Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management

Abstract

Double heterozygosity for disease-causing BRCA1 and BRCA2 mutations is a very rare condition in most populations. Here we describe genetic and clinical data of eight female double heterozygotes (DH) for BRCA1 and BRCA2 mutations found in a cohort of 8162 German breast/ovarian cancer families and compare it with the data of their single heterozygous relatives and of the index patients of the German Consortium for Hereditary Breast and Ovarian Cancer. Furthermore, we analyze the phenotypic features of these patients with respect to age at onset of first cancer, first breast/ovarian cancer and the number of disease manifestations and compare them to that of published Caucasian female DHs and their single heterozygous female relatives. German DHs were not significantly younger at diagnosis of first breast cancer than the single heterozygous index patients of the German Consortium. However, if the data of our study were pooled with that of the literature, DHs were substantially younger at onset of first cancer (mean age 40.4 years, 95 % CI = 36.6-44.1) than their single heterozygous female relatives (mean age 51.9 years, 95 % CI = 46.8-57.0). The two groups also differed concerning the onset of first breast cancer (mean age 40.6 years, 95 % CI = 36.6-44.5 vs. 52.6, 95 % CI = 47.5-57.6). In addition, DHs had a more severe disease than their female relatives carrying a single BRCA mutation (1.4 vs. 0.6 manifestations per person). In contrast to Ashkenazi Jewish females, Caucasian DH females might develop breast cancer at an earlier age and have a more severe disease than single heterozygous BRCA mutation carriers. Therefore, DHs may benefit from more intensive surveillance programs/follow-up care and prophylactic surgery.

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

“…Previously, 35 female TH individuals have been reported in the literature in a series of papers [1, 11, 14, 20, 21, 27, 28, 35, 36]. Only three relatively small studies have so far compared the characteristics of TH to SH women.…”

“…The mean age at diagnosis in TH was 44.6 years, compared with 48.1 in SH. In contrast, Heidemann et al [14] based on a study of 8 TH individuals suggested that TH develop BC at an earlier age and have more severe disease than those with single heterozygous BRCA mutation [14]. Zuradelli et al [39] reported TH, and provided the possible association between TH and gastric cancer.…”

“…A large clinic-based series of 1191 carriers from Israel [20] identified 16 TH females, 14 with the c.68_69delAG BRCA1 and c.5946delT BRCA2 mutations and two with the c.5266dupC BRCA1 and c.5946delT BRCA2 mutations. A study from Germany identified eight female TH from 8162 BC/OC families and compared the clinical characteristics of the TH to their SH relatives and to SH in the family-based study [14]. …”

DNA repair systems

“…As carriership of muta ons in BRCA genes is not uncommon, a small propor on of individuals at high risk may carry defects in both their BRCA1 and in BRCA2 genes. The associated risk is similar to the risk in carriers of a defec ve copy of either BRCA1 or BRCA2, albeit the first tumour/s may appear earlier and/or appear in more than one loca on in double heterozygotes [506,507]. For a double heterozygote, the risk of transmission of at least one defec ve allele to their children is higher, about 75% (compared to the 50% risk of transmission in carriers of muta on in one of the two genes).…”

Ovarian Cancer: BRCA Genetics Reveals Targets for New Therapies

“…Cancer development depends upon a second BRCA mutation in somatic cells and BRCA loss of function. As typical of autosomal dominant inheritance, one mutation segregates in each family, but rare examples of carriers with simultaneous mutation in BRCA1 and BRCA2 or two BRCA2 mutations have been also described [20].…”