Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study

Brouckaert, Olivier,Rudolph, Anja,Laenen, Annouschka,Keeman, Renske,Bolla, Manjeet K.,Wang, Qin,Soubry, Adelheid,Wildiers, Hans,Andrulis, Irene L.,Arndt, Volker,Beckmann, Matthias W.,Benitez, Javier,B BioMed Central 2017 Breast cancer research Vol.19 No.-

<P><B>Background</B></P><P>Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis.</P><P><B>Methods</B></P><P>We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years.</P><P><B>Results</B></P><P>Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16–1.65, <I>p</I> = 0.0004; <I>p</I> for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (<I>p</I> for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01–2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45–1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70–0.88, <I>p</I> < 0.0001), but this effect was not apparent at a later FFTP.</P><P><B>Conclusions</B></P><P>Our main findings suggest that parity is associated with TNBC across all ages at BC diagnosis, whereas the association with luminal HER2-like BC was present only for early onset BC.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1186/s13058-017-0909-3) contains supplementary material, which is available to authorized users.</P>

Assessment of variation in immunosuppressive pathway genes reveals <i>TGFBR2</i> to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

Lei, Jieping,Rudolph, Anja,Moysich, Kirsten B,Rafiq, Sajjad,Behrens, Sabine,Goode, Ellen L,Pharoah, Paul PD,Seibold, Petra,Fasching, Peter A,Andrulis, Irene L,Kristensen, Vessela N,Couch, Fergus J,Ham BioMed Central 2015 Breast cancer research Vol.17 No.-

<P><B>Introduction</B></P><P>Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).</P><P><B>Methods</B></P><P>We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.</P><P><B>Results</B></P><P>Three independent SNPs in <I>TGFBR2</I> and <I>IL12B</I> were associated with OS (<I>P</I> <10<SUP>−3</SUP>) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with <I>TGFBR2</I> rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), <I>P</I> = 3.08 × 10<SUP>−4</SUP>) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (<I>P</I> for interaction <10<SUP>−3</SUP>). Two SNPs in <I>IL12B</I> (r<SUP>2</SUP> = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), <I>P</I> = 1.81 × 10<SUP>−4</SUP>), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), <I>P</I> = 3.67 × 10<SUP>−4</SUP>). Similar associations were observed with BCSS. Association with <I>TGFBR2</I> rs1367610 but not <I>IL12B</I> variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), <I>P</I> = 2.05 × 10<SUP>−5</SUP>) without study heterogeneity.</P><P><B>Conclusions</B></P><P><I>TGFBR2</I> variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1186/s13058-015-0522-2) contains supplementary material, which is available to authorized users.</P>

Association of breast cancer risk in <i>BRCA1</i> and <i>BRCA2</i> mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Hamdi, Yosr,Soucy, Penny,Kuchenbaeker, Karoline B.,Pastinen, Tomi,Droit, Arnaud,Lemaç,on, Audrey,Adlard, Julian,Aittomä,ki, Kristiina,Andrulis, Irene L.,Arason, Adalgeir,Arnold, Norbert,Arun Springer US 2017 Breast cancer research and treatment Vol.161 No.1

<P><B>Purpose</B></P><P><I>Cis</I>-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among <I>BRCA1</I> and <I>BRCA2</I> mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.</P><P><B>Methods</B></P><P>Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 <I>BRCA1</I> and 8211 <I>BRCA2</I> mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of <I>BRCA1/2</I>.</P><P><B>Results</B></P><P>We identified a region on 11q22.3 that is significantly associated with breast cancer risk in <I>BRCA1</I> mutation carriers (most significant SNP rs228595 <I>p</I> = 7 × 10<SUP>−6</SUP>). This association was absent in <I>BRCA2</I> carriers (<I>p</I> = 0.57). The 11q22.3 region notably encompasses genes such as <I>ACAT1</I>, <I>NPAT</I>, and <I>ATM</I>. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for <I>ACAT1</I>, <I>ATM</I>, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.</P><P><B>Conclusion</B></P><P>We identified 11q22.3 as a new modifier locus in <I>BRCA1</I> carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1007/s10549-016-4018-2) contains supplementary material, which is available to authorized users.</P>