This category contains 18 posts

DNA polymerase proofreading associated-polyposis (PPAP): A new syndrome

An external file that holds a picture, illustration, etc. Object name is emss-53122-f0001.jpg

PAP family

Polymerase proofreading associated polyposis
(PPAP) is the suggested name for the condition predisposed by pathogenic mutations in the exoncuclease/proof reading domain of the POLE and POLD1 genes. This leads to a heritable susceptibility to developing multiple adenomas and/or early onset colorectal cancer.  The phenotype of PPAP is similar to that seen with MutYH associated polyposis (multiple adenomas) or Lynch syndrome (large adenomas or early onset carcinoma). Mutations in POLD1 are also associated with development of endometrial carcinoma.  Tumours tend to be microsatellite stable.

Mutations in related DNA polymerase genes POLE and POLD1 were described in families with oligopolyposis and endometrial cancer by Ian Tomlinson’s group in Oxford. An elegant approach was employed using whole-genome sequencing in 15 selected patients with more than ten adenomas before age 60 years. Several had a close relative with at least five adenomas who could also have whole-genome sequencing performed. All tested patients had CRC or a first-degree relative with CRC. All had negative APC, MYH, and MMR gene mutation test results. No variants were found to be in common among the evaluated families. In one family, however, linkage had established shared regions, in which one shared variant was found (POLE p.Leu424Val; c.1270C>G), with a predicted major derangement in protein structure and function. In a validation phase, nearly 4,000 affected cases enriched for the presence of multiple adenomas were tested for this variant and compared with nearly 7,000 controls. In this exercise, 12 additional unrelated cases were found to have the L424V variant, with none of the controls having the variant. In the affected families, inheritance of multiple-adenoma risk appeared to be autosomal dominant. Somatic mutations in tumors were generally consistent with the otherwise typical chromosome instability (CIN) pathway, as opposed to MSI or CIMP. No extracolonic manifestations were seen. A similar approach, whole-genome testing for shared variants, with further “filtering” by linkage analysis identified a variant in the POLD1 gene, p.Ser478Asn alteration, c.1433G>A). This S478N variant was identified in two of the originally evaluated families, suggesting evidence of common ancestry. The validation exercise showed one patient with polyps with the variant but no controls with the variant. Somatic mutation patterns were similar to the POLE variant. Several cases of early-onset endometrial cancer were seen. The mechanism underlying adenoma and carcinoma formation resulting from the POLE L424V variant appeared to be a decrease in the fidelity of replication-associated polymerase proofreading. This in turn appeared to lead to mutations related to base substitution.


The study authors recommend consideration of POLE and POLD1 testing in patients with multiple or large adenomas in whom alternatives mutation testing is uninformative and surveillance akin to that afforded patients with LS or MAP. POLE and POLD1 mutation testing is being incorporated into the new multigene CRC susceptibility panels.

Inherited Colorectal Cancer Course for the Multidisciplinary Team, London 15th January 2015


Date: January 15th, 2015

Venue: St Mark’s Hospital, London

Click here for more information

Target Audience:  All members of the Colorectal Cancer MDT (nurse specialists, oncologists, gastroenterologists, colorectal surgeons, pathologists), Geneticists, genetics counsellors

Learning Style: Lectures and case discussions

Learning Outcomes: On completion of this course, attendees will:

  • Appreciate the contribution of inheritance to colorectal cancer
  • Be able to assess family history and associated risk
  • Understand how to manage individuals at moderate risk of colorectal cancer
  • Understand the basic features and management of polyposis syndromes
  • Understand the diagnosis and management of Lynch syndrome

Course Fees:

£150.00 – Consultants
£75.00 – Nurses, Trainees and other Healthcare Professionals

To apply, complete the application form and send to

For further information, view the programme and brochure for the course. If you have any questions, please feel free to contact the Academic Institute.

American College of Medical Genetics and Genomics (ACMG) technical standards and guidelines for genetic testing for inherited colorectal cancer

Read the original article in Genetics in Medicine (2013) Hegde et al

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.




Guest Blog: Wellcome Witnesses to Contemporary Medicine series, ‘Clinical Cancer Genetics: Polyposis and Familial Colorectal Cancer c.1975–c.2010’.

