Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study.

Author(s): Johnson N,  Dudbridge F,  Orr N,  Gibson L,  Jones ME,  Schoemaker MJ,  Folkerd EJ,  Haynes BP,  Hopper JL,  Southey MC,  Dite GS,  Apicella C,  Schmidt MK,  Broeks A,  Van't Veer LJ,  Atsma F,  Muir K,  Lophatananon A,  Fasching PA,  Beckmann MW,  Ekici AB,  Renner SP,  Sawyer E,  Tomlinson I,  Kerin M,  Miller N,  Burwinkel B,  Marme F,  Schneeweiss A,  Sohn C,  Guénel P,  Truong T,  Cordina E,  Menegaux F,  Bojesen SE,  Nordestgaard BG,  Flyger H,  Milne R,  Zamora MP,  Arias Perez JI,  Benitez J,  Bernstein L,  Anton-Culver H,  Ziogas A,  Clarke Dur C,  Brenner H,  Müller H,  Arndt V,  Dieffenbach AK,  Meindl A,  Heil J,  Bartram CR,  Schmutzler RK,  Brauch H,  Justenhoven C,  Ko YD,  GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network,  Nevanlinna H,  Muranen TA,  Aittomäki K,  Blomqvist C,  Matsuo K,  Dörk T,  Bogdanova NV,  Antonenkova NN,  Lindblom A,  Mannermaa A,  Kataja V,  Kosma VM,  Hartikainen JM,  Chenevix-Trench G,  Beesley J,  kConFab Investigators,  Australian Ovarian Cancer Study Group,  Wu AH,  Van den Berg D,  Tseng CC,  Lambrechts D,  Smeets D,  Neven P,  Wildiers H,  Chang-Claude J,  Rudolph A,  Nickels S,  Flesch-Janys D,  Radice P,  Peterlongo P,  Bonanni B,  Pensotti V,  Couch FJ,  Olson JE,  Wang X,  Fredericksen Z,  Pankratz VS,  Giles GG,  Severi G,  Baglietto L,  Haiman C,  Simard J,  Goldberg MS,  Labrèche F,  Dumont M,  Soucy P,  Teo S,  Yip CH,  Phuah SY,  Cornes BK,  Kristensen VN,  Grenaker Alnæs G,  Børresen-Dale AL,  Zheng W,  Winqvist R,  Pylkäs K,  Jukkola-Vuorinen A,  Grip M,  Andrulis IL,  Knight JA,  Glendon G,  Mulligan AM,  Devillee P,  Figueroa J,  Chanock SJ,  Lissowska J,  Sherman ME,  Hall P,  Schoof N,  Hooning M,  Hollestelle A,  Oldenburg RA,  Tilanus-Linthorst M,  Liu J,  Cox A,  Brock IW,  Reed MW,  Cross SS,  Blot W,  Signorello LB,  Pharoah PD,  Dunning AM,  Shah M,  Kang D,  Noh DY,  Park SK,  Choi JY,  Hartman M,  Miao H,  Lim WY,  Tang A,  Hamann U,  Försti A,  Rüdiger T,  Ulmer HU,  Jakubowska A,  Lubinski J,  Jaworska-Bieniek K,  Durda K,  Sangrajrang S,  Gaborieau V,  Brennan P,  McKay J,  Slager S,  Toland AE,  Vachon C,  Yannoukakos D,  Shen CY,  Yu JC,  Huang CS,  Hou MF,  González-Neira A,  Tessier DC,  Vincent D,  Bacot F,  Luccarini C,  Dennis J,  Michailidou K,  Bolla MK,  Wang J,  Easton DF,  García-Closas M,  Dowsett M,  Ashworth A,  Swerdlow AJ,  Peto J,  dos Santos Silva I,  Fletcher O

Journal: Breast Cancer Res

Date: 2014 May 26

Major Program(s) or Research Group(s):

PubMed ID: 24887515

PMC ID: PMC4522594

Abstract: INTRODUCTION: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. METHODS: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. RESULTS: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29). CONCLUSIONS: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.