On the genetics of hereditary breast/ovarian cancer. BRCA1, BRCA2 and beyond

Abstract: Breast cancer is the most common malignancy in women. Most of the breast cancers are sporadic with no apparent inheritance factor but about 5-10% is believed to be caused by an inherited predisposition. Aims: This thesis aimed at defining the BRCA1/2 mutation spectrum of the west Swedish population and specifically to characterize the BRCA1c.3171ins5 mutation. We also wanted to evaluate and improve the mutation detection process and identify clinical characteristics associated with a germline BRCA1/2 mutation. Finally, we aimed at identifying novel breast cancer susceptibility genes. Results: Genotyping of markers flanking BRCA1 revealed a common haplotype of BRCA1c.3171ins5 carriers in 18 unrelated families. The haplotype was not found in a control material. Age estimations using founder allele fractions implied that the mutation originated in a founder individual 51 generations ago (95% CI, 31-71). The estimated penetrance of breast/ovarian cancer in BRCA1c.3171ins5 families was between 59-93% at age 70. The 5 years survival probability for women with BRCA1c.3171ins5-associated breast/ovarian cancer was 72% and 38% for breast and ovarian cancer, respectively. Evaluation of mutation analyses in paraffin-embedded tissue vs. blood provided completely congruent results. Mutation analyses of BRCA1 and BRCA2 in families with a high incidence of breast/ovarian cancer confirmed that BRCA1c.3171ins5 dominates the mutation spectrum and represents 65% (34/52) of all mutations detected. The detection rate of BRCA1/2 mutations was 39% (46/117) in high risk families, a high rate compared to many other populations. Ovarian cancer in the family greatly increases the detection rate (68%, 42/62). A genome-wide linkage scan in non-BRCA1/2 families yielded LOD scores of suggestive linkage on chromosome 10q23.32-q25.3 (HLOD 2.34). Markers on chromosome 12q and 19p produced HLOD ¡Ý 2.1. Affected members in one large family shared common haplotypes on 10q, 17p and 19q. TP53 and TGFBR2 were screened for mutations but no alterations were found. Conclusions: BRCA1c.3171ins5 is a true founder mutation originating in one single ancestor roughly 50 generations ago. The risk of developing breast/ovarian cancer by inheritance of BRCA1c.3171ins5 is similar to the risk conferred by BRCA1 mutations in general and the survival probability in affected carriers is comparable to that of age-matched breast cancer controls. Total agreement between paraffin-embedded tissue (PET) and blood analyses allows for using PET as the DNA source in clinical analyses. Complementary detection techniques are recommended in BRCA1/2 screening. Ovarian cancer provided the strongest indication for an inherited BRCA1 or BRCA2 mutation. Genes located in 10q, 12q, 17p, 19p and 19q may predispose to breast cancer but further investigation is required.