Polyposis (carpeting a rectum after a previous ileocolonic anastamosis)

Polyposis (carpeting a rectum after a previous ileocolonic anastamosis)

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 Yabsley

History of Modern Biomedicine Research Group
Queen Mary, University of London
Mile End Road
London E1 4NS
United Kindom

Retired Sailor overcomes bleak diagnosis, maintains positive attitude

Retired Sailor overcomes bleak diagnosis, maintains positive attitude

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…

Starting at age 50, it is encouraged that everyone get regular colonoscopies (in the USA), an examination that use a fiber-optic camera to view your lower gastrointestinal tract, to screen for colon cancer.In September 2011 when Daniel Shockley, a retired Sailor living on Oahu, went for his annual physical exam at Spark M. Matsunaga Veterans Affairs Medical Center, he thought besides a little weight loss, he had a clean bill of health.Since Shockley had just turned 50, he was referred to a Hawaii Pacific Health clinic in downtown Honolulu for his first colonoscopy.

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.”

Read More;

Polyposis Syndromes – Information for Patients


The Aetiology of Hyperplastic Polyposis Syndrome


K. J. Monahan1, L. Carvajal-Carmona2, T. Guenther3, T. O’Gorman4, J. Cazier2, I. P. Tomlinson2, H. J. W. Thomas1. 1Family Cancer Clinic, St Mark’s Hospital, 2Molecular and Population Genetics Lab, Cancer Research UK, 3Academic Department of Pathology, St Mark’s Hospital, London, UK, 4Department of Medicine, University College Hospital, Galway, Ireland. Gut 2008;57:A1-A172. BSG 2008.

Introduction: We have identified a family with a dominantly inherited predisposition to mixed histology multiple polyps and colorectal cancer. The family meet WHO criteria for hyperplastic polyposis syndrome. We have attempted to elucidate the gene which predisposes to this condition.

Aims & Methods: Mutations in APC, MYH, SMAD4 and genes which cause HNPCC were excluded by direct sequencing and other methods. Somatic mutations were screened in genes often mutated in colorectal cancers. Genome wide genotypes were obtained for over 10000 SNPs using Affymetrix 10k plus 2 arrays and linkage analysis was performed. Genome wide copy number variation analysis was also performed using the Goldengate SNP platform. Whole genome expression analysis profiles were obtained on cell line RNA using the Affymetrix U133 Plus 2.0 GeneChip oligonucleotide arrays.

Results: The polyps appear to follow a hyperplastic/serrated polyp to mixed serrated/adenomatous (see fig) to adenocarcinoma sequence. Linkage analysis shows a maximum parametric LOD score of 2.71 at 8p22–21.3. Genome wide copy number and loss of heterozygosity (LOH) studies reveal LOH at 8p and 17p in the cancers. A number of genes at that locus including BMP1 and MTUS1 have been screened, the latter gene having more than a fivefold up-regulation in expression.

Conclusion: We have identified a locus on chromosome 8p which predisposes to hyperplastic polyps and colorectal cancer in a large family from the West of Ireland. This is the first time such an association has been identified and may be useful in screening families at risk of colorectal neoplasia.


Juvenile Polyposis Syndrome

Juvenile polyposis (JPS) is defined by the presence of multiple hamartomatous polyps of the colon and rectum.  Estimates of the population prevalence of Juvenile Polyposis syndrome suggest a frequency of around 1:100 000.  It accounts for less than 0.1% of all colorectal cancer cases.

Histological differences and topographical distribution within the gastrointestinal tract serve to distinguish between this disorder and Peutz-Jeghers syndrome (PJS). Juvenile hamartomatous polyps have an apparently normal epithelium with a dense stroma, an inflammatory infiltrate, and a smooth surface with dilated, mucus-filled cystic glands in the lamina propria with smooth muscle fibres, which distinguishes these from PJS polyps. The glandular proliferative characteristics of adenomas are typically absent.

English: Very low magnification micrograph of ...

