Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study
BREAST CANCER RESEARCH
Authors: Milne, Roger L.; Gaudet, Mia M.; Spurdle, Amanda B.; Fasching, Peter A.; Couch, Fergus J.; Benitez, Javier; Arias Perez, Jose Ignacio; Pilar Zamora, M.; Malats, Nuria; dos Santos Silva, Isabel; Gibson, Lorna J.; Fletcher, Olivia; Johnson, Nichola; Anton-Culver, Hoda; Ziogas, Argyrios; Figueroa, Jonine; Brinton, Louise; Sherman, Mark E.; Lissowska, Jolanta; Hopper, John L.; Dite, Gillian S.; Apicella, Carmel; Southey, Melissa C.; Sigurdson, Alice J.; Linet, Martha S.; Schonfeld, Sara J.; Freedman, D. Michal; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Auvinen, Paeivi; Andrulis, Irene L.; Glendon, Gord; Knight, Julia A.; Weerasooriya, Nayana; Cox, Angela; Reed, Malcolm W. R.; Cross, Simon S.; Dunning, Alison M.; Ahmed, Shahana; Shah, Mitul; Brauch, Hiltrud; Ko, Yon-Dschun; Bruening, Thomas; Lambrechts, Diether; Reumers, Joke; Smeets, Ann; Wang-Gohrke, Shan; Hall, Per; Czene, Kamila; Liu, Jianjun; Irwanto, Astrid K.; Chenevix-Trench, Georgia; Holland, Helene; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca; Bojensen, Stig E.; Nordestgaard, Borge G.; Flyger, Henrik; John, Esther M.; West, Dee W.; Whittemore, Alice S.; Vachon, Celine; Olson, Janet E.; Fredericksen, Zachary; Kosel, Matthew; Hein, Rebecca; Vrieling, Alina; Flesch-Janys, Dieter; Heinz, Judith; Beckmann, Matthias W.; Heusinger, Katharina; Ekici, Arif B.; Haeberle, Lothar; Humphreys, Manjeet K.; Morrison, Jonathan; Easton, Doug F.; Pharoah, Paul D.; Garcia-Closas, Montserrat; Goode, Ellen L.; Chang-Claude, Jenny
Abstract
Introduction: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. Methods: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. Results: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. Conclusions: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.
Could perturbed fetal development of the ovary contribute to the development of polycystic ovary syndrome in later life?
PLOS ONE
Authors: Hartanti, Monica D.; Rosario, Roseanne; Hummitzsch, Katja; Bastian, Nicole A.; Hatzirodos, Nicholas; Bonner, Wendy M.; Bayne, Rosemary A.; Irving-Rodgers, Helen F.; Anderson, Richard A.; Rodgers, Raymond J.
Abstract
Polycystic ovary syndrome (PCOS) affects around 10% of young women, with adverse consequences on fertility and cardiometabolic outcomes. PCOS appears to result from a genetic predisposition interacting with developmental events during fetal or perinatal life. We hypothesised that PCOS candidate genes might be expressed in the fetal ovary when the stroma develops; mechanistically linking the genetics, fetal origins and adult ovarian phenotype of PCOS. In bovine fetal ovaries (n = 37) of 18 PCOS candidate genes only SUMO1P1 was not expressed. Three patterns of expression were observed: early gestation (FBN3, GATA4, HMGA2, TOX3, DENND1A, LHCGR and FSHB), late gestation (INSR, FSHR, and LHCGR) and throughout gestation (THADA, ERBB4, RAD50, C8H9orf3, YAP1, RAB5B, SUOX and KRR1). A splice variant of FSHB exon 3 was also detected early in the bovine ovaries, but exon 2 was not detected. Three other genes, likely to be related to the PCOS aetiology (AMH, AR and TGFB1I1), were also expressed late in gestation. Significantly within each of the three gene groups, the mRNA levels of many genes were highly correlated with each other, despite, in some instances, being expressed in different cell types. TGF beta is a well-known stimulator of stromal cell replication and collagen synthesis and TGF beta treatment of cultured fetal ovarian stromal cells inhibited the expression of INSR, AR, C8H9orf3 and RAD50 and stimulated the expression of TGFB1I1. In human ovaries (n = 15, < 150 days gestation) many of the same genes as in bovine (FBN3, GATA4, HMGA2, FSHR, DENND1A and LHCGR but not TOX3 or FSHB) were expressed and correlated with each other. With so many relationships between PCOS candidate genes during development of the fetal ovary, including TGF beta and androgen signalling, we suggest that future studies should determine if perturbations of these genes in the fetal ovary can lead to PCOS in later life.
COA
Publication 
Loading ......
