-
Stefan Nickels,
Thérèse Truong,
Rebecca Hein,
Kristen Stevens,
Katharina Buck,
Sabine Behrens,
Ursula Eilber,
Martina Schmidt,
Lothar Häberle,
Alina Vrieling, [......],
Alice J. Sigurdson,
Michele M. Doody,
Pascal Guénel,
Paul D. P. Pharoah,
Marjanka K. Schmidt,
Per Hall,
Doug F. Easton,
Montserrat Garcia-Closas,
Roger L. Milne,
Jenny Chang-Claude
[show abstract]
[hide abstract]
ABSTRACT: Author Summary
Breast cancer involves combined effects of numerous genetic, environmental, and behavioral risk factors that are unique to each individual. High risk genes, such as BRCA1 and BRCA2 , account for only a small proportion of disease occurrence. Recent genome-wide research has identified more than 20 common genetic variants, which individually alter breast cancer risk very moderately. We undertook an international collaborative study to determine whether the effect of these genetic variants vary with environmental factors, such as parity, body mass index (BMI), height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, and physical activity, which are known to affect risk of developing breast cancer. Using pooled data from 24 studies of the Breast Cancer Association Consortium (BCAC), we provide first convincing evidence that the breast cancer risk associated with a genetic variant in LSP1<
PLoS Genet. 03/2013; 9(3):e1003284.
-
Montserrat Garcia-Closas,
Fergus J Couch,
Sara Lindstrom,
Kyriaki Michailidou,
Marjanka K Schmidt,
Mark N Brook,
Nick Orr,
Suhn Kyong Rhie,
Elio Riboli,
Heather S Feigelson, [......],
Alison M Dunning,
Mark E Sherman,
Georgia Chenevix-Trench,
Stephen J Chanock,
Per Hall,
Paul D P Pharoah,
Celine Vachon,
Douglas F Easton,
Christopher A Haiman,
Peter Kraft
[show abstract]
[hide abstract]
ABSTRACT: Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
Nature Genetics 03/2013; 45(4):392-398. · 35.53 Impact Factor
-
Kyriaki Michailidou,
Per Hall,
Anna Gonzalez-Neira,
Maya Ghoussaini,
Joe Dennis,
Roger L Milne,
Marjanka K Schmidt,
Jenny Chang-Claude,
Stig E Bojesen,
Manjeet K Bolla, [......],
Sandra Deming-Halverson,
Martha Shrubsole,
Jirong Long,
Jacques Simard,
Montse Garcia-Closas,
Paul D P Pharoah,
Georgia Chenevix-Trench,
Alison M Dunning,
Javier Benitez,
Douglas F Easton
[show abstract]
[hide abstract]
ABSTRACT: Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
Nature Genetics 03/2013; 45(4):353-361. · 35.53 Impact Factor
-
Stig E Bojesen,
Karen A Pooley,
Sharon E Johnatty,
Jonathan Beesley,
Kyriaki Michailidou,
Jonathan P Tyrer,
Stacey L Edwards,
Hilda A Pickett,
Howard C Shen,
Chanel E Smart, [......],
Simon A Gayther,
Paul D P Pharoah,
Roger R Reddel,
Ellen L Goode,
Mark H Greene,
Douglas F Easton,
Andrew Berchuck,
Antonis C Antoniou,
Georgia Chenevix-Trench,
Alison M Dunning
[show abstract]
[hide abstract]
ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Nature Genetics 03/2013; 45(4):371-384. · 35.53 Impact Factor
-
Juliet D French,
Maya Ghoussaini,
Stacey L Edwards,
Kerstin B Meyer,
Kyriaki Michailidou,
Shahana Ahmed,
Sofia Khan,
Mel J Maranian,
Martin O'Reilly,
Kristine M Hillman, [......],
Anthony Swerdlow,
Alan Ashworth,
Nick Orr,
Minouk J Schoemaker,
Bruce A J Ponder,
Heli Nevanlinna,
Melissa A Brown,
Georgia Chenevix-Trench,
Douglas F Easton,
Alison M Dunning
[show abstract]
[hide abstract]
ABSTRACT: Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
The American Journal of Human Genetics 03/2013; · 10.60 Impact Factor
-
Stefan Nickels,
Thérèse Truong,
Rebecca Hein,
Kristen Stevens,
Katharina Buck,
Sabine Behrens,
Ursula Eilber,
Martina Schmidt,
Lothar Häberle,
Alina Vrieling, [......],
Alice J Sigurdson,
Michele M Doody,
Pascal Guénel,
Paul D P Pharoah,
Marjanka K Schmidt,
Per Hall,
Doug F Easton,
Montserrat Garcia-Closas,
Roger L Milne,
Jenny Chang-Claude
[show abstract]
[hide abstract]
ABSTRACT: Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
PLoS Genetics 03/2013; 9(3):e1003284. · 8.69 Impact Factor
-
Rebecca Hein,
Dieter Flesch-Janys,
Norbert Dahmen,
Lars Beckmann,
Sara Lindström,
Nils Schoof,
Kamila Czene,
Kirstin Mittelstraß,
Thomas Illig,
Petra Seibold, [......],
Hoda Anton-Culver,
Chen-Yang Shen,
Hiltrud Brauch,
Julian Peto,
Pascal Guénel,
Peter Kraft,
Fergus J Couch,
Douglas F Easton,
Per Hall,
Jenny Chang-Claude
[show abstract]
[hide abstract]
ABSTRACT: Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10(-6) for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10(-7)) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.