English: Very low magnification micrograph of a gastric juvenile polyp. H&E stain. Features of juvenile polyps: Dilated glands. Increased lamina propria & inflammation. Eroded surface. Stalk. Related images Image:Gastric juvenile polyp – 2 – very low mag.jpg (Photo credit: Wikipedia)

The term ‘juvenile’ refers to the polyp type rather than to the age of onset, although most individuals with juvenile polyposis have some polyps by 20 years of age. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than a hundred. Juvenile polyposis usually manifests during childhood, but diagnosis of the condition is confounded by the occurrence of isolated juvenile-type polyps in children. These solitary polyps are noteworthy because their identification in childhood does not necessarily indicate a heritable cancer predisposition syndrome, and they do not appear to be associated with excess cancer risk.  In contrast, juvenile polyposis is associated with a colorectal cancer risk of around 10-38% and a gastric cancer risk of 21%.

If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk of GI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have been reported.

Molecular Genetics

Around 20% of cases are due to mutations in the SMAD4 gene, while a further 20% are due to mutations in another gene in the same TGF-beta molecular signaling pathway, BMPR1A, indicative of genetic heterogeneity.  Mutations in BMPR1A have been particularly implicated in European populations and SMAD4 mutations may have a more aggressive clinical phenotype.  A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) (termed JPS/HHT) may be present in 15%-22% of individuals with an SMAD4 mutation.

Clinical Diagnosis

JPS is clinically diagnosed if any one of the three following findings is present:

  • More than five juvenile polyps of the colorectum
  • Multiple juvenile polyps throughout the GI tract
  • Any number of juvenile polyps and a family history of juvenile polyps

Testing relatives at risk: When the family-specific mutation is known, it is appropriate to perform molecular genetic testing on at-risk family members in the first to second decade of life to identify those who will benefit from early surveillance and intervention.

UK BSG Screening Guidelines

Colorectal surveillance

< Large bowel surveillance for at-risk individuals and mutation carriers every 1-2 years is recommended from age 15-18 years, or even earlier if the patient has presented with symptoms. Screening intervals could be extended at age 35 years in at-risk individuals. However, documented gene carriers or affected cases should be kept under surveillance until age 70 years and prophylactic surgery discussed. The intervention should visualise the whole colon and so colonoscopy is the preferred modality.  Although isolated juvenile polyps are relatively common, juvenile polyposis is rare and consequently experience is limited.  There are few large descriptive studies, and no comparative study to demonstrate potential benefit. Nonetheless, there is a substantial risk of colorectal cancer amounting to 10-38%.  Many polyps are located in the right colon, and so the whole colon should be visualised. There is particular risk of malignancy in cases where there is adenomatous change, or where there is a dysplastic element to the polyps.

Upper gastrointestinal surveillance

< Upper gastrointestinal surveillance every 1-2 years is recommended from age 25 years, contemporaneously with lower gastrointestinal surveillance.  The risk of gastric and duodenal cancer in juvenile polyposis is round 15-21%.

Peutz-Jeghers Syndrome (PJS)

English: Structure of the LKB1 (pink)- STRAD (...

Structure of the LKB1 protein

Disease characteristics. Peutz-Jeghers syndrome(PJS (OMIM 175200)) is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation.  Gastrointestinal cancer risks include gastro-oesophageal, small bowel, pancreatic and colorectal cancers with a cumulative risk of 57% by the age of 70.  here is a 50% lifetime risk of breast cancer, and clinicians managing PJS patients should ensure breast screening arrangements are in place. In 2063% of cases, inactivating mutations can be identified in the gene STK11 (LKB1). There is evidence for genetic heterogeneity with a possible further locus on chromosome 19q. Estimates of the population prevalence of PeutzJeghers syndrome suggest a frequency of around 1:50 000.

Peutz-Jeghers-type hamartomatous polyps are most common in the small intestine (in order of prevalence: in the jejunum, ileum, and duodenum) but can also occur in the stomach, large bowel, and nasal passages. Gastrointestinal polyps can result in chronic bleeding and anemia and cause recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection.

English: Low magnification micrograph of a Peu...

English: Low magnification micrograph of a Peutz-Jeghers type intestinal polyp. H&E stain. (Photo credit: Wikipedia)

Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa. Hyperpigmented macules on the fingers are common. The macules may fade in puberty and adulthood. Individuals with Peutz-Jeghers syndrome are at increased risk for a wide variety of epithelial malignancies (colorectal, gastric, pancreatic, breast, and ovarian cancers). Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer. Males occasionally develop calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia.

