BackgroundA single nucleotide polymorphism located in the 3'-untranslated region of the KRAS oncogene (KRAS variant; rs61764370) disrupts a let-7 miRNA binding and was recently reported to act as a genetic marker for increased risk of developing human cancers. We aimed to investigate an association of the KRAS variant with sporadic and familial breast cancer and breast tumor characteristics.MethodsGenotyping was accomplished in 530 sporadic postmenopausal breast cancer cases, 165 familial breast cancer cases (including N = 29, who test positive for BRCA1/2 mutations) and 270 postmenopausal control women using the flurogenic 5' nuclease assay. Information on hormone replacement therapy (HRT) use and tumor characteristics in sporadic breast cancer cases was ascertained from a postal questionnaire and pathology reports, respectively. Associations between the KRAS genotype and breast cancer or breast tumor characteristics were assessed using chi-square test and logistic regression models.ResultsNo evidence of association was observed between the KRAS variant and risk of sporadic and familial breast cancer - either among BRCA carriers or non-BRCA carriers. The KRAS variant was statistically significantly more often associated with human epidermal growth factor receptor 2 (HER2) - positive tumors and tumors of higher histopathologic grade. However, both associations were detected only in HRT users.ConclusionOur data do not support the hypothesis that the KRAS variant rs61764370 is implicated in the aetiology of sporadic or of familial breast cancer. In postmenopausal women using HRT, the KRAS variant might lead to HER2 overexpressed and poorly-differentiated breast tumors, both indicators of a worse prognosis.

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BackgroundThe BRCA1 and BRCA2 mutation spectrum and mutation detection rates according to different family histories were investigated in 521 subjects from 322 unrelated Slovenian cancer families with breast and/or ovarian cancer.MethodsThe BRCA1 and BRCA2 genes were screened using DGGE, PTT, HRM, MLPA and direct sequencing.ResultsEighteen different mutations were found in BRCA1 and 13 in BRCA2 gene. Mutations in one or other gene were found in 96 unrelated families. The mutation detection rates were the highest in the families with at least one breast and at least one ovarian cancer - 42% for BRCA1 and 8% for BRCA2. The mutation detection rate observed in the families with at least two breast cancers with disease onset before the age of 50 years and no ovarian cancer was 23% for BRCA1 and 13% for BRCA2. The mutation detection rate in the families with at least two breast cancers and only one with the disease onset before the age of 50 years was 11% for BRCA1 and 8% for BRCA2. In the families with at least two breast cancers, all of them with disease onset over the age of 50 years, the detection rate was 5% for BRCA2 and 0% for BRCA1.ConclusionAmong the mutations detected in Slovenian population, 5 mutations in BRCA1 and 4 mutations in BRCA2 have not been described in other populations until now. The most frequent mutations in our population were c.181T > G, c.1687C > T, c.5266dupC and c.844_850dupTCATTAC in BRCA1 gene and c.7806-2A > G, c.5291C > G and c.3978insTGCT in BRCA2 gene (detected in 69% of BRCA1 and BRCA2 positive families).

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Background High-grade serous ovarian cancer is a detrimental disease. Treatment options in patients with a recurrent disease are dependent on BRCA1/2 mutation status since only patients with known BRCA mutation are eligible for treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). The aim of this study was to compare concordance of BRCA mutation analyses from cytological samples (CS) with BRCA mutation analyses from histological formalin fixed paraffin embedded (FFPE) samples. Methods Mutation analysis of BRCA1 and BRCA2 genes was performed in 44 women diagnosed with primary or recurrent high-grade ovarian cancer from three different samples: blood, cytological sample (ascites, pleural effusion and enlarged lymph nodes) and tumor tissue. Results from all three samples were compared. Results Among 44 patients, there were 15 germline mutations and two somatic mutations. A 100% concordance was found between cytological and histologic samples. Conclusion There is a 100% concordance in BRCA mutation testing between cytological and histologic samples. BRCA mutation testing from CS could replace testing from FFPE tissue in clinical decision making in ovarian cancer patients. Trial registration The study was retrospectively registered at ISRCTN registry on 24/11/2015 - ISRCTN42408038 .

ObjectiveEstrogen plays a key role in breast cancer development and functionally relevant genetic variants within the estrogen metabolic pathway are prime candidates for a possible association with breast cancer risk. We investigated the independent and the combined effects of commonly occurring polymorphisms in four genes encoding key proteins of estrogen metabolic pathway on their potential contribution to breast cancer risk.MethodsWe studied 530 breast cancer cases and 270 controls of the same age and ethnicity participating in a case-control study of postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), and MnSOD (rs4880) polymorphisms by polymerase chain reaction based restriction fragment length polymorphism and TaqMan allelic discrimination method. Adjusted ORs and 95% CIs were calculated using logistic regression.ResultsNone of the 4 genetic variants examined contributed to breast cancer risk individually. When the combined effects of the risk genotypes were investigated, significant associations were observed among women with two high-risk genotypes in CYP1B1 and COMT (OR, 2.0; 95% CI, 1.1 to 3.5) and two high-risk genotypes in COMT and MnSOD (OR, 2.0; 95% CI, 1.0 to 3.8), compared to those with low-risk genotypes.ConclusionOur results suggest that individual susceptibility to breast cancer incidence may be increased by combined effects of the high-risk genotypes in CYP1B1, COMT, and MnSOD estrogen metabolic genes.

The estimated proportion of hereditary breast and ovarian cancers among all breast and ovarian cancer cases is 5–10%. According to the literature, inherited mutations in the BRCA1 and BRCA2 tumour-suppressor genes, account for the majority of hereditary breast and ovarian cancer cases. The aim of this report is to present novel mutations that have not yet been described in the literature and pathogenic BRCA1 and BRCA2 mutations which have been detected in HBOC families for the first time in the last three years. In the period between January 2009 and December 2011, 559 individuals from 379 families affected with breast and/or ovarian cancer were screened for mutations in the BRCA1 and BRCA2 genes. Three novel mutations were detected: one in BRCA1 - c.1193C>A (p.Ser398*) and two in BRCA2 - c.5101C>T (p.Gln1701*) and c.5433_5436delGGAA (p.Glu1811Aspfs*3). These novel mutations are located in the exons 11 of BRCA1 or BRCA2 and encode truncated proteins. Two of them are nonsense while one is a frameshift mutation. Also, 11 previously known pathogenic mutations were detected for the first time in the HBOC families studied here (three in BRCA1 and eight in BRCA2). All, except one cause premature formation of stop codons leading to truncation of the respective BRCA1 or BRCA2 proteins.

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