Breast Cancer Research and Treatment 02/2013; · 4.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: To identify country-level correlates of geographical variations in cervical cancer (CC) mortality in Latin America and the Caribbean (LAC). MATERIALS AND METHODS: CC mortality rates for LAC countries (n=26) were examined in relation to country-specific socio-economic indicators (n=58) and Human Papilloma Virus (HPV) prevalence using linear regression models. RESULTS: High mortality at ages <5 years, low per capita total expenditure on health, and low proportion of the population with access to sanitation were identified as the best independent predictors of CC mortality (R² =77%). In the subset of countries (n=10) with HPV prevalence estimates, these socio-economic indicators together with high-risk HPV prevalence explained almost all the between-country variability in CC mortality (R² =98%). CONCLUSION: The findings suggest that continuing socioeconomic improvements in LAC countries will be associated with further reductions in CC mortality even in the absence of organised population-based screening and vaccination programmes.
Salud publica de Mexico 02/2013; 55(1):5-15. · 0.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mammographic density (MD) is a strong marker of breast cancer risk, but it is debated whether the association holds, and is of a similar magnitude, for different subtypes of breast cancer defined by receptor status or gene expression profiles. A literature search conducted in June 2012 was used to identify all studies that had investigated the association of MD with subtype-specific breast cancer, independent of age. 7 cohort/case-control and 12 case-only studies were included, comprising a total of >24,000 breast cancer cases. Random effects meta-analysis models were used to combine relative risks (RR) of MD with subtype-specific breast cancer for case-control studies, and in case-only studies to combine relative risk ratios (RRR) of receptor positive versus negative breast tumors. In case-control/cohort studies, relative to women in the lowest density category, women in the highest density category had 3.1-fold (95 % confidence interval [CI] 2.2, 4.2) and 3.2-fold (1.7, 5.9) increased risk of estrogen receptor positive (ER+) and ER- breast cancer, respectively. In case-only analyses, RRRs of breast tumors being ER+ versus ER- were 1.13 (95 % CI 0.89, 1.42) for medium versus minimal MD. MD remained associated with screen-detected ER+ tumors, despite the expectation of this association to be attenuated due to masking bias and overdiagnoses of ER+ tumors. In eight contributing studies, the association of MD did not differ by HER2 status. This combined evidence strengthens the importance of MD as a strong marker of overall and of subtype-specific risk, and confirms its value in overall breast cancer risk assessment and monitoring for both research and clinical purposes.