Diagnosis/testing. The diagnosis of Peutz-Jeghers syndrome is based on clinical findings. In individuals with a clinical diagnosis of PJS, molecular genetic testing of STK11 (LKB1) reveals disease-causing mutations in nearly all individuals who have a positive family history and approximately 90% of individuals who have no family history of PJS. Such testing is available clinically.


English: A graphical representation of the nat...

English: A graphical representation of the natural history of Peutz-Jeghers syndrome. Most patients will develop melanotic macules during the first year of life and a patient’s first intussusception usually occurs between the ages of six and 18 years old. Cumulative lifetime cancer risk begins to rise in middle age. Cumulative risks by age 70 for all cancers, gastrointestinal (GI) cancers, and pancreatic cancer are 85%, 57%, and 11%, respectively. (Photo credit: Wikipedia)

Colorectal surveillance

Large bowel surveillance is recommended 2-yearly from age 25 years. The intervention should visualise the whole colon and so colonoscopy is the preferred mode of surveillance. PJS is rare and so evidence on effectiveness of surveillance is limited to case series and anecdote.  The risk of colorectal cancer increases with age being 3%, 5%, 15%, and 39% at ages 40, 50, 60, and 70 years, respectively. Males may be at greater risk. There is also an excess risk of small bowel, pancreatic and oesophago-gastric cancer. The risk for all gastrointestinal cancers combined is 1%, 9%, 15%, 33%, and 57% up to ages 30, 40, 50, 60 and 70 years, respectively.154

Treatment of other manifestations:

Upper gastrointestinal surveillance is recommended 2-yearly from age 25 years, comprising gastro-duodenoscopy. Intermittent MRI enteroclysis or small bowel contrast radiography is recommended.

There is an elevated risk of gastric malignancy in PeutzJeghers syndrome amounting to around 510%.  Although evidence from pooled case series indicates that small intestinal cancer is rare, the risk is sufficient to merit intermittent imaging.  MRI enteroclysis appears appropriate for surveillance because it avoids repeated radiation exposure in young individuals and has very good sensitivity and overall accuracy for small bowel polyps in PJS as well as for patients with small bowel tumours who do not have PJS.  However, video capsule endoscopy is also an option, with evidence of better sensitivity than MRI enteroclysis for smaller lesions in small bowel polyposis syndromes in one small comparative study.

Testing of relatives at risk: If the family mutation is known, offer molecular genetic testing to at-risk relatives so that morbidity and mortality can be reduced in those with the family-specific mutation by early diagnosis and treatment and appropriate surveillance; if the family mutation is not known, offer clinical diagnostic evaluations to identify those family members who will benefit from early treatment and appropriate surveillance.

Other: Although not studied in individuals with PJS, the following could be considered: prophylactic mastectomy to manage high risk for breast cancer and prophylactic hysterectomy and bilateral salpingo-oophorectomy after age 35 years or after child-bearing has been completed to prevent gynecologic malignancy.

Genetic counseling. Peutz-Jeghers syndrome is inherited in an autosomal dominant manner. About 50% of affected individuals have an affected parent and about 50% have no family history of PJS; the proportion of cases caused by de novo gene mutations is unknown as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient. The risk to the offspring of an individual with a pathogenic STK11 mutation is 50%. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known

Squaring Genetic vs Clinical Findings in Familial Polyposis

Journal CoverPrevalence and Phenotypes of APC and MUTYH Mutations in Patients With Multiple Colorectal Adenomas

Grover S, Kastrinos F, Steyerberg EW, et al

JAMA. 2012;308:485-492


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.[2] 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.[3]

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,[1] 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.

via Squaring Genetic vs Clinical Findings in Familial Polyposis.

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


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].

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
  • 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.

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

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)

  • 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, 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.

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,301 other followers

Live twitter feed

Facebook page for this Clinic

RSS Familial Cancer

  • An error has occurred; the feed is probably down. Try again later.


Google Plus

%d bloggers like this: