Venue: St Mark’s Hospital, London
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:
£150.00 – Consultants
£75.00 – Nurses, Trainees and other Healthcare Professionals
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.”
Gut 2011;60:A116-A117 doi:10.1136/gut.2011.239301.246
Family History of Bowel `Cancer Clinic, West Middlesex University Hospital, London, UK; Cancer Medicine, Imperial College, London, UK; Molecular and Population Genetics, Cancer Research UK, London, UK
Introduction Progressive loss of cell cycle control is an important feature on the adenoma-carcinoma sequence of colorectal cancer. Cyclin-dependent kinase inhibitor 1A (P21/CDKN1A) is an important target of the TGFβ signalling pathway, and it is commonly under-expressed as colorectal neoplasia develop. The aim of this study was to identify low penetrance germline variation in this gene which predisposes individuals to colorectal cancer.
Methods Variation in the coding region of CDKN1A was determined in fifty colorectal cancer cases with a strong family history and 50 controls were tested using the Lightscanner and direct sequencing. 15 tagging SNPs around CDKN1A were typed in the CORGI cases and controls as part of a genome-wide analysis using the Illumina Hap550 platform in 930 cases and 960 controls performed by colleagues (Tomlinson et al 2007). Allele-specific expression of the gene was examined using quantitative reverse transcriptase PCR linked to SNPs in an upstream promoter region.
Results A novel amino-acid changing variant Phe22Leu was identified in a single colorectal cancer patient. Six patients were identified in the case group and 5 in the control group with Arg31Ser. In the association study the two most significant SNPs lie in an upstream promoter region and are in linkage disequilibrium, both are risk alleles for colorectal cancer (OR 1.13; 95% CI 1.06 to 1.2).
p ( χ2)
There were significant differences in expression between CDKN1A and the controls in 94 samples (p=0.037, Student’s t test), demonstrating linkage of these upstream polymorphisms to allele-specific expression of CDKN1A.
Conclusion Rare variants of P21/CDKN1A are an infrequent cause of predisposition to colorectal neoplasia. A promoter region upstream of the CDKN1A is associated with prediposition to colorectal neoplasia, and is linked to allele-specific expression of this gene.
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.
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.(JPS) is defined by the presence of multiple hamartomatous
Histological differences and topographical distribution within the gastrointestinal tract serve to distinguish between this disorder and (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.
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.
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.
JPS is clinically diagnosed if any one of the three following findings is present:
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
< 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%.
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 20–63% 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 Peutz–Jeghers 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.
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.
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 Peutz–Jeghers syndrome amounting to around 5–10%. 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
The hyperplastic polyp and serrated adenoma pathway
The first series of mixed hyperplastic-adenomatous polyps were described in 1990 (Longacre and Fenoglio-Preiser 1990), and have been an increasingly recognised phenomenon. Most hyperplastic polyps have no malignant potential, although there is now some have malignant potential, especially those with serrated architecture (sessile serrated adenomas – SSAs), large hyperplastic polyps, mixed polyps and polyps on the right side of the colon (Torlakovic et al. 2003).
Classification of hyperplastic polyps
A new understanding of the clinical relevance of hyperplastic polyps has emerged over the past decade (Young and Jass 2010). The simple hyperplastic polyp has itself been subclassified into a goblet cell variant and a microvesicular variant, the latter appear to be the precursors for serrated adenomas and thus colorectal cancer. Serrated adenomas usually have serrations low in the crypts which help differentiate them from hyperplastic polyps.
However, serrated polyps also include a broader spectrum of polyp subtypes ranging from these small common lesions to the recently described sessile serrated adenoma (SS
A), which is often large and proximal with abundant mucin secretion, exaggerated serration, and atypical architecture. Rarer serrated polyp subtypes with unequivocal dysplasia include traditional serrated adenoma (SA), which combines the dysplastic features of an adenoma with the architectural features of a hyperplastic polyp and the mixed polyp (MP) in which separate hyperplastic and dysplastic elements are combined within a single polyp (see figure). SSA, SA, and MP are described as “advanced serrated polyps” and comprise ∼5% of all serrated polyps retrieved in colonscopy patients. Importantly, these advanced serrated lesions show frequent BRAF mutation and widespread DNA methylation.
