Distribution of coding apoptotic gene polymorphisms in women with extreme phenotypes of breast cancer predisposition and tolerance.

AIMS AND BACKGROUND: Comparison of subjects with extreme phenotypes of cancer susceptibility and tolerance allows to detect low-penetrance gene-disease interactions with a relatively small study size. METHODS AND STUDY DESIGN: We analyzed the distribution of 19 coding apoptotic gene polymorphisms (Bid Gly10Ser; Casp2 Leu141Val; Casp5 Ala90Thr and Val318Leu; Casp7 Glu255Asp; Casp8 His302Asp; Casp9 Val28Ala, His173Arg and Arg221Gln; Casp10 Ile479Leu; Faim Thr117Ala and Ser127Leu; DR4 Arg141His, Thr209Arg, Ala228Glu and Lys441Arg; Survivin Lys129Glu; TNFR1 Gln121Arg; XIAP Pro423Gln) in 121 breast cancer patients with clinical features of a hereditary predisposition (family history and/or early onset and/or bilaterality) and 142 elderly tumor-free women. RESULTS: None of the individual single nucleotide polymorphisms (SNPs) demonstrated an association with breast cancer risk. The analysis of gene interactions revealed that the combination of XIAP Pro423Gln (rs5956583) AA genotype with Casp7 Glu255Asp (rs2227310) CG genotype appeared to prevail in "supercases" relative to "supercontrols" (25/121 [21%] vs 11/142 [8%], P = 0.002). We attempted to validate this association in the second round of case-control analysis, which involved 519 randomly selected breast cancer patients and 509 age-matched healthy women, but no difference was detected upon this comparison. CONCLUSIONS: Coding apoptotic gene polymorphisms do not play a major role in BC predisposition. The results of this investigation may be considered while designing future studies on breast cancer-associated candidate SNPs.

Paired distribution of molecular subtypes in bilateral breast carcinomas.

The last decade has revealed fundamental new insight into the existence of intrinsic molecular subclasses of breast carcinomas. By using immunostaining on archival tissue, we classified tumor pairs from 50 patients with bilateral disease into molecular subgroups (luminal, triple-negative basal-like, and triple-negative unclassified). Synchronous tumors showed a slightly higher rate of concordant pairs than metachronous tumors, and luminal tumors were highly concordant regardless of being synchronous or metachronous (P = 0.001 and P = 0.002, respectively). Metachronous cases had a higher degree of discordance if the time interval was longer than 10 years; this was most pronounced for triple-negative tumors. The relationship found between subtypes of bilateral tumors provides additional evidence for the role of host-related factors in determining the molecular type of breast cancer.

Mixed epithelial/mesenchymal metaplastic carcinoma (carcinosarcoma) of the breast in BRCA1 carrier.

This case report describes a 35-year-old woman who was diagnosed with mixed epithelial/mesenchymal metaplastic carcinoma (carcinosarcoma) of the breast. Genetic analysis of blood DNA revealed a common founder mutation, BRCA1 5382insC. Examination of microdissected tumor samples determined that both epithelial and mesenchymal components contained deletion of the wild-type BRCA1 allele. This report exemplifies that even very uncommon breast tumor types may develop through biallelic inactivation of BRCA1 gene, that has to be considered in the genetic testing settings.

Non-founder BRCA1 mutations in Russian breast cancer patients.

A few founder BRCA1 mutations (5382insC, 4154delA, 185delAG) account for up to 15% of high-risk (young-onset or familial or bilateral) breast cancer (BC) cases in Russia. The impact of non-founder BRCA1 mutations in this country is less studied; in particular, there are no reports analyzing gross rearrangements of this gene in the Russian patient series. We selected for the study 95 founder mutation negative high-risk BC cases. Combination of high-resolution melting (HRM) and sequencing revealed six presumably BC-associated alleles (2080delA, 4808C>G, 5214C>T, 5236G>A, 5460G>T, 5622C>T) and one variant of an unknown significance (4885G>A). The pathogenic role of the 5236G>A mutation leading to G1706E substitution was further confirmed by the loss of heterozygosity analysis of the corresponding tumor tissue. Multiplex ligation-dependent probe amplification (MLPA) revealed two additional BRCA1 heterozygotes, which carried BRCA1 deletions involving exons 1-2 and 3-7, respectively. Based on the results of this investigation and the review of prior Russian studies, three BRCA1 mutations (2080delA, 3819del5, 3875del4) were considered with respect to their possible founder effect and tested in the additional series of 210 high-risk BC patients; two BRCA heterozygotes (2080delA and 3819del5) were revealed. We conclude that the non-founder mutations constitute the minority of BRCA1 defects in Russia.

Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing.

Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele.

Founder mutations in early-onset, familial and bilateral breast cancer patients from Russia.

Previous studies indicate that founder mutations may play a noticeable role in breast cancer (BC) predisposition in Russia. Here we performed a systematic analysis of eight recurrent mutations in 302 BC cases (St.-Petersburg, Russia), which were selected due to the presence of clinical indicators of hereditary disease (bilaterality and/or early onset (< or =40 years) and/or family history). BC-associated alleles were revealed in 46 (15.2%) women. BRCA1 5382insC mutation was detected in 29 (9.6%) patients, CHEK2 1100delC in 9 (3.0%), BRCA1 4153delA in 3 (1.0%), CHEK2 IVS2+1G>A in 2 (0.7%), and BRCA1 185delAG, BRCA2 6174delT and NBS1 657del5 in 1 (0.3%) patient each. No cases with BRCA1 300T>G (C61G) mutation was identified. The obtained data suggest that a significant fraction of hereditary BC cases in Russia can be diagnosed using only a limited number of simple PCR tests.

CHEK2 1100delC mutation is frequent among Russian breast cancer patients.

This study was aimed to assess the role of CHEK2 1100delC mutation in breast cancer (BC) predisposition in Russia. The 1100delC allele was detected in 14/660 (2.1%) unilateral BC cases and in 8/155 (5.2%) patients with the bilateral form of the disease, but only in 1/448 (0.2%) middle-aged control females and in none of 373 elderly tumor-free women. The obtained data point at potentially high clinical relevance of CHEK2 1100delC testing in females of Russian origin and warrant similar case-control studies in ethnically and geographically related regions, especially in Ukraine, Belarus and Baltic countries.