Familial bowel cancer

Abstract

Health Education England recognises the increasing relevance of genomics in medicine, and therefore, the importance for all specialists of applying knowledge and understanding of genomics to their work. This article looks specifically at familial colorectal cancer and the role of primary care clinicians in diagnosis and management.

Clinical case scenario 1

Amanda is a 36-year-old lady who has booked a telephone consultation because her mother has just been diagnosed with colorectal cancer at the age of 61. Amanda has no symptoms herself. You draw a family tree with the patient and establish that her maternal uncle was also diagnosed with colorectal cancer 5 years ago when he was 59. There have been no other malignancies in the family.

The role of primary care

In primary care, our role in dealing with familial bowel cancer is concerned with three main groups of patients. Firstly, we will see patients concerned about their risk of developing colorectal cancer because one or more of their family members have colorectal cancer. We need to be able to decide which of these patients require onward referral to determine whether they have an inherited cancer predisposition syndrome. Secondly, we will have patients under our care who are already known, or thought, to have a genetic predisposition to colorectal cancer. We will have a role in helping to mitigate the risk to these patients through encouraging and facilitating lifestyle change and prescribing risk-reducing medication if recommended by their specialists. We will also be the clinicians caring for them both physically and psychologically as they navigate their way through difficult life decisions, such as whether to start a family or undergo potentially invasive treatments to reduce their risk of colorectal cancer. Thirdly, there will be patients under our care who do not fulfil the criteria for referral to secondary care, as they are at near-population risk of developing colorectal cancer, but who will particularly benefit from encouragement to engage in the national bowel cancer screening programme and education about lifestyle changes which will help to decrease their risk.

When approached by patients concerned about the possibility of familial bowel cancer, our first task is to take a thorough family history to determine which members have been affected by colorectal cancer. We should ask about family members affected by other cancers, since some of the inherited cancer predisposition syndromes, such as Lynch syndrome, increase the risk of several types of malignancy. It may be helpful to draw a family tree with the patient. In 2019, the British Society of Gastroenterology, the Association of Coloproctology of Great Britain and Ireland and the United Kingdom Cancer Genetics Group published guidance on the categorisation of risk based on family history (Monahan et al., 2020). Their recommendations are summarised in Box 1.

Box 1.

Categories of patients with a family history of colorectal cancer.

• Average risk: No FHCC, or a FHCC that does not fulfil moderate or high-risk categories • Moderate risk FHCC: One FDR diagnosed with CRC under 50 years, or Two FDRs (in first degree kinship) diagnosed with CRC at any age, of whom the patient under assessment is an FDR of at least one affected individual • High risk FHCC: Families with a cluster of at least three affected FDRs with CRC diagnosed at any age, across at least two generations, of whom the patient under assessment is an FDR of at least one affected individual.12 (FHCC: family history of colorectal cancer; CRC: colorectal cancer; FDR: first degree relative)

Source: Monahan et al. (2020)

It is recommended that patients who fall into the moderate or high-risk categories should receive specialist referral. A risk assessment for the presence of an inherited cancer predisposition syndrome is then carried out, based on family history and the medical records of affected family members. If indicated, tissue testing of affected family members can be offered. It should be noted that there are different criteria for Lynch syndrome, described in more detail later.

Cancer genetics

Cancers arise as a result of abnormal cell division or because cells have escaped the normal mechanisms that promote cell death. In the majority of cases of cancer, these changes arise due to sporadic pathogenic genomic variation in somatic cells. This type of genomic variation arises in cells after conception and can affect any cell in the body other than gametes. It therefore cannot be inherited, but in some cases may have been made more likely by exposure to certain environmental factors. However, in some people who develop cancer, this is a consequence of inherited pathogenic genomic variation in the germline cells. This type of variation affects every cell in the body, including gametes, which is why it can be inherited.

