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

• Published in: Human molecular genetics Vol. 20; no. 16; pp. 3289 - 3303
• Main Authors: BROEKS, Annegien, SCHMIDT, Marjanka K, VAN 'T VEER, Laura J, DE GROOT, Renate, SMIT, Vincent T. H. B. M, FASCHING, Peter A, BECKMANN, Matthias W, JUD, Sebastian, EKICI, Arif B, HARTMANN, Arndt, HEIN, Alexander, SCHULZ-WENDTLAND, Ruediger, SHERMAN, Mark E, BURWINKEL, Barbara, MARME, Frederik, SCHNEEWEISS, Andreas, SINN, Hans-Peter, SOHN, Christof, TCHATCHOU, Sandrine, BOJESEN, Stig E, NORDESTGAARD, Borge G, FLYGER, Henrik, ØRSTED, David D, COUCH, Fergus J, KAUR-KNUDSEN, Diljit, MILNE, Roger L, ARIAS PEREZ, Jose I, ZAMORA, Pilar, MENENDEZ RODRIGUEZ, Primitiva, BENITEZ, Javier, BRAUCH, Hiltrud, JUSTENHOVEN, Christina, KO, Yon-Dschun, HAMANN, Ute, HOPPER, John L, FISCHER, Hans-Peter, BRÜNING, Thomas, PESCH, Beate, CHANG-CLAUDE, Jenny, WANG-GOHRKE, Shan, BREMER, Michael, KARSTENS, Johann H, HILLEMANNS, Peter, DÖRK, Thilo, NEVANLINNA, Heli A, DITE, Gillian S, HEIKKINEN, Tuomas, HEIKKILÄ, Päivi, BLOMQVIST, Carl, AITTOMÄKI, Kristiina, AALTONEN, Kirsimari, LINDBLOM, Annika, MARGOLIN, Sara, MANNERMAA, Arto, KOSMA, Veli-Matti, KAUPPINEN, Jaana M, APICELLA, Carmel, SMITH, Letitia D, HAMMET, Fleur, SOUTHEY, Melissa C
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.08.2011
• Subjects: Asian People - genetics; Association Studies; Biological and medical sciences; Biomarkers, Tumor - metabolism; Breast Neoplasms - classification; Breast Neoplasms - genetics; Female; Fundamental and applied biological sciences. Psychology; Genetic Loci - genetics; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Medicin och hälsovetenskap; Molecular and cellular biology; Odds Ratio; Penetrance; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Risk Factors; Tumors; White People - genetics; Mammary gland diseases; Breast disease; Gene penetrance; Breast tumor; Genetics; Breast cancer; Malignant tumor; Locus; Subtype; Cancer
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddr228

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.