Endoscopic appearances of serrated adenomas
Serrated and hyperplastic polyps present endoscopic features that could help to differentiate them from adenomatous polyps. HPs appear flat and pale and are often covered by a thin film of mucus. They exhibit Kudo type 2 pit pattern typically. As they are not highly vascular they will appear pale compared to surrounding mucosa using narrow-band imaging (NBI). In addition, chromoendoscopy may be helpful in the endoscopic characterisation of these lesions.
Inherited Colorectal Cancer Syndrome?
An inherited hyperplastic polyposis syndrome (HPS) has also been increasingly recognised (Cohen et al. 1981; Sumner et al. 1981). It is now more commonly known as serrated polyposis syndrome. There is no sex predominance and the mean age at diagnosis is around 55 years. HPS has largely been considered a genetic disease, but the pattern of inheritance remains unknown: both autosomal recessive and autosomal dominant patterns have been suggested. Environmental factors could be partially responsible for the phenotypic differences and model the unknown pattern of inheritance. Smoking, being overweight and some drugs have been postulated as potential risk factors of HPs.
In HPS, multiple serrated polyps develop in the colorectum, and approximately 50% of cases present with at least one CRC (Ferrandez et al. 2004; Young and Jass 2006). Boparai et al (2011) have recently described an increased risk of CRC [relative risk (RR) = 5.4] and HPS (RR = 39) in first-degree relatives of probands diagnosed with HPS compared to the general population. Estimates for CRC risk associated with serrated polyposis may range from 7% to 50% and vary with phenotype.
Classification of the Syndrome
In the WHO criteria, Burt and Jass defined HPS as at least five HPs proximal to the sigmoid colon, two of which are > 1 cm diameter, or more than 30 HPs at any site in the large bowel (Burt 2000). Rashid et al, however, used a different classification system, in which HPS was defined as any person with more than 20 HPs, and separate classes were used for patients with large (>1 cm diameter) or multiple (5-10) HPs (Rashid et al. 2000). These differing classification systems reflect a syndrome which may be both genetically and phenotypically heterogeneous, but one which is becoming increasingly recognised.
The serrated pathway to colorectal cancer
Some evidence suggests that some but not all of these tumours develop along a ‘serrated pathway’ separate from the classical adenoma-carcinoma sequence (Sawyer et al. 2002; Spring, Zhao et al. 2006). This serrated pathway involves one group who accumulate BRAF V600E mutations and another separate pathway which involves KRAS mutations(Carvajal-Carmona et al. 2007). In addition the tumours often have methylation of the MLH1 promoter with subsequent microsatellite instability, and other genes such as P16, MGMT, or IGFBP7 may also be epigenetically inactivated. The CIMP phenotype identified by increased levels of methylation in the CpG island marker MINT31(Jass 2005).
HPS (sometimes known as the ‘serrated pathway syndrome’ or ‘serrated pathway syndrome’ (SPS) and sometimes ‘Jass Syndrome’) may, in fact, be a heterogeneous group of conditions leading to sporadic and inherited cases of colorectal neoplasia. There are two alternative clinical criteria for the diagnosis of HPS families (Burt 2000; Rashid, Houlihan et al. 2000). This syndrome is usually associated with somatic mutations in either BRAF or KRAS, but not both together (Carvajal-Carmona, Howarth et al. 2007), providing further evidence of molecular as well as phenotypic heterogeneity. BRAF mutations are associated with low-grade microsatellite instability due to methylation in CpG islands (CIMP)(Young, Jenkins et al. 2007). This may result in loss of expression of DNA repair genes MLH1 and MGMT (O(6)-methylguanine-DNA methyltransferase) in dysplastic mixed polyps from HPS patients, possibly as a result of promoter methylation (Oh et al. 2005).
Linkage analysis in a large family affected with hyperplastic polyposis syndrome demonstrated a maximum parametric LOD score of 2.71 on the short arm of chromosome 8 (8p.21; Monahan et al 2007). Another group have identified genetic linkage to chromosome 2q32.2-q33.3 with a LOD score of 2.07 (Roberts et al 2011 Fam Cancer).
As of this time however, there is no known causative germline mutation responsible for this condition, therefore genetic testing for predisposition is not possible. Because the natural history of HPS is poorly understood, colonoscopic screening guidelines have not been developed. Empirically we recommend 5 yearly colonoscopic screening from the age of the earliest known affected relative, or from 45 years of age.
