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Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.

ABSTRACT: BACKGROUND:The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium. METHODS:Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression. RESULTS:For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08-1.14, P = 7 × 10(-18)) for invasive breast cancer and 1.10 (95% CI = 1.01-1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99-1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12-1.20, P = 1 × 10(-18) vs. OR = 1.03, 95% CI = 0.99-1.07, P = 0.2 for PR-negative disease; P(heterogeneity) = 2 × 10(-7)); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14-1.25), 1.13 (1.09-1.16), and 1.04 (0.99-1.08) for grade 1, 2, and 3/4, respectively; P(trend) = 5 × 10(-7)]. CONCLUSION:5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer. IMPACT:Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.

SUBMITTER: Milne RL

PROVIDER: S-EPMC4164116 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.

Milne Roger L RL Goode Ellen L EL García-Closas Montserrat M Couch Fergus J FJ Severi Gianluca G Hein Rebecca R Fredericksen Zachary Z Malats Núria N Zamora M Pilar MP Arias Pérez Jose Ignacio JI Benítez Javier J Dörk Thilo T Schürmann Peter P Karstens Johann H JH Hillemanns Peter P Cox Angela A Brock Ian W IW Elliot Graeme G Cross Simon S SS Seal Sheila S Turnbull Clare C Renwick Anthony A Rahman Nazneen N Shen Chen-Yang CY Yu Jyh-Cherng JC Huang Chiun-Sheng CS Hou Ming-Feng MF Nordestgaard Børge G BG Bojesen Stig E SE Lanng Charlotte C Grenaker Alnæs Grethe G Kristensen Vessela V Børrensen-Dale Anne-Lise AL Hopper John L JL Dite Gillian S GS Apicella Carmel C Southey Melissa C MC Lambrechts Diether D Yesilyurt Betül T BT Floris Giuseppe G Leunen Karin K Sangrajrang Suleeporn S Gaborieau Valerie V Brennan Paul P McKay James J Chang-Claude Jenny J Wang-Gohrke Shan S Radice Paolo P Peterlongo Paolo P Manoukian Siranoush S Barile Monica M Giles Graham G GG Baglietto Laura L John Esther M EM Miron Alexander A Chanock Stephen J SJ Lissowska Jolanta J Sherman Mark E ME Figueroa Jonine D JD Bogdanova Natalia V NV Antonenkova Natalia N NN Zalutsky Iosif V IV Rogov Yuri I YI Fasching Peter A PA Bayer Christian M CM Ekici Arif B AB Beckmann Matthias W MW Brenner Hermann H Müller Heiko H Arndt Volker V Stegmaier Christa C Andrulis Irene L IL Knight Julia A JA Glendon Gord G Mulligan Anna Marie AM Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Meindl Alfons A Heil Joerg J Bartram Claus R CR Schmutzler Rita K RK Thomas Gilles D GD Hoover Robert N RN Fletcher Olivia O Gibson Lorna J LJ dos Santos Silva Isabel I Peto Julian J Nickels Stefan S Flesch-Janys Dieter D Anton-Culver Hoda H Ziogas Argyrios A Sawyer Elinor E Tomlinson Ian I Kerin Michael M Miller Nicola N Schmidt Marjanka K MK Broeks Annegien A Van 't Veer Laura J LJ Tollenaar Rob A E M RA Pharoah Paul D P PD Dunning Alison M AM Pooley Karen A KA Marme Frederik F Schneeweiss Andreas A Sohn Christof C Burwinkel Barbara B Jakubowska Anna A Lubinski Jan J Jaworska Katarzyna K Durda Katarzyna K Kang Daehee D Yoo Keun-Young KY Noh Dong-Young DY Ahn Sei-Hyun SH Hunter David J DJ Hankinson Susan E SE Kraft Peter P Lindstrom Sara S Chen Xiaoqing X Beesley Jonathan J Hamann Ute U Harth Volker V Justenhoven Christina C Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Grip Mervi M Hooning Maartje M Hollestelle Antoinette A Oldenburg Rogier A RA Tilanus-Linthorst Madeleine M Khusnutdinova Elza E Bermisheva Marina M Prokofieva Darya D Farahtdinova Albina A Olson Janet E JE Wang Xianshu X Humphreys Manjeet K MK Wang Qin Q Chenevix-Trench Georgia G Easton Douglas F DF

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20110727 10

<h4>Background</h4>The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.<h4>Methods</h4>Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestr ...[more]

PMID: 21795498

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Project description:IntroductionEstrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer. While the clinical utility of ER as a predictive biomarker to identify patients likely to benefit from hormonal therapy is well-established, the added value of PR is less well-defined. The primary goals of our study were to assess the distribution, inter-assay reproducibility, and prognostic significance of breast cancer subtypes defined by patterns of ER and PR expression.MethodsWe integrated gene expression microarray (GEM) and clinico-pathologic data from 20 published studies to determine the frequency (n = 4,111) and inter-assay reproducibility (n = 1,752) of ER/PR subtypes (ER+/PR+, ER+/PR-, ER-/PR-, ER-/PR+). To extend our findings, we utilized a cohort of patients from the Nurses' Health Study (NHS) with ER/PR data recorded in the medical record and assessed on tissue microarrays (n = 2,011). In both datasets, we assessed the association of ER and PR expression with survival.ResultsIn a genome-wide analysis, progesterone receptor was among the least variable genes in ER- breast cancer. The ER-/PR+ subtype was rare (approximately 1 to 4%) and showed no significant reproducibility (Kappa = 0.02 and 0.06, in the GEM and NHS datasets, respectively). The vast majority of patients classified as ER-/PR+ in the medical record (97% and 94%, in the GEM and NHS datasets) were re-classified by a second method. In the GEM dataset (n = 2,731), progesterone receptor mRNA expression was associated with prognosis in ER+ breast cancer (adjusted P <0.001), but not in ER- breast cancer (adjusted P = 0.21). PR protein expression did not contribute significant prognostic information to multivariate models considering ER and other standard clinico-pathologic features in the GEM or NHS datasets.ConclusionER-/PR+ breast cancer is not a reproducible subtype. PR expression is not associated with prognosis in ER- breast cancer, and PR does not contribute significant independent prognostic information to multivariate models considering ER and other standard clinico-pathologic factors. Given that PR provides no clinically actionable information in ER+ breast cancer, these findings question the utility of routine PR testing in breast cancer.

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Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.

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Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.

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