Guideline 67: Management of colorectal cancer

Management of colorectal cancer
Section 4: Genetics

In this section consideration is given to asymptomatic individuals with a family history of colorectal cancer and the problems of both hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP).

4.1 Family history of colorectal cancer

A family history of colorectal cancer is common.⁶¹ The Scottish Cancer Group’s Sub-Group on Cancer Genetics has defined three levels of risk; low, moderate and high.⁶² The criteria for each level are given in Table 1. The guidelines for management of individuals in the moderate risk category recommend the offer of a one-off colonoscopy around the age of 35 with a further colonoscopy at 55. Individuals at moderate risk undergoing colonoscopic screening should be included in the audit of the Scottish Executive cancer genetics guidelines. Evidence level 4

Table 1:The Scottish Cancer Group criteria for screening individuals at risk of colorectal cancer (CRC)

Risk level	Criteria for screening	Screening	Age of screening
High	at least three family members affected by CRC or at least two with CRC and one with endometrial cancer in at least two generations; one affected relative must be age =< 50 years at diagnosis; one of the relatives must be a first degree relative of the other two gene carriers (HNPCC genes) untested primary relatives of gene carriers	colonoscopy every 2 years discuss gynaecological screening for endometrial and ovarian cancer offer 2-yearly upper gastrointestinal endoscopy for gastric cancer consider screening for other cancers which may occur in specific families and are part of theHNPCC spectrum	from 30 to 70 years (or 5 years younger than the youngest affected relative) for stomach cancer from 50 to 70 years or 5 years younger than the youngest stomach cancer
Moderate	one first degree relative affected by colorectal cancer when aged <45 years; or two affected first degree relatives (one less than 55 years); or two (one CRC less than 55 years) or three affected individuals with colorectal or endometrial cancer who are first degree relatives of each other and one a first degree relative of consultand	single colonoscopy single repeat colonoscopy if first colonoscopy normal	at 30 - 35 years and again at 55 years
Low	anyone not fulfilling medium or high risk criteria	reassure and encourage healthy lifestyle	Not required

Individuals with two or more first degree relatives with colorectal cancer, one of whom is aged under 55 or one relative with colorectal cancer under the age of 45, have a moderate increase in their risk of developing colon cancer. Their risk is greater than five times the risk to an individual of the same age in the general population without a family history.^{61,
63} No data on absolute risk of development of bowel cancer have been published, although a simple estimate can be made by multiplying age-specific risk by five. Evidence level 2++

As genetically determined tumours are frequently located on the right side of the colon, colonoscopy is a more appropriate investigation than flexible sigmoidoscopy.⁶⁴ There is general consensus that the risk of a 40 year old with a family history developing colorectal cancer is equivalent to the risk of a 50 year old with no family history.^{35,
61, 63} Colonic adenoma rates at colonoscopy in first degree relatives of colorectal cancer patients are 2.1% for the age group 30-39 and 8.3% for the age group 40-49 compared with 0% in age matched controls.⁶⁵ Evidence level 2+,4

Reviews of published reports on the outcome of screening of at-risk relatives show the pick up rate of carcinomas under the age of 50 is low with none of the studies reviewed identifying a cancer in a relative under 40 years.^{66,
67} Evidence level 2++,2+

A three generation family history should be taken from all individuals with colorectal cancer.

Individuals at moderate risk of developing colorectal cancer on the basis of their family history should be offered a single colonoscopy at 30-35 years and again at 55 years.

Referral to Clinical Genetics for risk estimation should be considered prior to enrollment of an asymptomatic individual in a colonoscopic screening programme.

4.2 Individuals with a high risk family history of colorectal cancer (including HNPCC)

HNPCC is an autosomal dominant condition caused by a mismatch repair gene mutation.

Diagnosis requires:

at least three relatives with a HNPCC-associated cancer (colorectal, endometrial, small bowel, ureter or renal pelvis) one of whom should be a first degree relative of the other two
at least two consecutive generations should be affected
at least one individual should be diagnosed before age 50.⁶⁸

DNA mismatch repair gene mutations also predispose patients to extracolonic tumours, predominantly endometrial but also ovarian, genitourinary, small bowel and biliary tract. Broadening of the criteria for HNPCC to include extracolonic tumours increases the proportion of families with mismatch repair mutations identified,^{69,
70} but with reduction in positive predictive value in some cases.^{71,
72, 73} Evidence level 2+,3

There are considerable clinical benefits in identifying families in whom a mismatch repair gene defect is present. Individuals carrying the mutation can be targeted for regular endoscopic screening whilst those demonstrated not to carry the mutation can be spared invasive investigations. The majority of tumours associated with mismatch repair gene mutations exhibit microsatellite instability (MSI) whilst only about 15% of unselected tumours have this property.⁷⁴ The testing of all colorectal tumours for MSI as a prescreen for subsequent mutation analysis has been proposed.⁷⁵ However, the technique is not routinely available and would require considerable resource to establish. A more cost-effective approach would be to test a clinically defined subset of tumours, and this is currently under assessment in Scotland.

When a mismatch repair gene mutation has been identified, the risk of the carrier developing colorectal cancer by the age of 70 is over 70% for men and 40% for women. A significant proportion of these patients will have developed their cancer before the age of 35 years.^{76,
77} Female mismatch repair mutation carriers have a risk of gynaecological malignancy equivalent to their risk of colorectal cancer.^{76,
77} As presymptomatic screening for ovarian and endometrial cancer is of unproven benefit, prophylactic surgery should be discussed as an option for female mutation carriers who have completed their families. Evidence level 2+

First degree relatives of individuals in whom a mismatch repair gene mutation has been identified should be offered presymptomatic testing through a local clinical genetic service.

Referral of individuals with a high risk of developing colorectal cancer should be made to the local clinical genetic service for consideration of mismatch repair gene mutation analysis.

Individuals carrying a mismatch repair gene mutation or fulfilling high risk criteria for HNPCC should be offered endoscopic screening starting in the twenties if possible and repeated every two to three years, taking into account the patient’s general condition and uptake.

4.3 Familial adenomatous polyposis (FAP)

FAP is an autosomal dominant condition caused by an APC gene mutation and characterised by the development of multiple adenomatous colorectal polyps and the subsequent development of one or more colorectal cancers.⁷⁸ Where a diagnosis of FAP has been made on clinical criteria, contact should be made with the regional genetic service to discuss the possibility of searches being initiated for the APC mutation in members of the families at risk. When an individual has been identified as being at risk of FAP, regular endoscopic screening should be offered, and when adenomas have developed, surgical treatment is recommended.

The main therapeutic options in FAP are proctocolectomy with ileostomy or ileoanal pouch reconstruction and colectomy with ileorectal anastomosis.^{76,
79} The former procedures are associated with greater operative morbidity and less satisfactory functional results. The latter requires regular sigmoidoscopic surveillance of the rectum postoperatively because of the risk of developing cancer in the retained rectum. It must also be remembered that FAP patients are at risk of developing duodenal adenomas and cancer. Evidence level 2+,4

Patients with clinically diagnosed FAP should be referred to the local clinical genetic service for APC gene mutation analysis.

Individuals at risk of FAP, determined either by a positive family history or on the basis of mutation analysis, should be offered colonoscopy every two to three years and yearly sigmoidoscopy.

Patients with FAP should be offered proctocolectomy with or without ileoanal reconstruction or total colectomy with ileorectal anastomosis once adenomas have developed.
Subsequent management should include lifelong surveillance of the residual rectum where appropriate and regular upper gastrointestinal endoscopy to detect duodenal adenomas or malignancy.