Hereditary colorectal cancer syndromes
Germline mutations which predispose to multiple polyps
Multiple polyp patients are a clinically heterogeneous group. Classical familial adenomatous polyposis (FAP; OMIM 175100) is caused by mutation of the APC gene which activates the Wnt pathway (Bodmer et al. 1987; Groden et al. 1991; Clevers 2006). This gene is somatically mutated in approximately 70% of sporadic colorectal cancer.
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 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 partitioned out as AFAP.
From the perspective of 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.
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 evidence of a genotype-phenotype relationship with regard to APC mutations. 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).
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 particularlyassociated 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.
Damaged DNA is repaired by several mechanisms, one of which involves a family of enzymes involved in base-excision repair (BER). The MYH gene encodes a DNA glycosylaseinvolved in the repair of the oxidative lesion 8-oxoguanine, a by-product of cellular metabolism and oxidative damage of DNA.
The products of three BER repair genes, OGG1, MTH1 and MYH work together to prevent 8-oxo-G induced mutagenesis. Mutations in MYH cause an autosomal recessive colorectal cancer and polyposis syndrome MYH-associated polyposis (MAP; OMIM 608456) (Al-Tassan et al. 2002). Somatic mutations in the APC gene in polyps from individuals affected with MAP are almost invariably G to T transversions (Sieber et al. 2003), and it was by understanding the underlying DNA repair mechanism of this mutation, base-excision repair, that MYHwas identified as a candidate-predisposition
gene. G to T transversion mutations were also identified in KRAS in codon 12 (Lipton et al. 2003). The adenoma to carcinoma pathway in MAP does not involve BRAF V600E, SMAD4 or TGFBIIR mutations, or microsatellite instability, and the cancers are near-diploid (Lipton, Halford et al. 2003). Thus, tumours with germline MYH mutations tend to follow a distinct pathway.
The term MYH-associated polyposis (MAP) may be misleading as up to 20% of biallelic MYH mutation carriers are diagnosed with colorectal cancer without polyposis (Wang et al. 2004). Biallelic mutations in MYH have been found to account for approximately 10% of polyposis patients, but <1% of all colorectal cancer (Halford et al. 2003; Wang, Baudhuin et al. 2004). The largest population study to date indicates that approximately 0.2% of all colorectal cancer is caused by biallelic mutations in MYH (Webb et al. 2006). It was demonstrated in the same study that monoallelic MYH mutations are not associated with an increased risk of colorectal cancer. The MAP phenotype typically falls in to the AFAP group, with extra-colonic manifestations consisting of duodenal polyps but not intra-abdominal desmoids. Among Caucasians approximately 80% of mutations in MYH causing MAP are Y165C or G382D (Sieber, Lipton et al. 2003). The E466X mutation is a common founder mutation among Pakistani populations, and the most common mutation in the St Mark’s Hospital MAP population (unpublished data). Y90X is a founder mutation in Indian populations (Sieber, Lipton et al. 2003).
Hereditary mixed polyposis syndrome (HMPS)
Hereditary mixed polyposis syndrome (HMPS OMIM 601228) is a mixed colorectal tumour syndrome which has been linked to the CRAC1 locus on 15q13-14 (Thomas et al. 1996; Jaeger et al. 2003). It is a rare condition found in a few families of Ashkenazi descent, with an autosomal dominant inheritance, mixed juvenile, adenomatous and hyperplastic polyps, as well as colorectal cancer (Whitelaw et al. 1997). The best screening protocol for polyps in HMPS is not clear as the condtion is rare. In addition genome-wide association revealed common low-penetrance predisposition alleles at the CRAC1 locus which are linked to sporadic colorectal cancer risk (Jaeger et al. 2008). The gene which causes HMPS was recently identified as a 40kb duplication upstream of the gene GREM1 at the CRAC1 locus (Jaeger et al 2012) which causes disruption of the BMP pathway, a pathway also disrupted in Juvenile Polyposis Syndrome.
The hyperplastic polyp and serrated adenoma pathway
The first series of mixed hyperplastic-adenomatous polyps were described in 1990 (Longacre and Fenoglio-Preiser 1990), and have been an increasingly recognised phenomenon. Most hyperplastic polyps have no malignant potential, although some recent studies have indicated that some have malignant potential, especially those with serrated architecture (sessile serrated adenomas – SSAs), large hyperplastic polyps, mixed polyps and polyps on the right side of the colon (Torlakovic et al. 2003).