Breast Cancer Research and Treatment 12/2012; · 4.43 Impact Factor
-
Afshan Siddiq,
Fergus J Couch,
Gary K Chen,
Sara Lindström,
Diana Eccles,
Robert C Millikan,
Kyriaki Michailidou,
Daniel O Stram,
Lars Beckmann,
Suhn Kyong Rhie, [......],
Elad Ziv,
Heli Nevanlinna,
Douglas F Easton,
David J Hunter,
Brian E Henderson,
Stephen J Chanock,
Montserrat Garcia-Closas,
Peter Kraft,
Christopher A Haiman,
Celine M Vachon
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
Human Molecular Genetics 09/2012; · 7.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Studies on cancer in migrants are informative about the relative influence of environmental and genetic factors on cancer risk. This study investigates trends in incidence from colorectal, lung, breast and prostate cancer in England among South Asians and examines the influence of deprivation, a key environmental exposure. South Asian ethnicity was assigned to patients recorded in the population-based National Cancer Registry of England during 1986-2004, using the computerized algorithm SANGRA: South Asian Names and Groups Recognition Algorithm. Population denominators were derived from population censuses. Multivariable flexible (splines) Poisson models were used to estimate trends and socioeconomic differentials in incidence in South Asians compared to non-South Asians. Overall, age-adjusted cancer incidence in South Asians was half that in non-South Asians but rose over time. Cancer-specific incidence trends and patterns by age and deprivation differed widely between the two ethnic groups. In contrast to non-South Asians, lung cancer incidence in South Asians did not fall. Colorectal and breast cancer incidence rose in both groups, more steeply in South Asians though remaining less common than in non-South Asians. The deprivation gaps in cancer-specific incidence were much less marked among South Asians, explaining some of the ethnic differences in overall incidence. Although still lower than in non-South Asians, cancer incidence is rising in South Asians, supporting the concept of transition in cancer incidence among South Asians living in England. Although these trends vary by cancer, they have important implications for both prevention and anticipating health-care demand.
International Journal of Cancer 09/2012; · 5.44 Impact Factor
-
Helen Warren,
Frank Dudbridge,
Olivia Fletcher,
Nick Orr,
Nichola Johnson,
John L Hopper,
Carmel Apicella,
Melissa C Southey,
Maryam Mahmoodi,
Marjanka K Schmidt, [......],
Maya Ghoussaini,
Alan Ashworth,
Anthony Swerdlow,
Michael Jones,
Minouk Schoemaker,
Douglas F Easton,
Manjeet Humphreys,
Qin Wang,
Julian Peto, Isabel Dos-Santos-Silva
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). METHODS: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). RESULTS: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors. CONCLUSIONS: This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783-. ©2012 AACR.
Cancer Epidemiology Biomarkers & Prevention 08/2012; 21(10):1783-1791. · 4.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Flight crew are occupationally exposed to several potentially carcinogenic hazards; however, previous investigations have been hampered by lack of information on lifestyle exposures. The authors identified, through the United Kingdom Civil Aviation Authority medical records, a cohort of 16,329 flight crew and 3,165 air traffic control officers (ATCOs) and assembled data on their occupational and lifestyle exposures. Standardised incidence ratios (SIRs) were estimated to compare cancer incidence in each occupation to that of the general population; internal analyses were conducted by fitting Cox regression models. All-cancer incidence was 20-29% lower in each occupation than in the general population, mainly due to a lower incidence of smoking-related cancers [SIR (95% CI) = 0.33 (0.27-0.38) and 0.42 (0.28-0.60) for flight crew and ATCOs, respectively], consistent with their much lower prevalence of smoking. Skin melanoma rates were increased in both flight crew (SIR = 1.87; 95% CI = 1.45-2.38) and ATCOs (2.66; 1.55-4.25), with rates among the former increasing with increasing number of flight hours (p-trend = 0.02). However, internal analyses revealed no differences in skin melanoma rates between flight crew and ATCOs (hazard ratio: 0.78, 95% CI = 0.37-1.66) and identified skin that burns easily when exposed to sunlight (p = 0.001) and sunbathing to get a tan (p = 0.07) as the strongest risk predictors of skin melanoma in both occupations. The similar site-specific cancer risks between the two occupational groups argue against risks among flight crew being driven by occupation-specific exposures. The skin melanoma excess reflects sun-related behaviour rather than cosmic radiation exposure.
International Journal of Cancer 04/2012; · 5.44 Impact Factor
-
Nichola Johnson,
Kate Walker,
Lorna J Gibson,
Nick Orr,
Elizabeth Folkerd,
Ben Haynes,
Claire Palles,
Ben Coupland,
Minouk Schoemaker,
Michael Jones, [......],
Jill Williamson,
Stephen G Hillier,
Gillian Ross,
Richard S Houlston,
Anthony Swerdlow,
Alan Ashworth,
Mitch Dowsett,
Julian Peto, Isabel Dos Santos Silva,
Olivia Fletcher
[show abstract]
[hide abstract]
ABSTRACT: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women.
We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided.
rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82).
Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.
CancerSpectrum Knowledge Environment 04/2012; 104(9):657-69. · 14.07 Impact Factor
-
Celine M Vachon,
Christopher G Scott,
Peter A Fasching,
Per Hall,
Rulla M Tamimi,
Jingmei Li,
Jennifer Stone,
Carmel Apicella,
Fabrice Odefrey,
Gretchen L Gierach, [......],
Agnieszka Bukowska,
Edyta Reszka,
JianJun Liu,
Louise Eriksson,
Kamila Czene,
Tina Audley,
Anna H Wu,
V Shane Pankratz,
John L Hopper, Isabel dos-Santos-Silva
[show abstract]
[hide abstract]
ABSTRACT: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures.
