FaCD Online Syndrome Fact Sheet

Last updated: 15 Aug 2008

Name: Colorectal Cancer, Familial Clustering of

Mode of Inheritance: multifact

Tumor features

cervical cancer
colorectal cancer
endometrial cancer
ovarian cancer (i.e. epithelial origin)

Comment

In 15-25 % of cases patients with colorectal cancer (CRC) have one or more affected relatives[1;2]. There is a large body of evidence to show that the risk of developing CRC is influenced by the number and degree of affected relatives, the age at which their tumors were diagnosed, and tumor site [1-17]. In general the association is stronger at younger ages of colorectal cancer onset and proximal colon cancer in the family. In addition, risk of CRC appears to be increased by the presence of colorectal adenomas in relatives and vice versa[18-22]. Differences in risk between sexes and type of first degree relatives (sibs versus parents) have been observed.

Two recent meta-analyses have looked at the impact of family history on CRC risk[40,41]. Relative risks (RR's) for CRC in individuals having 1 first degree relative with CRC found are generally estimated between 2 and 3. RR's associated with having 1 first degree relative with CRC diagnosed before the age of 50 are approximately 3, but are dependent of the age of the asymptomatic relative, for example RR is approximately 5 if the at risk relative is <40 and less than 2 if he/she is>70[40]. Additional affected relatives are associated with a further increase in relative risk: for first-degree relatives of 2 or more CRC patients diagnosed between 50 and 70 years RR is approximately 4, and RR is 6 if one of the patients would have been diagnosed <50 years.
In terms of absolute risks, depending on the number and degree of affected relatives, cumulative life-time risks of 6 % ( one 1st degree relative), 8 % (one 1st + one 2nd degree relative), 10 % (one 1st degree relative, diagnosed < 45 yr), 17 % (two 1st degree relatives) have been estimated[1;23].

First degree relatives of patients with leukemia or cancer of the breast, cervix, ovary, endometrium or prostate in the Utah Population Database were also shown to have an increased risk of colorectal cancer[7;24]. Colon cancer has also been shown to be associated with a family history of stomach, bone and kidney cancer, while rectal cancer was associated with the occurrence of lymphomas in relatives [17].

Patients with a past history of cancer of the uterine cervix, uterine corpus or ovaries have moderately elevated risks for cancer of the colon[25] and a subset of the patients with endometrial or ovarian cancer may actually have Lynch syndrome. The occurrence in a proband of double primary cancers of the endometrium and colorectum strongly increases the risk in first-degree relatives to develop endometrial cancer under age 55 (RR 7-28) or at any age (RR 3-10), colorectal cancer under age 55 (11-22) or at any age (RR 3-6) and pancreatic cancer under age 55 (RR 3-29) or at any age (RR 1-6) as calculated by Pal et al.[26]. Germline mutations in DNA mismatch repair genes may underlie the occurrence of primary tumors of both colorectum and endometrium (18 % in a series reported by Millar et al.[27]). Recently Fernandez et al.[28] calculated that dietary risk factors for subjects with a family history of colorectal cancer in first-degree relatives were not appreciably different from recognized other risk factors of the disease in the general population. However, Vecchia et al.[29] concluded from their own study that low physical activity, high energy and low vegetable intake were associated with increased colorectal cancer risk in subjects without a positive family history, but not in those with such a history. An opposite conclusion was reached by Marchand et al.[30], who observed that life-style risk factors had a stronger impact on colorectal cancer risk in men with a positive family history (combined relative risk 11.7) than in those without such a history (combined relative risk 4.8). Hormones may modify large bowel cancer risk; a study by Newcomb et al.[31] showed no indication that the effect of family history on colorectal cancer risk in women is modified by levels of endogenous or exogenous sex hormones.

A long list of genes have been associated with mildly increased colorectal cancer risk[40]. Rare germline EPHB2 variants may contribute to a small fraction of hereditary colorectal cancer[42].

References