Some evidence suggests that some but not all of these tumours develop along a ‘serrated pathway’ separate from the classical adenoma-carcinoma sequence (Sawyer et al. 2002; Spring, Zhao et al. 2006). This serrated pathway involves one group who accumulate BRAF V600E mutations and another separate pathway which involves KRAS mutations(Carvajal-Carmona et al. 2007). In addition the tumours often have methylation of the MLH1 promoter with subsequent microsatellite instability and CIMP phenotype(Jass 2005).
An inherited hyperplastic polyposis syndrome (HPS) has also been increasingly recognised (Cohen et al. 1981; Sumner et al. 1981). In HPS, multiple serrated polyps develop in the colorectum, and approximately 50% of cases present with at least one CRC (Ferrandez et al. 2004; Young and Jass 2006). In the WHO criteria, Burt and Jass defined HPS as at least five HPs proximal to the sigmoid colon, two of which are > 1 cm diameter, or more than 30 HPs at any site in the large bowel (Burt 2000). Rashid et al, however, used a different classification system, in which HPS was defined as any person with more than 20 HPs, and separate classes were used for patients with large (>1 cm diameter) or multiple (5-10) HPs (Rashid et al. 2000). These differing classification systems reflect a syndrome which may be both genetically and phenotypically heterogeneous, but one which is becoming increasingly recognised.
HPS (sometimes known as the ‘serrated pathway syndrome’ (SPS)) may, in fact, be a heterogeneous group of conditions leading to sporadic and inherited cases of colorectal neoplasia. There are two alternative clinical criteria for the diagnosis of HPS families (Burt 2000; Rashid, Houlihan et al. 2000). This syndrome is usually associated with somatic mutations in either BRAF or KRAS, but not both together (Carvajal-Carmona, Howarth et al. 2007), providing further evidence of molecular as well as phenotypic heterogeneity. BRAF mutations are associated with low-grade microsatellite instability due to methylation in CpG islands (CIMP)(Young, Jenkins et al. 2007). This may result in loss of expression of DNA repair genes MLH1 and MGMT (O(6)-methylguanine-DNA methyltransferase) in dysplastic mixed polyps from HPS patients, possibly as a result of promoter methylation (Oh et al. 2005).
Linkage analysis in a large family affected with hyperplastic polyposis syndrome deomstrated a maximum LOD score of 2.71 on the short arm of chromosome 8 (8p.21; Monahan et al 2007).
Other causes of multiple colorectal polyp predisposition
Germline mutations in exon 7 of the AXIN2 gene have recently been very rarely associated with a predisposition to colorectal polyposis and tooth agenesis ((Lammi et al. 2004) OMIM 608615). Somatic mutations have been found in AXIN2 previously, but germline mutations have not been found in other studies (Lejeune et al. 2006).
Other mutated genes which cause polyps such as SMAD4, PTEN and BMPR1A lead to multiple polyp syndromes with clinically recognisable differences from the above conditions, such as Juvenile Polyposis (OMIM 174900) and Peutz-Jeghers syndrome (OMIM 175200). The BMPR1A gene product, mutated in Juvenile Polyposis, is a receptor for bone-morphogenetic proteins (BMPs) which are members of TGF-β superfamily and part of the BMP pathway which regulates colonocyte growth and proliferation (Howe et al. 2001). Germline mutations in PTEN can cause a number of polyposis and multi-systemic syndromes including Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS), and the umbrella term ‘PTEN-mutation spectrum’. We recommend the Cleveland Calculator which can help determine the likelihood of a germline mutation in PTEN for any of these conditions and thus the need for genetic testing;
Cleveland Calculator: http://www.lerner.ccf.org/gmi/ccscore/index.php
Unknown genetic predispositions account for over 50% of all patients who develop 10-100 colorectal adenomas during their lifetime, and for about 20% of those with more than 100 polyps(Lamlum et al. 2000) (Spirio et al. 1993). To develop as many as 10-100 colorectal adenomas is a priori indicative of an inherited predisposition and many of these patients have a family history of multiple polyps. It is overwhelmingly likely, therefore, that the remaining multiple polyp patients have an inherited disease of an unknown genetic origin. Molecular characterisation of tumours from these patients remains deficient.
