Six large kindreds were selected from the Utah Population Database for this study based on having a statistical excess of colorectal cancer as compared to the database as a whole. These families represent the more extreme subset of the CRC population with both high-risk CRC and familial clustering. Importantly, rigorous exclusion of the known hereditary CRC syndromes was performed. The use of a large population database with ascertainment of family history and cancers was a key advantage of this study since inaccuracy of family history data obtained from extended family members is well known 13
. The large Utah Population Database families made statistical evaluation of excess cancers relative to the general Utah population possible. This study purposely evaluated large families with high-risk colorectal cancers. This enabled not only analysis of adenoma risk in first-degree relatives of the colorectal cancers, but also permitted the comparison to second- and third-degrees of relationship. The resulting analysis represents a well characterized population with increased genetic homogeneity, rather than many small nuclear families with one or more colorectal cancer cases.
The colonoscopies revealed important risk factors for adenomatous polyps in relatives of colorectal cancer cases. As expected, there was a significant effect of age on the incidence of colonic adenomas. However, even after correction for the age of the relatives, male gender and closer degree of relation to a colorectal cancer case were independently and significantly associated with an increased incidence of simple and advanced adenomatous polyps. However, no such associations were observed for hyperplastic polyps throughout the colon.
Previous studies have shown that the relative risk of colorectal cancers is significantly related to the number and age of first-degree relatives of colorectal cancer cases 26
. However, accurate assessment of the effects of degree of relation to colorectal cancer cases on the risk for simple and advanced adenomatous polyps has been lacking. Our finding that the degree of relation to colorectal cancer cases is significantly associated with the risk for simple and advanced colorectal adenomas brings justification to the more rigorous colon cancer screening recommendations for those with a strong family history of colorectal cancer. The similar incidence of adenomas in the right or left colon in first-degree relatives of colorectal cancer cases supports whole colon screening in those with a stronger family history as well.
The large difference between the occurrence of adenomas in men and women was striking. The women in the study had 2.4-fold fewer adenomas than men, yet had a similar incidence of colorectal cancer as men. This effect of gender was not due to age or degree of relation, as these were accounted for in the analyses, nor were they due to differences in colonoscopy completion rates. These results suggest that while adenoma initiation events may be less common in women, adenoma-carcinoma progression is strongly influenced by female gender. Previous studies have shown a protective effect of estrogens in colonic tumorigenesis 27
and it is possible that adenoma-carcinoma progression is accelerated in post-menopausal women who are not on estrogen replacement. We were unable to retrospectively analyze this factor in our data set. However, this observation is supported by a study of polyps in the colons of 445 consecutive autopsies 28
whereby adenomas were fewer in women than men, but showed more atypia, villous histology, and larger size in women. Additionally, in a retrospective study of 12,960 individuals who underwent flexible sigmoidoscopy screening, distal colonic adenomas were 1.6-fold less common in women than men 29
. Thus, several studies, including ours, suggest that adenomas are less common in women than men, but that adenoma-carcinoma progression is more likely in women than men.
Other studies have suggested that adenoma-carcinoma progression, rather than adenoma initiation is influenced strongly by degree of relation to colorectal cancer cases. Pariente et al. found that adenomas occurred with similar frequency in first-degree relatives of colorectal cancer cases and matched controls with no family history of colorectal cancer 30
. However, advanced adenomas (≥ 10mm in diameter and/or villous histology) were significantly (odds ratio = 2.5, p < 0.01) more frequent in the first-degree relatives than the sex- and age- matched controls. Lindgren et al. found that non-Lynch Syndrome colorectal cancer family members demonstrated significantly higher colorectal cancer risk on a per adenoma basis than controls 25
. Almendigen et al. found that a family history of colorectal cancer was associated with an adjusted odds ratio = 3.9 (95% C.I. = 1.2-13.4) for net adenoma growth but not baseline adenoma occurrence compared with sex- and age- matched controls 31
. Our results showed a significant relationship between the degree of relation to colorectal cancer cases and the incidence of simple adenomas. Furthermore, the incidence of advanced adenomas was significantly associated with degree of relation to colorectal cancer cases in our study as well. These results suggest that both initiation of adenomas and progression to advanced adenomas are related to the degree of relation to colorectal cancer cases.
The current recommendation to initiate earlier colorectal cancer screening in individuals with a strong family history of colorectal cancer arose largely from the observation that the average age of onset of colorectal cancer is significantly earlier in the hereditary colorectal cancer syndromes than for sporadic cases. The assumption was that a hereditary predisposition to colorectal cancer would shorten the length of time to develop colorectal neoplasms. In our study, the average age of diagnosis of colorectal cancer was 63 years (versus 70 years for the general population) and the average age of advanced adenomas was 56 years.
Since up to one-third of one's risk for colorectal cancer can be attributed to heredity 25
, it is important to seek out a family history of colorectal cancer. Although most regions in our country do not have the large families represented here, it is still imperative that a careful family history of colorectal cancer be obtained for first- and second-degree relatives in order to risk stratify individuals for screening. It is also important that close relatives of patients affected with colorectal cancer receive counseling for colorectal cancer screening.
In conclusion, the significant association between simple and advanced adenomatous polyps and the degree of relation to colorectal cancer cases provides important support of the current recommendations for earlier and colonoscopic colorectal cancer screening for those with a strong family history of colorectal cancer. The lack of differences in the distribution of colonic adenomatous polyps between the right and left colon in first-degree relatives of colorectal cancer cases supports the current recommendations for using colonoscopy to screen those with a strong family history of colorectal cancer. The average age of detection of advanced adenomas in the 6th decade of life in close relatives of colorectal cancers supports current recommendations for the initiation of colon screening in individuals with a strong family history of colorectal cancer before the age of 50 years. Our study provides long-needed evidence in support of the current guidelines issued by the American Cancer Society, U.S. Preventive Services Task Force, American College of Gastroenterology, and American Gastroenterological Association for earlier and more rigorous colorectal cancer screening for those with a strong family history of colorectal cancer (cancer or polyps in a first-degree relative (parent, sibling, or child) younger than 60 or in 2 first-degree relatives of any age).
- 1) What is current knowledge
- Colon cancer risk is increased in individuals with a strong family history.
- The effect of family history of colorectal cancer on adenoma risk is not well known.
- 2) What is new here
- Family history, specifically the degree of relation to colorectal cancer, increases adenoma risk.
- Adenoma-carcinoma progression appears stronger in women than men with a strong family history of colorectal cancer.
- Undefined genetic and environmental factors are responsible for common familial colorectal cancer; known colon cancer genes are not involved.