Family Risk

Malcolm Dunlop, Academic Coloproctology, Western General Hospital, Edinburgh EH4 2XU

Powerpoint File

Twin studies indicate that 35% of colorectal cancer incidence is attributable to genetic susceptibility. Dominant heritable disorders for which the causative genes have been identified include HNPCC, FAP, Juvenile Polyposis and Peutz-Jeghers Syndrome, collectively accounting for <3% of colorectal cancer cases. Members of such families with single gene defects have a high personal cancer risk. However, there is growing evidence that low risk dominant gene variants and recessive traits have a small effect on individual risk but make a major contribution to overall cancer incidence due to high population prevalence of such variants.

Despite the evidence that genes of minor effect collectively have a major impact on disease incidence, currently it is only clinically possible to use empiric family history criteria to guide the need for surveillance. Family history is that acting as a surrogate for molecular genetic profiling of risk based on a global understanding of aggregate risk. The use of family history criteria is a useful and pragmatic approach to identifying those at risk. However, it does have some inherent problems because although relative risk can be quite high for certain categories of FH, the absolute risk is low. Indeed, increasing age is a far better predictor of the likelihood of developing cancer than family history as a risk parameter. The evidence base that family history is of value in predicting cancer risk will be reviewed in the context of absolute risk and the risk:benefit ratio and competing causes of death.

In addition to shortcomings in the use of family history in principle to guide the need for surveillance on the basis of estimated risk of colorectal cancer, there also is considerable potential for recall bias and inaccuracy of family history. We recently systematically assessed accuracy of family history reported at interview compared to actual cancer experience in relatives using data from face-to-face interviews of 199 colorectal cancer cases and 133 community controls, totalling 5637 first and second degree relatives (FDRs/SDRs). We linked computerised Cancer Registry data to interview information to determine accuracy of family history reporting. Patients with colorectal cancer substantially under-reported colorectal cancer arising both in first degree relatives (Sensitivity 0.566, 95% CI = 0.433,0.690) and in second degree relatives (Sensitivity 0.271, 95% CI = 0.166, 0.410). There was no observable difference in accuracy of reporting family history between case and control interviewees. Control subjects similarly under-reported colorectal cancer in first degree and second degree relatives (Sensitivity 0.529, Sensitivity 0.333 respectively). To determine practical implications of inaccurate family history, we applied family history criteria before and after record linkage. Only 2 of 5 families reported at interview to meet surveillance criteria did so after validation, whereas only 2 of 6 families that actually merited surveillance were identified by interview. Hence it is clear that there is considerable inaccuracy of interview in identifying people at risk of colorectal cancer due to a family history. The fact that colorectal cancer is substantially under-reported is of particular concern because it is not usual practice to confirm a negative family history. These findings have considerable relevance to identifying people who merit surveillance colonoscopy and to epidemiological studies.

There is a paucity of prospective data on the potential benefit of colonoscopic surveillance in groups categorised by empiric family history criteria who are not from families segregating dominant genes. We prospectively studied 448 individuals seeking counselling about their perceived family history of colorectal cancer. Following pedigree tracing, verification and risk assignment by genetic counsellors, colonoscopy was undertaken for those at a moderate or high risk (HNPCC). Those classified as low risk were reassured and discharged without surveillance. Here we report our findings at the prevalence screen in the 176 patients who underwent colonoscopy of the 448 assessed. Fifty-three individuals had a family history that met Amsterdam criteria (median age 43 years) and 123 individuals were classed as moderate risk (median age 43 years). No cancers were detected at colonoscopy in any group. Four individuals (8%; 95% c.l. 0.4%-15%) in the high risk group had an adenoma detected at a median age of 46 years and all four were under the age of 50 years. Five (4%; 95% c.l. 0.6%- 8%) of the moderate risk individuals had an adenoma at a median age of 54 years, two of whom were under 50. These findings indicate that the prevalence of significant neoplasia in groups defined by family history is low, particularly in younger age groups. This prospective data calls into question the value of colonoscopy before the age of 50 years in moderate risk individuals.

The practical implications of using family history as a population method to identify those at risk will be discussed in light of our population data on the prevalence of a family history of large bowel malignancy.

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