Predisposition to colorectal cancer in patients without multiple polyps
Lynch Syndrome/Hereditary non-polyposis colorectal cancer (HNPCC) and related syndromes
Lynch Syndrome (also known as Hereditary non-polyposis colorectal cancer(HNPCC; OMIM 120435)) accounts for approximately 2.2-4% of all colorectal cancer (Hampel et al. 2005). Lynch Syndrome is a familial cancer syndrome which accounts for approximately 2-3% of all colorectal cancer in the UK. It has formerly been known as Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), however the phenotype is more complex with multiple extracolonic tumours, for example, so this term has now been largely abandoned.
LS is an autosomally dominant inherited condition commonly caused by germline mutation in one of four DNA mismatch repair genes, MLH1, MSH2, MSH6 and PMS2. A minority of these families may be identified because they have multiple affected members diagnosed at an early age. The Amsterdam Criteria I and II (Vasen et al. 1993; Vasen et al. 1999)(see below) identify patients for colonoscopic and other screening. Approximately 40-80% of patients meet these criteria, with 50% of the remainder meeting the modified criteria which include extracolonic cancers. The revised Bethesda criteria (Umar et al. 2004) are used to identify patients for molecular screening of HNPCC, i.e. microsatellite instability ± immunohistochemistry studies. Approximately 80% of patients are identified using the Bethesda criteria, although the specificity is low.
Amsterdam I Criteria
Amsterdam II Criteria
Most families with LS, however, do not fulfil the Amsterdam criteria. The Revised Bethesda criteria are another set of diagnostic criteria designed to increase the diagnostic yield of testing for LS . For example, all individuals diagnosed under the age of 50 years should be tested for the molecular features of LS in their tumours. If molecular testing is diagnostic of LS, it can subsequently determine which families should undergo colonoscopic and other investigations, and to screen other high risk family members. The Revised Bethesda guidelines are designed to streamline the clinical diagnostic pathways used to identify mutation carriers in patients with colorectal cancer who might or might not fulfil the Amsterdam criteria, thus increasing diagnostic yield screening for LS.
The identification of such families with Lynch syndrome involves an extensive diagnostic work up comprising of various screening tools combined with genetic and immunohistochemical tests. Initially the tumour from an affected individual may be tested for features suggestive of this condition by either immunohistochemistry of the mismatch repair proteins and/or DNA microsatellite instability (a hallmark of faulty DNA mismatch repair). If either of these tests are abnormal, then germline testing may be performed to identify a putative heritable mutation in one of the causative genes.
Patient selection using Amsterdam and revised Bethesda criteria have been applied to clinical pathways in the United Kingdom through the use of national guidelines. Given the implication of family history and known mortality benefit, the early recognition of Lynch syndrome is highly desirable. There have been concerns over the sensitivity, specificity, and predictive value of already existing guidelines. About 22% of affected individuals do not fulfil either Amsterdam or the Revised Bethesda criteria. As Barnetson et al argues, there might be multiple reasons for this such as small family size, unknown or inadequately taken family history, adoption, and patients without available tumour data . A number of alternative screening models have been developed, such as MMRpredict, PREMM 1,2,6, MMRPro, and MsPath whilst searching for a careening tool that is simple, accurate, and clinically useful for predicting the likelihood of Lynch Syndrome.
Bethesda (revised) Criteria (Umar et al 2003)
There is a slight preponderance of right-sided tumours (70% proximal to the splenic flexure) in Lynch Syndrome. It is a highly penetrant condition which also features extracolonic cancers such as endometrial and gastric cancer. The adenoma to carcinoma sequence is rapid with interval cancers occurring in 5% of patients despite two-yearly colonoscopic surveillance (Jarvinen, Aarnio et al. 2000). The tumours are characteristically associated with a local lymphocytic infiltrate and a good prognosis when surgically resected (Jass 2000; Takemoto et al. 2004).
Screening tumours for Lynch Syndrome – is it cost effective?
There are clinical and economic trade-offs when implementing screening protocol on a large scale. As nondirected germline mutation testing for Lynch syndrome is prohibitively expensive at £1000 per gene, MSI and IHC are the screening tests of choice. In view of high costs of testing of all colorectal cancers for MSI or loss or MMR protein, an approach described by Heather Hampel of The Ohio State University, the Revised Bethesda Guidelines were felt to be an appropriate tool to select patients for genetic testing. However, the question remains open: is the “reflex” molecular tumour testing justified clinically and economically? Kastrinos et al, have looked into the popularity of the universal testing across several centres in US. Unsurprisingly, a pessimistic picture emerged showing the low uptake of the concept. The benefits of the universal testing are counterbalanced by practical problems such as an informed consent controversy, practicalities of dealing with the complexity of test results and the resultant implications. The fact that the cost effectiveness of this approach has not been yet validated plays heavily against such approach.
