Cancer as a complex phenotype: pattern of cancer distribution within and beyond the nuclear family

Abstract

Background: The contribution of low-penetrant susceptibility variants to cancer is not clear. With the aim of searching for genetic factors that contribute to cancer at one or more sites in the body, we have analyzed familial aggregation of cancer in extended families based on all cancer cases diagnosed in Iceland over almost half a century.

Methods and findings: We have estimated risk ratios (RRs) of cancer for first- and up to fifth-degree relatives both within and between all types of cancers diagnosed in Iceland from 1955 to 2002 by linking patient information from the Icelandic Cancer Registry to an extensive genealogical database, containing all living Icelanders and most of their ancestors since the settlement of Iceland. We evaluated the significance of the familial clustering for each relationship separately, all relationships combined (first- to fifth-degree relatives) and for close (first- and second-degree) and distant (third- to fifth-degree) relatives. Most cancer sites demonstrate a significantly increased RR for the same cancer, beyond the nuclear family. Significantly increased familial clustering between different cancer sites is also documented in both close and distant relatives. Some of these associations have been suggested previously but others not.

Conclusion: We conclude that genetic factors are involved in the etiology of many cancers and that these factors are in some cases shared by different cancer sites. However, a significantly increased RR conferred upon mates of patients with cancer at some sites indicates that shared environment or nonrandom mating for certain risk factors also play a role in the familial clustering of cancer. Our results indicate that cancer is a complex, often non-site-specific disease for which increased risk extends beyond the nuclear family.

Figure 1. A Schematic Representation of Cancer Pairs Demonstrating Significant Familial Aggregation

Cancer pairs that demonstrate significant familial co-clustering (first- to fifth-degree relatives) at the 0.05 level after adjustment for multiple testing (nominal p value < 1 × 10^-4) are joined by lines. The thickness of the lines joining the pairs are based on nominal p values corresponding to the significance of the familiality in distant relatives (third to fifth degree): bold, p ≤ 0.001; solid, p ≤ 0.01; and dashed, p ≤ 0.05. The number on the lines joining each pair indicates the cross-cancer RR in first-degree relatives. Shaded ovals correspond to individual cancer sites that were significant for the combined group of first- to fifth-degree relatives at the 0.05 level after Bonferroni adjustment (see Table 1).