Sometimes, those who have inherited a predisposition to develop cancer will be suffering from a defined inherited cancer predisposition syndrome. In others, there will be a family history highly suggestive of an inherited cancer predisposition syndrome, but the precise pathogenic variant causing the disease will not yet be apparent (Turnpenny and Ellard, 2017).

In the case of colorectal cancer, it is estimated that 35% of cases are caused by hereditary factors, with 5–10% of all colorectal cancer patients being found to have a defined inherited cancer predisposition syndrome (Monahan et al., 2020). The majority of colorectal cancers are thought to arise from benign adenomas. In individuals who develop cancer, the cells that make up the adenomas accumulate pathogenic variants in their genes, each of which increases the likelihood that the adenoma will become an invasive cancer. These pathogenic variants are much more likely in those who have inherited abnormalities in genes that repair errors in DNA (mismatch repair genes) or regulate cell signalling and apoptosis (tumour suppressor genes). When an individual inherits a gene with a pathogenic genomic variant from one parent, this means that they only have one functioning copy of the gene. If they then lose the normally functioning copy of the gene through a somatic event, for example gene deletion, this is referred to as loss of heterozygosity and predisposes them to the development of malignancy (Turnpenny and Ellard, 2017).

Inherited cancer predisposition syndromes associated with colorectal cancer: Polyposis syndromes

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is caused by an inherited pathogenic genomic variant in the adenomatous polyposis coli gene, which is a tumour suppressor gene on chromosome 5. The pathogenic variant causes loss of function, and this makes the development of adenomas and their progression to carcinomas more likely. FAP is inherited in an autosomal dominant fashion and affects approximately 1 in 8000 people. Affected individuals develop hundreds to thousands of polyps in the colon during their adolescence and almost all go on to develop colorectal cancer by the time they are in their forties. Patients also develop adenomas in the duodenum and stomach. Around 10% of duodenal adenomas develop into malignancy, but gastric cancer is rare (Health Education England, 2018).

MUTYH-associated polyposis

MUTYH-associated polyposis (MAP) is a similar condition to FAP, but is inherited in an autosomal recessive way. It is due to a pathogenic variant in the MutY DNA Glycosylase (MUTYH) gene which is a mismatch repair gene on chromosome 1 and is part of the oxidative DNA damage repair pathway. The condition affects approximately 1 in 30 000 people. The number of polyps is smaller than is seen in FAP, meaning that cancer tends to develop later in life than in those with FAP. However, the lifetime risk of developing colorectal cancer is still up to 90%. There is also a much smaller (2–5%) risk of small bowel malignancy, as well as an increased risk of breast, ovarian and endometrial cancers (Health Education England, 2018).

Juvenile polyposis syndrome

Juvenile polyposis syndrome (JPS) is caused by pathogenic variants in the BMPR1A (chromosome 10) or SMAD4 (chromosome 18) genes and is inherited in autosomal dominant fashion. It leads to gastric and colonic polyps that develop in childhood. It affects around 1 in 150 000 people. It is estimated that by age 60, the risk of affected individuals having developed colorectal cancer is 60%, and gastric cancer 20% (Health Education England, 2018).

Peutz–Jeghers syndrome

Peutz–Jeghers syndrome causes gastrointestinal polyps and mucocutaneous pigmentation. It is due to a pathogenic variant in the STK11 gene, which is found on chromosome 19 and regulates apoptosis pathways. Inheritance is autosomal dominant, and the condition affects approximately 1 in 50 000 people. The majority of patients have freckling of the lips and perioral area, as seen in Fig.1, although this may become less apparent in adulthood. Freckling can also be seen on the fingers, toes, anus and vulva. Around half of affected patients will have developed cancer by the age of 50, most commonly gastrointestinal, pancreatic, breast or ovarian (Health Education England, 2018).

Figure 1.

Freckling of the lips seen in Peutz–Jeghers syndrome.

