Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Diagnostics of mycobacteriosis in HIV-positive patients

The article analyzes publications dealing with the problem of mycobacteriosis, which show that in 95% of cases its cause in HIVpositive individuals are bacteria referring to M. avium complex (MAC) that cause disease-MAC infection with a high (up to 50%) lethality level. Early adminiatration of adequate therapy might improve the prognosis for this cohort of patients. But similarity of clinical-radial signs of MAC infection and other secondary diseases require fast and reliable methods of etiological diagnosis of mycobacteriosis. The most characteristic clinical-radial and laboratory markers of MAC infection in HIV-infected individuals are as follows: B symptoms, namely, weight loss, fever, weakness, abdominal pains, diarrhoea; mesenteric lymphadenopathy in combination with or without intrathoracic lymphadenopathy; profound immunodeficiency (number of CD4+-lymphocytes below 50 cell/μ l); anaemia, haemoglobin levels below 90 g/l in combination with or without cytopenia. Laboratory diagnostics of mycobacterioses is progressively developing: automated analyzers with liquid nutrient media are extensively used; rapid immunochromatographic tests enabling fast differentiation of tuberculosis from non-tuberculosis mycobacteria have become available; reagent kits allowing differentiation of the most common NTM have been introduced. Also, differentiation of NTM by the sequencing technology considered as the "gold standard" is possible. But so far, only cultures can serve as identification material, which increases the time of making a diagnosis. Along with fast determination of a causative agent, detection of MAC sensitivity to antimicrobial drugs also presents a serious difficulty, which also tells on the effectiveness of therapy

Diagnostics of mycobacteriosis in HIV-positive patients

The article analyzes publications dealing with the problem of mycobacteriosis, which show that in 95% of cases its cause in HIVpositive individuals are bacteria referring to M. avium complex (MAC) that cause disease-MAC infection with a high (up to 50%) lethality level. Early adminiatration of adequate therapy might improve the prognosis for this cohort of patients. But similarity of clinical-radial signs of MAC infection and other secondary diseases require fast and reliable methods of etiological diagnosis of mycobacteriosis. The most characteristic clinical-radial and laboratory markers of MAC infection in HIV-infected individuals are as follows: B symptoms, namely, weight loss, fever, weakness, abdominal pains, diarrhoea; mesenteric lymphadenopathy in combination with or without intrathoracic lymphadenopathy; profound immunodeficiency (number of CD4+-lymphocytes below 50 cell/μ l); anaemia, haemoglobin levels below 90 g/l in combination with or without cytopenia. Laboratory diagnostics of mycobacterioses is progressively developing: automated analyzers with liquid nutrient media are extensively used; rapid immunochromatographic tests enabling fast differentiation of tuberculosis from non-tuberculosis mycobacteria have become available; reagent kits allowing differentiation of the most common NTM have been introduced. Also, differentiation of NTM by the sequencing technology considered as the "gold standard" is possible. But so far, only cultures can serve as identification material, which increases the time of making a diagnosis. Along with fast determination of a causative agent, detection of MAC sensitivity to antimicrobial drugs also presents a serious difficulty, which also tells on the effectiveness of therapy

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PAM, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and pArg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM(-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.Surgical oncolog