Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk,JNCI Journal of the National Cancer Institute

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Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk
JNCI Journal of the National Cancer Institute Pub Date : 2022-04-30 , DOI: 10.1093/jnci/djac094
Yu Tian _{1,

2} , Andre E Kim ₃ , Stephanie A Bien ₄ , Yi Lin ₄ , Conghui Qu ₄ , Tabitha A Harrison ₄ , Robert Carreras-Torres _{5,

6,

7} , Virginia Díez-Obrero _{5,

6,

7} , Niki Dimou ₈ , David A Drew _{9,

10} , Akihisa Hidaka ₄ , Jeroen R Huyghe ₄ , Kristina M Jordahl _{4,

11} , John Morrison ₃ , Neil Murphy ₈ , Mireia Obón-Santacana _{5,

6,

7} , Cornelia M Ulrich _{12,

13} , Jennifer Ose _{12,

13} , Anita R Peoples _{12,

13} , Edward A Ruiz-Narvaez ₁₄ , Anna Shcherbina ₁₅ , Mariana C Stern ₁₆ , Yu-Ru Su _{4,

17} , Franzel J B van Duijnhoven ₁₈ , Volker Arndt ₁₉ , James W Baurley _{20,

21} , Sonja I Berndt ₂₂ , D Timothy Bishop ₂₃ , Hermann Brenner _{19,

24,

25} , Daniel D Buchanan _{26,

27,

28} , Andrew T Chan _{9,

10,

29,

30,

31,

32} , Jane C Figueiredo _{33,

34} , Steven Gallinger ₃₅ , Stephen B Gruber ₁₆ , Sophia Harlid ₃₆ , Michael Hoffmeister ₁₉ , Mark A Jenkins ₃₇ , Amit D Joshi ₃₁ , Temitope O Keku ₃₈ , Susanna C Larsson ₃₉ , Loic Le Marchand ₄₀ , Li Li ₄₁ , Graham G Giles _{37,

42,

43} , Roger L Milne _{37,

42,

43} , Hongmei Nan _{44,

45} , Rami Nassir ₄₆ , Shuji Ogino _{30,

31,

47,

48} , Arif Budiarto ₂₀ , Elizabeth A Platz ₄₉ , John D Potter _{4,

50} , Ross L Prentice _{4,

51} , Gad Rennert _{52,

53,

54} , Lori C Sakoda _{4,

55} , Robert E Schoen ₅₆ , Martha L Slattery ₅₇ , Stephen N Thibodeau ₅₈ , Bethany Van Guelpen _{36,

59} , Kala Visvanathan ₄₉ , Emily White _{4,

11} , Alicja Wolk ₃₉ , Michael O Woods ₆₀ , Anna H Wu ₃₄ , Peter T Campbell ₆₁ , Graham Casey ₆₂ , David V Conti ₁₆ , Marc J Gunter ₈ , Anshul Kundaje _{63,

64} , Juan Pablo Lewinger ₃ , Victor Moreno _{5,

6,

7,

65} , Polly A Newcomb _{4,

11} , Bens Pardamean ₂₀ , Duncan C Thomas ₁₆ , Konstantinos K Tsilidis _{66,

67} , Ulrike Peters _{4,

11} , W James Gauderman ₁₆ , Li Hsu _{4,

51} , Jenny Chang-Claude _{1,

68}

Affiliation

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
School of Public Health, Capital Medical University, Beijing, China.
Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
Huntsman Cancer Institute, Salt Lake City, UT, USA.
Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Biomedical Informatics Program, Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA.
Division of Biostatistics, Department of Population and Public Health Sciences & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
BioRealm LLC, Walnut, CA, USA.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
University of Hawaii Cancer Center, Honolulu, HI, USA.
Department of Family Medicine, University of Virginia, Charlottesville, VA, USA.
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
Department of Global Health, Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA.
Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA.
Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Research Centre for Hauora and Health, Massey University, Wellington, New Zealand.
Department of Biostatistics, University of Washington, Seattle, WA, USA.
Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Clalit National Cancer Control Center, Haifa, Israel.
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL,Canada.
Department of Population Science, American Cancer Society, Atlanta, GA, USA.
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Department of Genetics, Stanford University, Stanford, CA, USA.
Department of Computer Science, Stanford University, Stanford, CA, USA.
Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
University Cancer Centre Hamburg (UCCH), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Abstract Background The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2– or 3–degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2–degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10−4). Conclusion Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

中文翻译：

遗传变异与绝经期激素治疗结直肠癌风险的全基因组相互作用分析

摘要背景更年期激素疗法（MHT）的使用可能与遗传变异相互作用，从而影响结直肠癌（CRC）风险。方法我们在 28 486 名绝经后妇女（11 519 名 CRC 患者和 16 967 名未接受过 CRC 治疗的参与者）中进行了单核苷酸多态性与使用任何 MHT、仅使用雌激素以及雌激素-孕激素联合治疗与 CRC 风险之间的全基因组、基因-环境相互作用。 CRC）来自 38 项研究，使用逻辑回归、两步法和 2 或 3 自由度联合检验。基于集合的评分测试适用于罕见的遗传变异。结果使用任何 MHT、仅使用雌激素和雌激素-孕激素均可降低 CRC 风险（比值比 [OR] = 0.71，95% 置信区间 [CI] = 0.64 至 0.78；OR = 0.65，95% CI = 0.53至 0.79；OR = 0.73，95% CI = 0.59 至 0.90。两步法确定了 GRIN2B 变体 rs117868593 和 MHT 使用之间存在统计学上显着的相互作用，其中 GG 基因型女性中 MHT 相关的 CRC 风险在统计学上显着降低（OR = 0.68，95% CI = 0.64 至 0.72），但并非如此。在 GC 或 CC 基因型的层内。通过 2 自由度联合测试发现 6q22.1 (rs10782186) 处的 DCBLD1 内含子变异与 MHT 使用之间存在统计学上显着的相互作用。 MHT 相关的 CRC 风险随着 rs10782186-C 等位基因数量的增加而降低，TT 的比值比为 0.78（95% CI = 0.70 至 0.87），TC 为 0.68（95% CI = 0.63 至 0.73），TC 为 0.66（95% CI = 0.70 至 0.87）。 CC 基因型的 95% CI = 0.60 至 0.74)。此外，罕见变异分析中的 5 个基因显示出与 MHT 的暗示相互作用（2 侧 P < 1.2 × 10−4）。结论确定了改变 MHT 和 CRC 风险之间关联的基因变异，为 CRC 致癌途径和相关潜在机制提供了新的见解。

更新日期：2022-04-30

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