Polymerase-proofreading-associated polyposis

Polymerase-proofreading-associated polyposis (PPAP) is the most recently identified inherited cancer predisposition syndrome associated with colorectal cancer. It is caused by pathogenic genomic variants in the genes POLE (chromosome 12) and POLD1 (chromosome 19), both of which are involved in DNA repair. It exhibits autosomal dominant inheritance. Affected individuals develop multiple large bowel adenomas and the risk of developing colorectal cancer is approximately 80% by age 70 in those with the POLE pathogenic genomic variant and 30% by age 70 in those with the POLD1 pathogenic genomic variant. There is also an association with breast, duodenal, ovarian and nervous system malignancies (Health Education England, 2018).

Inherited cancer predisposition syndromes associated with colorectal cancer: Lynch syndrome

Lynch syndrome (also known as hereditary non-polyposis colorectal cancer) is caused by pathogenic genomic variants in one of the mismatch repair genes, MLH1, MSH2, MSH6, PMS1, PMS 2 or TACSTD, which are found on chromosomes 2, 3 and 7. Inheritance is autosomal dominant. There is a risk of up to 68% of an affected individual developing colorectal cancer in their lifetime. Affected women also have a much-increased risk of developing ovarian cancer (up to 17% lifetime risk) and endometrial cancer (up to 49% lifetime risk). Amsterdam criteria (please see Box 2) are used to identify individuals who should be offered testing for Lynch syndrome based upon their family history (Health Education England, 2018; UK Cancer Genetics Group).

Box 2.

Amsterdam criteria for testing for Lynch syndrome.

All criteria should be met for testing to take place:

• Three or more relatives with an associated cancer (colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis)

• Two or more successive generations affected

• One or more relatives diagnosed before the age of 50 years

• One should be a first-degree relative of the other two

Source: NICE (2016)

Clinical case scenario 2

David is a 32-year-old man who books a telephone appointment to speak to you. He has just been diagnosed with Lynch syndrome after being offered genetic testing because his uncle was found to have the condition. He has had an initial discussion with the genetics clinic, but found it hard to take in all of the information. He has recently got married and he and his wife are planning to start a family. He is aware that he has not taken very good care of himself in recent years. He smokes 10 cigarettes a day and has a body mass index (BMI) of 32 kg/m².

He has agreed to enter a trial looking at optimal aspirin dosing in Lynch syndrome and is awaiting an appointment for his first screening colonoscopy.

Management of patients diagnosed with a genetic syndrome

Patients found to have a specific inherited cancer predisposition syndrome will require regular screening and, in some cases, will be offered risk-reducing surgery. The recommended screening and treatment protocols are outlined in Table 1. Patients with Lynch syndrome are advised to take aspirin daily to reduce their risk of developing colorectal cancer. However, the optimum dose has not yet been determined, so patients should be offered the opportunity to take part in research studies to try to determine the most effective dose. For those not participating in a trial, it is currently advised that they should be given 150 mg daily, unless their BMI is above 25 kg/m², in which case the dose should be 300 mg daily. There is currently insufficient evidence to suggest that aspirin is beneficial for those with polyposis syndromes.

Table 1.

Management of patients diagnosed with an inherited cancer predisposition syndrome.

