Modifiers Of Penetrance And Breast Cancer Genes Other Than Brca

Several studies have noted an increased penetrance for BRCA1/2 in more recent birth cohorts. The NYBCS (9) confirmed Narod's earlier observation of a significant increase in breast cancer risk by the age of 50 years in birth cohorts after 1940 (67% after 1940, 24% before 1940) (39). Ovarian cancer risk did not differ by birth cohort. This increase in incidence for BRCA1/2 mutation carriers parallels an increase in breast cancer in the general U.S. population over that period (37). Antoniou et al. (61) analyzed the results of 22 studies in which cases were unselected for family history. The RR for breast cancer among BRCA1/2 mutation carriers in the post-1960 birth cohorts was two to three times the RR in the preceding four decades. A study of Austrian BRCA1 mutation-positive women found that those from birth cohorts after 1958 had a significantly higher incidence of breast cancer by 40 years of age than those from earlier birth cohorts: 46% versus 27%, respectively (89). Finally, Tryggvadottir et al. (90) quantified the increase in breast cancer risk in the Icelandic population between 1921 and 2002. During this period in Iceland, the overall cumulative incidence of breast cancer by the age of 70 years increased from 2.3% to 7.4%. Among carriers of a common Icelandic BRCA2 mutation, the increase over the same period was from 17.9% to 65.5%, roughly the equivalent multiple.

Environmental factors and reproductive lifestyle changes have certainly contributed to the gradual, long-term increase in cumulative incidence of breast cancer, but more recent age-related changes in diagnostic screening have led to more abrupt increases in detection of breast cancer. For example, after the implementation of a nationwide breast-screening program in the United Kingdom, breast cancer incidence between 50 to 64 years of age increased by ~25% in the half decade from 1987 to 1992 (78).

Disaggregating the relative effects of screening and etiologic events is a daunting endeavor. Because the baseline incidence of breast cancer is higher for mutation carriers, small changes in either of these factors may have large multiplier effects on penetrance estimates for mutation carriers. This may account for some of the variance in penetrance estimates seen in both population-based and case-based studies. Figure 2, showing the penetrance estimates for BRCA1/2 mutation carriers, illustrates just how widely varied these estimates are. For example, some studies have estimated a higher cumulative risk for BRCA2 mutation carriers compared to BRCA1 mutation carriers (59,91), while others have estimated the opposite (61). In addition to the sources of analytic and ascertainment biases mentioned earlier in this chapter, the differences in penetrance found in the specific populations in these studies may have resulted from population-specific mutations.

The incidence of breast cancer varies significantly by geographical location. Although these differences may be diminishing over time, those who live in developed countries currently have up to five times the RR of those who live in developing nations (92,93). Neither susceptibility genes, such as BRCA1/2, nor familial clustering can account for this degree of geographical variability. Furthermore, studies of migrants who have moved from low- to high-incidence areas have shown that within one decade, their breast cancer rates approached the local rates, and within one to two generations, their offspring adopted local breast cancer incidence rates (94-96). Thus, it is clear that one's environment, and sociocultural influences, are significant contributors to overall breast cancer incidence along with genetic variation.

The combined frequency of BRCA1/2 mutations is relatively low in most populations, from 0.1% to 0.4 % (91,97). Do other known heritable causes account for the residual risk of familial breast cancer? To date, as covered in other chapters of this volume, major genes associated with breast cancer susceptibility include MSH2/MLH1 (Muir-Torre syndrome), TP53 (Li-Fraumeni syndrome), PTEN (Cowden syndrome), STK11 (Peutz-Jeghers syndrome), and the low-penetrance mutations of CHEK2. However, these gene mutations are all relatively rare and cannot explain the residual risk of familial breast cancer beyond that attributable to BRCA1/2. Despite intensive investigation, other major breast cancer genes are yet to be identified, and it is believed that a number of low-penetrance genes with high population frequencies represent the majority of the residual familial risk (98). Whether these other putative genes modify the effects of BRCA1 2 or represent independent etiologies is a matter of ongoing research (Chapter 8). However, their impact on penetrance is relevant to this discussion. As established earlier in this discussion, when penetrance estimates for BRCA1/2 are derived from case probands, particularly if those probands are members of high-risk families, all breast and ovarian cancer risk factors, including putative genetic modifiers, will likely be over-represented in these individuals. Penetrance estimates based on the assumption that the susceptibility gene under investigation, e.g., BRCA1, is the sole cause of the disease may incur significant error, and the bias in these estimates is a direct function of all other risk factors present in mutation carriers (1).

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