We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status.
Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07).
We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland.
We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association.
Cancer Epidemiology Biomarkers & Prevention 03/2012; 21(7):1156-66. · 4.12 Impact Factor
-
Diether Lambrechts,
Therese Truong,
Christina Justenhoven,
Manjeet K Humphreys,
Jean Wang,
John L Hopper,
Gillian S Dite,
Carmel Apicella,
Melissa C Southey,
Marjanka K Schmidt, [......],
Daehee Kang,
Keun-Young Yoo,
Dong-Young Noh,
Annika Lindblom,
Sara Margolin,
Alison M Dunning,
Paul D P Pharoah,
Douglas F Easton,
Pascal Guénel,
Hiltrud Brauch
[show abstract]
[hide abstract]
ABSTRACT: A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.
Human Mutation 03/2012; 33(7):1123-32. · 5.69 Impact Factor
-
Kristen N Stevens,
Zachary Fredericksen,
Celine M Vachon,
Xianshu Wang,
Sara Margolin,
Annika Lindblom,
Heli Nevanlinna,
Dario Greco,
Kristiina Aittomäki,
Carl Blomqvist, [......],
Marie-Rose Christiaens,
Georgia Chenevix-Trench,
Jonathan Beesley,
Xiaoqing Chen,
Arto Mannermaa,
Veli-Matti Kosma,
Jaana M Hartikainen,
Ylermi Soini,
Douglas F Easton,
Fergus J Couch
[show abstract]
[hide abstract]
ABSTRACT: The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways.
Cancer Research 02/2012; 72(7):1795-803. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cases with a family history are enriched for genetic risk variants, and the power of association studies can be improved by selecting cases with a family history of disease. However, in recent genome-wide association scans utilizing familial sampling, the excess relative risk for familial cases is less than predicted when compared with unselected cases. This can be explained by incomplete linkage disequilibrium between the tested marker and the underlying causal variant.
We show that the allele frequency and effect size of the underlying causal variant can be estimated by combining marker data from studies that ascertain cases based on different family histories. This allows us to learn about the genetic architecture of a complex trait, without having identified any causal variants. We consider several validated common marker alleles for breast cancer, using our own study of high risk, predominantly bilateral cases, cases preferentially selected to have at least two affected first- or second-degree relatives, and published estimates of relative risk from standard case-control studies.
To obtain realistic estimates and to accommodate some prior beliefs, we use Bayesian estimation to infer that the causal variants are probably common, with minor allele frequency >5%, and have small effects, with relative risk around 1.2.
These results strongly support the common disease common variant hypothesis for these specific loci associated with breast cancer. Impact: Our results agree with recent assertions that synthetic associations of rare variants are unlikely to account for most associations seen in genome-wide studies.
Cancer Epidemiology Biomarkers & Prevention 02/2012; 21(2):262-72. · 4.12 Impact Factor
-
Rebecca Hein,
Melanie Maranian,
John L Hopper,
Miroslaw K Kapuscinski,
Melissa C Southey,
Daniel J Park,
Marjanka K Schmidt,
Annegien Broeks,
Frans B L Hogervorst,
H Bas Bueno-de-Mesquit, [......],
Polly A Newcomb,
Linda Titus,
Kathleen M Egan,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Manjeet K Humphreys,
Jonathan Morrison,
Jenny Chang-Claude,
Douglas F Easton,
Alison M Dunning
[show abstract]
[hide abstract]
ABSTRACT: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
PLoS ONE 01/2012; 7(8):e42380. · 4.09 Impact Factor
-
Rebecca Hein,
Melanie Maranian,
John L Hopper,
Miroslaw K Kapuscinski,
Melissa C Southey,
Daniel J Park,
Marjanka K Schmidt,
Annegien Broeks,
Frans B L Hogervorst,
H Bas Bueno-de-Mesquit, [......],
Polly A Newcomb,
Linda Titus,
Kathleen M Egan,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Manjeet K Humphreys,
Jonathan Morrison,
Jenny Chang-Claude,
Douglas F Easton,
Alison M Dunning
PLoS ONE 01/2012; 7(10). · 4.09 Impact Factor