Condition	Screening protocol	Risk-reducing treatment
Familial adenomatous polyposis	• Colonoscopy from age 12–14 years. Frequency is determined by the number of adenomas found • Upper gastrointestinal (GI) endoscopy from age 25 years. Frequency is determined on risk assessment (Spiegelman classification).	Risk-reducing bowel surgery, timing determined according to the following criteria: • Polyps >10 mm diameter • High-grade dysplasia in polyps • Significant increase in polyp burden between screening examinations
MUTYH-associated polyposis	• Colorectal surveillance starting between the ages of 18 and 20 years and continued annually • Upper GI surveillance from age 35 years. Frequency is determined by risk assessment (Spiegelman classification)	• Polyps are removed endoscopically • Bowel resection surgery may be required if endoscopic treatment is no longer possible
Juvenile polyposis syndrome	• Colonoscopies from age 15 years or earlier if symptomatic (e.g. with rectal bleeding or anaemia) • Screening interval of 1–3 years, depending upon the polyp burden. • Upper GI endoscopy from age 18 years for those with SMAD4 pathogenic genomic variant and 25 years for those with BMPR1A pathogenic genomic variant. Screening interval of 1–3 years, depending upon the polyp burden	• Gastrectomy and/or colectomy may be required where polyps cannot be managed endoscopically
Peutz–Jeghers syndrome	• Upper GI endoscopy, colonoscopy and video capsule endoscopy from age 8 years • Frequency of screening determined by initial findings • Women should undergo annual mammography between the ages of 30 and 60	• Polypectomy advised to prevent complications, such as intussusception
Polymerase proofreading associated polyposis	• Colorectal surveillance starting between the ages of 18 and 20 years with interval determined by the number of polyps found • Upper GI endoscopy from age 30	• Endoscopic removal of polyps • If endoscopic management is not possible then surgery to remove the colon, and occasionally the rectum, may be needed
Lynch syndrome	• 2-yearly colonoscopy, starting at either age 25 years or 35 years, depending upon the pathogenic genetic variant • Gastric, small bowel and pancreatic surveillance not recommended. However, screening for Helicobacter pylori is recommended, with eradication if it is detected. • Screening for endometrial and ovarian malignancies not recommended	• Daily aspirin is recommended • Segmental or total colectomy may be required where disease cannot be managed endoscopically • Total hysterectomy and bilateral salpingo-oopherectomy is offered to most affected women

Source: Monahan et al. (2020)

Management of patients with a moderate or high-risk family history

If no inherited cancer predisposition syndrome is diagnosed, further screening of the referred individual will be guided by the degree of risk suggested by the family history. It is recommended that those with a moderate familial colorectal cancer risk should have a one-off colonoscopy at age 55 years. If polyps are removed, further surveillance should be determined by post-polypectomy guidance. Those with a high familial colorectal cancer risk are advised to have a colonoscopy five yearly from the age of 40 years. All patients at increased risk of colorectal cancer should be advised not to smoke, to maintain a healthy BMI, to exercise regularly and to moderate their intake of red and processed meats.

KEY POINTS

It is important for primary care clinicians to have an understanding of the spectrum of inherited colorectal cancer predisposition syndromes so that we can identify those patients who may be affected and refer them for a specialist opinion

Those patients not meeting the criteria for referral need appropriate explanations and reassurance

GPs can manage patients’ expectations by explaining that even those with a moderate or high-risk family history will often not have a defined inherited cancer predisposition syndrome

GPs and patients need to understand the risk-reducing measures for affected patients

GPs can support affected patients in adhering to risk-reducing measures

Footnotes

ORCID iD

Lara Stewart

References

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Monahan

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NICE (2016) Diagnostics assessment programme: Molecular testing for Lynch syndrome in people with colorectal cancer Available at: www.nice.org.uk/guidance/dg27/documents/final-scope (accessed 21 October 2020).

Primary Care Dermatology Society. www.pcds.org.uk.

RCGP. Clinical topic guide: Gastroenterology. Available at: www.rcgp.org.uk/training-exams/training/gp-curriculum-overview/document-version.aspx (accessed 03 November 2020).

RCGP. Clinical topic guide: Genomic medicine. Available at: www.rcgp.org.uk/training-exams/training/gp-curriculum-overview.aspx (accessed 03 November 2020).

Turnpenny

Ellard

(2017) Emery’s Elements of Medical Genetics, China: Elsevier.

UK Cancer Genetics Group. Lynch Syndrome Gene Specific Guidelines. Documents & websites. Available at: www.ukcgg.org/information-education/documents-websites/#LynchSyndromeGeneSpecificGuidelines (accessed 26 February 2021).