In US, Ramsey et al have carried out a study looking at cost-effectiveness of different strategies for identifying of persons with Lynch syndrome. The average cost per carrier detected using Bethesda guidelines was $15,787, and expanding this strategy to include costs and benefits for first degree relatives greatly improves the cost effectiveness of the program. Expanding the program to first degree relatives leads to savings from intensive screening to exceed the cost of testing.
In Europe, Pinol et al, has carried out a similar study evaluating cost-minimization analysis of identification strategies for MSH2/MLH1-associated Lynch syndrome. Authors concluded that clinical selection of patients using the Revised Bethesda Guidelines followed by either MSI analysis (€11,989 per detected mutation) or IHC (€10,644 per detected mutation) has proved to be more cost effective than performing any of these tests directly (€32,140 and €37,956 per detected mutation, respectively).
Further research has been carried out by Dinh et al in 2010 looking at the cost effectiveness of MMR gene mutations screening, and reached the conclusion that it is comparable to that of already established cancer screening protocols such as colorectal, cervical, and breast cancer screening. Authors argue that primary screening of individuals for MMR gene mutations, starting with the risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost effective manner relative to current practise with the average cost-effectiveness ratio of $26,000 per QALY.
These results echo several European studies, such as that carried out by Pinol V et al, 2005 in Spain, where authors suggest that MSI and IHC testing are equivalent strategies in terms of cost effectiveness when it comes to screening selected patients for MMR mutations
Other non-polyposis predisposition to colorectal neoplasia
About 15% of sporadic colorectal cancers are also microsatellite unstable and feature loss of protein staining on immunohistochemistry but are not caused by germline mutations in mismatch repair genes. Often they are acquired sporadic type cancers caused by methylation of MLH1. These associated with a particular genetic pathway which differs from HNPCC by the presence of BRAF V600E mutations, the absence of β-CATENIN exon 3 mutations and a methylator genotype (Young et al. 2005) (Oliveira et al. 2005). Recently kindreds demonstrating some inheritance of MLH1 promoter methylation have been identified (Suter et al. 2004; Hitchins, Williams et al. 2005), although the evidence for this inherited epimutation is limited to a few case studies and may be related in imprinting (Chong et al. 2007; Hitchins and Ward 2007).
In addition there are a number of families which fulfil Amsterdam criteria but do not demonstrate microsatellite instability (Dove-Edwin, de Jong et al. 2006). These families are termed by one group familial colorectal cancer type X (Lindor et al. 2005), and have a lower incidence of colorectal cancer occurring at a later age. The genetic aetiology is not known for these families.
Approximately 93% of colorectal cancer occurs after the age of 50 years, and thus those young patients who develop cancer are likely to have an inherited or other risk factor such as chronic colitis. The genetic risk is partially made up by inherited mutations which cause HNPCC. However, there are likely to be a number of other lower penetrance genes which cause cancer predisposition, many of which may have a recessive form of inheritance and few polyps, and therefore a less clearly identifiable phenotype.
Risk factors other than family history can play a more important role in the development of bowel cancer. The main risk factor for bowel cancer is increasing age. Only 7% of bowel cancer occurs before the age of 50 years. However, even if you have a family history or other genetic risk of bowel cancer, this risk can be reduced by leading a healthy lifestyle. This kind of healthy lifestyle can also reduce your risk of heart disease, stroke and other cancers. It has been recently estimated that approximately 70% of colorectal cancer could be avoided by changes in lifestyle in Western countries.
A good further source of information about dietary and other lifestyle related risk factors is available from Cancer Research UK at http://www.cancerresearchuk.org/cancer-info/cancerstats/types/bowel/riskfactors/bowel-cancer-risk-factors
Summary: A diet high in red meat and animal fat and low in fruit and vegetables increases your risk of bowel cancer. So if you want to reduce your risk of bowel cancer, whether or not you have a genetic risk, eat 5 pieces of fruit or vegetables daily, plenty of fibre, and don’t eat too much processed or red meat.
