Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus

Abstract

A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, ‫؍‬ 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations. Breast Cancer Linkage Consortium data on 237 breastovarian cancer families showed that 52% were linked to BRCA1 and 32% to BRCA2 (1). Recent reports indicate that the proportion of breast cancer families attributable to the BRCA1 and BRCA2 genes may be smaller than initially thought, especially in studies that have been based on population-based family materials. For instance, in Finnish breast cancer families with three or more affected cases, mutations of the BRCA1 gene were seen in only 10% and those of BRCA2 in only 11% of the families (2). In southern Sweden, the corresponding percentages were 23% and 11% (3). These studies suggest that in the Nordic populations, a significant proportion of familial breast cancer is not explained by the two known major susceptibility genes. Therefore, identification of additional breast cancer susceptibility genes is an important goal.According to the two-hit model of cancer development (4), hereditary cancers arise as a result of a germ-line mutation in a recessive tumor suppressor gene, followed by the somatic deletion of the wild-type allele of the gene. Somatic deletions detected from tumor tissues of patients with a genetic predisposition therefore may pinpoint those loci that harbor recessive germ-line mutations. Such somatic deletions detected by comparative genomic hybridization (CGH) recently were used to assign the locus for the Peutz-Jeghers' cancer syndrome, an intesti...

A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

“…This is in agreement with our results from 12/13 (92%) 10/13 (77%) 12/13 (92%) Number of families with the probability >10% 67/148 (45%) 42/148 (28%) 63/148 (43%) Mean probability for BRCA 1/2-carriers 53% 41% 55% Mean probability for BRCA 1-carriers 50% 41% 59% Mean probability for BRCA 2-carriers 55% 40% 50% Mean probability for non-BRCA 1/2-carriers 12% 7% 11% 1035 unselected breast cancer patients, where all 15 cases with heavy breast cancer family history were also mutation negative . Other, yet unknown susceptibility genes remain to be identified and may account for a large proportion of breast cancer families (Rebbeck et al, 1996;Serova et al, 1997;Vehmanen et al, 1997b;Ford et al, 1998;Kainu et al, 2000). In 295 breast cancer cases with one affected 1st degree relative only one mutation (BRCA2, 7708 C → T) was found giving the mutation frequency of 0.3%.…”

“…In admixed populations, most mutations appear uniquely in single families only, making the mutation screening laborious and expensive. Furthermore, there is also evidence of other predisposing genes (Ford et al, 1998;Kainu et al, 2000). It is, therefore, important to find the clinical risk factors that could best predict the presence of BRCA1 and BRCA2 mutations, so that the screening could be directed to potential mutation carrier families.…”

Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population

“…3 353 A3G Y42C 38x 2 1 1 yes 3 451 G3C A75P 6x 1 1 yes 10 1199 G3C R324T 0x 1 1 yes 10 1206 C3A S326R 7x 1 1 no 10 1239 C3G N337K 0x 1 1 no 10 1379C3T S384F 12x 2 2 no 10 1570 C3T R448C 1x 1 1 no 10 1613 A3G E462G 9x 1 1 yes 11 2192 C3G P655R 23x 1 1 yes 11 2719 A3G V831I 0x 1 1 48 and for 13q21. 49 In summary, the BRCA1/BRCA2 mutation profile established for the German breast/ovarian cancer population facilitates the application of rapid prescreening strategies. The identified UVs can be characterized in more detail by extended control studies and investigation of the corresponding tumors.…”

Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization

“…Genetic analyses on BRCAX patients identified several chromosomal regions potentially harbouring other breast cancer susceptibility genes. They include 8p12-p21, 10 13q21, 11 and 2q32, 12 however, they were excluded or need to be evaluated with regards to population specificity. 13 There are no comprehensive molecular cytogenetic studies that report characteristic chromosomal imbalances involved in tumour progression in BRCAX patients.…”