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Common germline polymorphisms associated with breast cancer-specific survival.

ABSTRACT: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium.A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect.Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease.Although no variants reached genome-wide significance (P <5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.

SUBMITTER: Pirie A

PROVIDER: S-EPMC4484708 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Common germline polymorphisms associated with breast cancer-specific survival.

Pirie Ailith A Guo Qi Q Kraft Peter P Canisius Sander S Eccles Diana M DM Rahman Nazneen N Nevanlinna Heli H Chen Constance C Khan Sofia S Tyrer Jonathan J Bolla Manjeet K MK Wang Qin Q Dennis Joe J Michailidou Kyriaki K Lush Michael M Dunning Alison M AM Shah Mitul M Czene Kamila K Darabi Hatef H Eriksson Mikael M Lambrechts Dieter D Weltens Caroline C Leunen Karin K van Ongeval Chantal C Nordestgaard Børge G BG Nielsen Sune F SF Flyger Henrik H Rudolph Anja A Seibold Petra P Flesch-Janys Dieter D Blomqvist Carl C Aittomäki Kristiina K Fagerholm Rainer R Muranen Taru A TA Olsen Janet E JE Hallberg Emily E Vachon Celine C Knight Julia A JA Glendon Gord G Mulligan Anna Marie AM Broeks Annegien A Cornelissen Sten S Haiman Christopher A CA Henderson Brian E BE Schumacher Frederick F Le Marchand Loic L Hopper John L JL Tsimiklis Helen H Apicella Carmel C Southey Melissa C MC Cross Simon S SS Reed Malcolm Wr MW Giles Graham G GG Milne Roger L RL McLean Catriona C Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Grip Mervi M Hooning Maartje J MJ Hollestelle Antoinette A Martens John Wm JW van den Ouweland Ans Mw AM Marme Federick F Schneeweiss Andreas A Yang Rongxi R Burwinkel Barbara B Figueroa Jonine J Chanock Stephen J SJ Lissowska Jolanta J Sawyer Elinor J EJ Tomlinson Ian I Kerin Michael J MJ Miller Nicola N Brenner Hermann H Butterbach Katja K Holleczek Bernd B Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Li Jingmei J Brand Judith S JS Humphreys Keith K Devilee Peter P Tollenaar Robert Aem RA Seynaeve Caroline C Radice Paolo P Peterlongo Paolo P Manoukian Siranoush S Ficarazzi Filomena F Beckmann Matthias W MW Hein Alexander A Ekici Arif B AB Balleine Rosemary R Phillips Kelly-Anne KA Benitez Javier J Zamora M Pilar MP Perez Jose Ignacio Arias JI Menéndez Primitiva P Jakubowska Anna A Lubinski Jan J Gronwald Jacek J Durda Katarzyna K Hamann Ute U Kabisch Maria M Ulmer Hans Ulrich HU Rüdiger Thomas T Margolin Sara S Kristensen Vessela V Nord Siljie S Evans D Gareth DG Abraham Jean J Earl Helena H Poole Christopher J CJ Hiller Louise L Dunn Janet A JA Bowden Sarah S Yang Rose R Campa Daniele D Diver W Ryan WR Gapstur Susan M SM Gaudet Mia M MM Hankinson Susan S Hoover Robert N RN Hüsing Anika A Kaaks Rudolf R Machiela Mitchell J MJ Willett Walter W Barrdahl Myrto M Canzian Federico F Chin Suet-Feung SF Caldas Carlos C Hunter David J DJ Lindstrom Sara S Garcia-Closas Montserrat M Couch Fergus J FJ Chenevix-Trench Georgia G Mannermaa Arto A Andrulis Irene L IL Hall Per P Chang-Claude Jenny J Easton Douglas F DF Bojesen Stig E SE Cox Angela A Fasching Peter A PA Pharoah Paul Dp PD Schmidt Marjanka K MK

Breast cancer research : BCR 20150422

<h4>Introduction</h4>Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium.<h4>Methods</h4>A literatu ...[more]

PMID: 25897948

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Project description:IntroductionGermline variants in androgen metabolism genes may influence clinical response to androgen deprivation therapy (ADT) in advanced prostate cancer. We sought to investigate the prognostic significance of germline variants in androgen metabolism genes with respect to overall survival (OS) after ADT, and to associate germline variants with tumor genomic features.MethodsGermline and somatic whole-genome sequencing (WGS) data were evaluated in a cohort of 101 men with metastatic castration-resistant prostate cancer (mCRPC). Survival analyses were performed to identify polymorphisms associated with impaired OS after primary ADT. Germline variants found to be prognostic of OS were associated with tumor somatic DNA-sequence alterations based on WGS performed on paired metastasis biopsies from the same 101 patients. Gene set enrichment analysis was performed based on tumor RNA-sequencing data to identify genomic pathways differentially expressed in patients with germline variants.ResultsA comprehensive literature review identified 17 candidate polymorphisms in nine androgen metabolism genes that have been previously shown to have an association with response to ADT in prostate cancer. Of these, the variant rs1856888 allele located 13 kb upstream of HSD3B1 was found to be significantly associated with impaired OS (P = 0.029). Variant rs1856888 was commonly co-inherited with the well-characterized HSD3B1(1245A>C) polymorphism, and there was a trend toward shorter median OS in patients with HSD3B1(1245A>C) compared with homozygous wild-type patients (P = 0.052). While HSD3B1 germline variants were not associated with common somatic tumor DNA alterations, they were associated with increased tumor expression of cell proliferation and cell cycle genes.ConclusionsThis study presents a comprehensive assessment of germline variants in androgen metabolism genes and highlights HSD3B1 polymorphisms as prognostic of OS after ADT and associated with an aggressive gene expression tumor profile in mCRPC.

Project description:BackgroundMutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent.MethodsGene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease.ResultsPTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28]).ConclusionsPTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.

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Common germline polymorphisms associated with breast cancer-specific survival.

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Common germline polymorphisms associated with breast cancer-specific survival.

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