Putative anti-carcinogenic mechanisms of dietary fibre within the bowel include: the formation of short-chain fatty acids from fermentation by colonic bacteria; the reduction of secondary bile acid production; the reduction in intestinal transit time and increase of faecal bulk; and a reduction in insulin resistance. In the European Prospective Investigation into Cancer and Nutrition (EPIC) study after an average 6.2 years of follow-up, and 1,721 colorectal cancer cases, a 21% reduced risk amongst participants in the highest intake quintile was observed when compared against the lowest intake group. These results support our previous conclusion, of the potential of reducing colorectal cancer incidence by increasing fibre intake from cereal, fruit, and vegetable food sources.
In the EPIC study high intake of red or processed meat may increase risk by 71%. The mechanisms underlying the association between colorectal cancer risk and high intake of red and processed meat are uncertain. Controlled human intervention studies have raised the possibility that the endogenous nitrosation that arises from ingestion of heme iron but not of inorganic iron or protein may account for the increased risk associated with red and processed meat consumption. Heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAH) in diet may pose a potential risk of cancer to humans, depending on the extent to which the compounds are activated in vivo by metabolic enzymes. HCAs are formed as a byproduct of reactions during the cooking of meat, poultry, and fish at high temperatures, such as pan-frying or grilling with charcoal or on a gas grill; PAHs are formed in grilled and barbecued meat and in cured, processed foods. It has been suggested that processed meat intake has a stronger association with colorectal cancer than red meat intake.
Folate (a water-soluble B vitamin) appears to protect against bowel cancer, but it remains unclear whether the same level of benefit is derived from dietary folate (from food, particularly fruit and vegetables) and synthetic folate (folic acid supplements). Selenium can be obtained in food (particularly brazil nuts) and supplements; evidence for its effect on bowel cancer risk is mixed. The WCRF/AICR 2010 Report concluded that “Evidence for foods containing folate… and selenium… is less consistent and no conclusion could be drawn”.
Some experts have proposed that folate plays a dual role in bowel cancer in which moderate dietary intake before development of pre-cancerous adenomas reduces risk of adenoma development, but increased folate intake once adenomas have developed increases risk of cancer. Data from interventional studies indicate that folate supplementation decreases colonic mucosal cell proliferation . A large prospective study showing a 31% reduction in bowel cancer risk for people with the highest overall folate intake 12-16 years before diagnosis, but no effect of intakes in the more recent past.
The US Government was sufficiently convinced of the health benefits (and absence of risk) from folic acid that it introduced mandatory folic acid fortification of grain products in 1997, and a recent large cohort study found that 8.5 years on, higher total folate intake (including intake specifically from supplements) was associated with a decreased bowel cancer risk. There is some evidence that it is better to take folic acid in its natural form rather than as supplements i.e. tablets.
A 2011 meta analysis found men with the highest concentrations of selenium in the blood had 32% lower bowel cancer risk compared with men with the lowest concentrations, but found no association between selenium level and bowel cancer risk in women.3A 2004 pooled analysis found a similar level of risk reduction for both sexes combined.
Obesity is associated with an increased risk of colon cancer, particularly for men. Meta analyses show the risk of colon cancer increases by an estimated 24-30% per 5kg/m2 increase in body mass index (BMI) for men. In comparison to healthy-weight men (BMI less than 25 kg/m2), overweight men (BMI 25-29.9kg/m2) have a 23% higher risk of colon cancer, and obese men (BMI 30kg/m2 or more) have a 53% higher risk. The association is weaker in women, with colon cancer risk increasing by 9-12% per 5kg/m2 BMI increase, and the association proving non-significant in one meta analysis.
Larger waist size has been associated with increases in colon cancer risk in men (33% risk increase per 10cm waist circumference increase) and women (16% risk increase per 10cm waist circumference increase), as has increasing waist-to-hip ratio in both men (43% risk increase per 0.1-unit increase in ratio) and women (20% risk increase per 0.1 unit increase in ratio).
Higher BMI is linked less strongly to higher rectal cancer risk: a 5kg/m2 BMI increase is associated with a 9-12% higher rectal cancer risk for men (obese men have a 27% higher rectal cancer risk than healthy-weight men), but with no effect on rectal cancer risk in women
Regular physical activity can reduce your risk of bowel cancer, this is clearly shown in many studies. We would recommend 2-3 30 minute sessions per week of dedicated exercise (rather than more ‘passive’ exercise such as being busy at work!).
The relationship between physical activity and a reduced risk is one of the most consistent findings in epidemiologic literature.
Not smoking and drinking less than the upper recommended limit of normal (less than 21 units for men and less than 14 units for women) may also be helpful.