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Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.

ABSTRACT: Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10(-18)), rs3803662 (16q12) (P = 3.7 × 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10(-6) and P = 4.1 × 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ? 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ? 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.

SUBMITTER: Broeks A

PROVIDER: S-EPMC3140824 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.

Broeks Annegien A Schmidt Marjanka K MK Sherman Mark E ME Couch Fergus J FJ Hopper John L JL Dite Gillian S GS Apicella Carmel C Smith Letitia D LD Hammet Fleur F Southey Melissa C MC Van 't Veer Laura J LJ de Groot Renate R Smit Vincent T H B M VT Fasching Peter A PA Beckmann Matthias W MW Jud Sebastian S Ekici Arif B AB Hartmann Arndt A Hein Alexander A Schulz-Wendtland Ruediger R Burwinkel Barbara B Marme Frederik F Schneeweiss Andreas A Sinn Hans-Peter HP Sohn Christof C Tchatchou Sandrine S Bojesen Stig E SE Nordestgaard Børge G BG Flyger Henrik H Ørsted David D DD Kaur-Knudsen Diljit D Milne Roger L RL Pérez Jose I Arias JI Zamora Pilar P Rodríguez Primitiva Menéndez PM Benítez Javier J Brauch Hiltrud H Justenhoven Christina C Ko Yon-Dschun YD Hamann Ute U Fischer Hans-Peter HP Brüning Thomas T Pesch Beate B Chang-Claude Jenny J Wang-Gohrke Shan S Bremer Michael M Karstens Johann H JH Hillemanns Peter P Dörk Thilo T Nevanlinna Heli A HA Heikkinen Tuomas T Heikkilä Päivi P Blomqvist Carl C Aittomäki Kristiina K Aaltonen Kirsimari K Lindblom Annika A Margolin Sara S Mannermaa Arto A Kosma Veli-Matti VM Kauppinen Jaana M JM Kataja Vesa V Auvinen Päivi P Eskelinen Matti M Soini Ylermi Y Chenevix-Trench Georgia G Spurdle Amanda B AB Beesley Jonathan J Chen Xiaoqing X Holland Helene H Lambrechts Diether D Claes Bart B Vandorpe Thijs T Neven Patrick P Wildiers Hans H Flesch-Janys Dieter D Hein Rebecca R Löning Thomas T Kosel Matthew M Fredericksen Zachary S ZS Wang Xianshu X Giles Graham G GG Baglietto Laura L Severi Gianluca G McLean Catriona C Haiman Christopher A CA Henderson Brian E BE Le Marchand Loic L Kolonel Laurence N LN Alnæs Grethe Grenaker GG Kristensen Vessela V Børresen-Dale Anne-Lise AL Hunter David J DJ Hankinson Susan E SE Andrulis Irene L IL Mulligan Anna Marie AM O'Malley Frances P FP Devilee Peter P Huijts Petra E A PE Tollenaar Rob A E M RA Van Asperen Christi J CJ Seynaeve Caroline S CS Chanock Stephen J SJ Lissowska Jolanta J Brinton Louise L Peplonska Beata B Figueroa Jonine J Yang Xiaohong R XR Hooning Maartje J MJ Hollestelle Antoinette A Oldenburg Rogier A RA Jager Agnes A Kriege Mieke M Ozturk Bahar B van Leenders Geert J L H GJ Hall Per P Czene Kamila K Humphreys Keith K Liu Jianjun J Cox Angela A Connley Daniel D Cramp Helen E HE Cross Simon S SS Balasubramanian Sabapathy P SP Reed Malcolm W R MW Dunning Alison M AM Easton Douglas F DF Humphreys Manjeet K MK Caldas Carlos C Blows Fiona F Driver Kristy K Provenzano Elena E Lubinski Jan J Jakubowska Anna A Huzarski Tomasz T Byrski Tomasz T Cybulski Cezary C Gorski Bohdan B Gronwald Jacek J Brennan Paul P Sangrajrang Suleeporn S Gaborieau Valerie V Shen Chen-Yang CY Hsiung Chia-Ni CN Yu Jyh-Cherng JC Chen Shou-Tung ST Hsu Giu-Cheng GC Hou Ming-Feng MF Huang Chiun-Sheng CS Anton-Culver Hoda H Ziogas Argyrios A Pharoah Paul D P PD Garcia-Closas Montserrat M

Human molecular genetics 20110519 16

Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies wi ...[more]

PMID: 21596841

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Project description:Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Project description:BackgroundRecent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined.MethodsWe applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence.ResultsFirst, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk.ConclusionThis study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins.

Project description:BackgroundPrevious studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.MethodsWe pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.ResultsIn case-case analyses, of the epidemiological risk factors examined, early age at menarche (?12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ? 30 kg/m(2)) in younger women (?50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.ConclusionsThis study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

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Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.

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Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.

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