Identification of two novel mammographic density loci at 6Q25.1

INTRODUCTION: Mammographic density (MD) is a strong heritable and intermediate phenotype for breast cancer, but much of its genetic variation remains unexplained. We performed a large-scale genetic association study including 8,419 women of European ancestry to identify MD loci. METHODS: Participants of three Swedish studies were genotyped on a custom Illumina iSelect genotyping array and percent and absolute mammographic density were ascertained using semiautomated and fully automated methods from film and digital mammograms. Linear regression analysis was used to test for SNP-MD associations, adjusting for age, body mass index, menopausal status and six principal components. Meta-analyses were performed by combining P values taking sample size, study-specific inflation factor and direction of effect into account. RESULTS: Genome-wide significant associations were observed for two previously identified loci: ZNF365 (rs10995194, P = 2.3 × 10(−8) for percent MD and P = 8.7 × 10(−9) for absolute MD) and AREG (rs10034692, P = 6.7 × 10(−9) for absolute MD). In addition, we found evidence of association for two variants at 6q25.1, both of which are known breast cancer susceptibility loci: rs9485370 in the TAB2 gene (P = 4.8 × 10(−9) for percent MD and P = 2.5 × 10(−8) for absolute MD) and rs60705924 in the CCDC170/ESR1 region (P = 2.2 × 10(−8) for absolute MD). Both regions have been implicated in estrogen receptor signaling with TAB2 being a potential regulator of tamoxifen response. CONCLUSIONS: We identified two novel MD loci at 6q25.1. These findings underscore the importance of 6q25.1 as a susceptibility region and provide more insight into the mechanisms through which MD influences breast cancer risk. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0591-2) contains supplementary material, which is available to authorized users

Adiposity and sex-specific cancer risk.

Obesity is associated with several types of cancer and fat distribution, which differs dramatically between sexes, has been suggested to be an independent risk factor. However, sex-specific effects on cancer risk have rarely been studied. Here we estimate the effects of fat accumulation and distribution on cancer risk in females and males. We performed a prospective study in 442,519 UK Biobank participants, for 19 cancer types and additional histological subtypes, with a mean follow-up time of 13.4 years. Cox proportional hazard models were used to estimate the effect of 14 different adiposity phenotypes on cancer rates, and a 5% false discovery rate was considered statistically significant. Adiposity-related traits are associated with all but three cancer types, and fat accumulation is associated with a larger number of cancers compared to fat distribution. In addition, fat accumulation or distribution exhibit differential effects between sexes on colorectal, esophageal, and liver cancer

Tgf ß receptor 1: An immune susceptibility gene in hpv-associated cancer

Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein-protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFßR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFbR1 containing p38-MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFßR1 was overexpressed in oropharyngeal cancer, cervical cancer, andHPV+ head and neck cancer tumors. These concordant analyses implicate TGFßR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGF ßR1/TGFß signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer. © 2014 American Association for Cancer Research