A, and the cyclin-dependent kinase inhibitors (CDKIs) p15INK4B, p21WAF1/CIP1, and p27KIP1 (Ko et al. 1994; Ko et al. 1995). Other targets of this pathway include the SMAD (Small mothers against decapentaplegic) and BMP genes (bone morphogenetic proteins), important mediators of signal transduction. In vivo, there is increased expression of both TGF-ß1 and the TGF-ß type II receptor in intestinal epithelial cells as they migrate from the proliferative compartment toward the lumen in both the small intestine and the colon (Winesett et al. 1996). This pattern of expression is inversely correlated with the mitotic activity in the gut epithelium. Reduced expression of the TGF-ß type I receptor was been strongly linked to colorectal cancer predisposition (Valle et al. 2008). However a larger study published subsequently did not demonstrate allele-specific expression or an association polymorphisms within this gene with colorectal neoplasia (Carvajal-Carmona et al 2010).
Colorectal Cancer Development
Colorectal cancer develops via an adenoma to carcinoma sequence with the accumulation of a number of genetic and epigenetic mutations (Figure 1‑3) (Morson 1968; Fearon and Vogelstein 1990). The mutations accumulated vary in hereditary cancer depending on the initiating mutation. In their normal state, tumour suppressor genes inhibit cell proliferation. Growth inhibition is lost when both alleles are inactivated by mutation and/or epigenetic changes, such as promoter methylation which stifles expression of the gene. Tumour suppressor genes broadly conform to Knudson’s classic two-hit hypothesis, where inactivation of both alleles is required for tumour suppressor genes to lose their normal function (Knudson 1971). In contrast, proto-oncogenes act by promoting cell proliferation. Mutation of these genes leads to abnormal oncogenic over-expression or increased activity of the protein.
The adenoma-to-carcinoma sequence for colorectal cancer is probably most commonly initiated by bi-allelic mutation of the APC tumour suppressor gene. APC mutations have been found in microadenomas (Otori et al. 1998), the earliest lesion on the pathway (also called aberrant crypt foci (Roncucci et al. 1991)), and in ~60-80% of early sporadic adenomas and carcinomas (Cottrell et al. 1992; Miyoshi et al. 1992; Nakamura et al. 1992). APC is a key member of the canonical Wnt signalling pathway, and the key mechanism by which mutation of this gene contributes to carcinogenesis is by activation of this pathway. However, further accumulated mutations in additional genes are required for progression of the early lesions to cancer.
Activating mutations of the oncogenes KRAS (Kirsten rat sarcoma viral oncogene homolog) and BRAF (v-raf murine sarcoma viral oncogene homolog B1), both members of the MAPK (mitogen activated protein kinase) signalling pathway, are found in the transition from early to an intermediate lesion in approximately 50% and 10% of cases respectively (Bos et al. 1987; Rajagopalan et al. 2002; Yuen et al. 2002). Mutations of codons 12 and 13 in exon 2 of KRAS tend to occur in 30-60% of colorectal carcinomas (Kressner et al. 1998). The KRAS gene product,a 21 kDa protein located at the inner plasma membrane, is involved in the transduction of mitogenic signals. The Ras protein is activated transiently as a response to extracellular signals such as growth factors, cytokines and hormones that stimulate cell surface receptors (Campbell et al. 1998), and mutations in KRAS constitutively activate the Ras protein.
The substitution mutation of BRAF V600E is present in 4-12% of unselected colorectal tumours, and it is associated with sporadic MSI tumours but not HNPCC tumours (Vandrovcova et al. 2006). MSI tumours outside the context of HNPCC are usually caused by methylation of the MLH1 promoter. Indeed, there is a hypothesis that some tumours might develop through a separate hyperplastic polyp-serrated adenoma pathway (Spring et al. 2006).
Epigenetic changes such as promoter hypo-/hyper-methylation can cause disregulation of expression of many genes important in colorectal cancer (Hitchins et al. 2005; Hitchins et al. 2006). Further progression to late type adenoma is associated with loss of 18q in 50% of large adenomas and 75% of carcinomas (Vogelstein et al. 1988; Fearon et al. 1990). This causes loss of SMAD2 and SMAD4, members of the TGF-ß signalling pathway. Point mutations of these genes have also been identified in colorectal cancer (Eppert et al. 1996; Hahn et al. 1996; Thiagalingam et al. 1996). The adenoma to carcinoma transition appears to be associated with loss of 17p (Fearon et al. 1987; Rodrigues et al. 1990; Akiyama et al. 1998). The 17p locus contains the P53 gene (Baker et al. 1990), the so-called gatekeeper of the cell which has important roles in the regulation of the cell cycle and apoptosis. Loss of heterozygosity of 17p correlates with missense and truncating mutations in P53 (Baker et al. 1989; Baker, Preisinger et al. 1990). Tumour invasion and metastasis are associated with loss of 8p (Hughes et al. 2006), and loss of E-cadherin function, a component of adherens-junctions (Hao et al. 1997; Christofori and Semb 1999).
The progression from adenoma to invasive carcinoma probably takes 10-40 years (Ilyas et al. 1999). However, not all lesions will undergo malignant transformation, the reason for which is unclear. It may be that the necessary mutations do not accumulate because of death, or because of environmental influences such as diet.
Colorectal cancer may be subdivided genetically by the types of mutations which accumulate genome-wide during carcinogenesis. It had been observed nearly a century ago that most cancers were aneuploid, and it has been noted that the degree of aneuploidy in colorectal cancer correlates with the severity of the neoplastic behaviour (Heim and Mitelman 1989). A series of deletions, duplications, and rearrangements occur. Allelic losses appear to be important in the progression from premalignant to malignant neoplasia in the colorectum. This process is called chromosomal instability (CIN) and accounts for approximately 75% of colorectal cancers. Ten to 15% are not CIN but do have smaller mutational events which are caused by loss of DNA mismatch repair (Fishel et al. 1993) and are referred to as MSI tumours. The CpG island mutator phenotype (CIMP) is associated with methylation of promoter regions, CpG rich regions, which causes silencing of genes. Tumours are often both MIN and CIMP, as methylation of mismatch repair gene promoters usually occurs in sporadic MSI tumours (Kane et al. 1997).
The role of genomic instability in causing and promoting tumour growth remains controversial (Lengauer et al. 1998; Tomlinson and Bodmer 1999). Some argue that instabilityis necessary for tumourigenesis (Loeb 1991), while others take the viewthat Darwinian selection is the driving force. It is becoming clear that many cancers harbour multiple mutations, the great majority ofwhich probably have no significant effect on tumour growth. It may well be that some tumours with an inherited DNA repair defect accumulate more mutations than others.