TY - JOUR
T1 - Telomere maintenance variants and survival after colorectal cancer
T2 - smoking- And sex-specific associations
AU - Yin, Hang
AU - Hardikar, Sheetal
AU - Lindstroem, Sara
AU - Hsu, Li
AU - Anderson, Kristin E.
AU - Banbury, Barbara L.
AU - Berndt, Sonja I.
AU - Chan, Andrew T.
AU - Giovanucci, Edward L.
AU - Harrison, Tabitha A.
AU - Joshi, Amit D.
AU - Nan, Hongmei
AU - Potter, John D.
AU - Sakoda, Lori C.
AU - Slattery, Martha L.
AU - Schoen, Robert E.
AU - White, Emily
AU - Peters, Ulrike
AU - Newcomb, Polly A.
N1 - Funding Information:
GECCO: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) is supported by grants from the NCI, NIH, U.S. Department of Health and Human Services (U01 CA164930 and R01 CA059045, to U. Peters). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. The authors thank all people who made the study possible. They appreciate the efforts of the GECCO Coordinating Center to ensure the data collaboration.
Funding Information:
PLCO: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) is supported by grants from the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, NCI, NIH, DHHS. Funding was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. The authors thank the PLCO Cancer Screening Trial screening center investigators and the staff from Information Management Services Inc and Westat Inc. Most importantly, they thank the study participants for their contributions that made this study possible.
Funding Information:
Harvard cohorts (HPFS, NHS, PHS): Health Professionals Follow-up Study (HPFS) is supported by the NIH (P01 CA055075, to E.L. Giovanucci; UM1 CA167552 and U01 CA167552, to W.C. Willett; R01 CA151993 and R35 CA197735, to S. Ogino; K07 CA190673, to R. Nishihara; R01 CA137178 and P50 CA127003, to A.T. Chan), Nurses' Health Study (NHS) by the NIH (P01 CA087969, to E. Giovanucci; UM1 CA186107, to M. Stampfer; R01 CA151993 and R35 CA197735, to S. Ogino; K07 CA190673, to R. Nishihara; R01 CA137178 and P50 CA127003, to A.T. Chan), and Physician's Health Study (PHS) by the NIH (R01 CA042182, to J. Ma). The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. The authors thank the participants and staff of the HPFS, NHS, and PHS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/9
Y1 - 2020/9
N2 - Background: Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated. Methods: We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer–specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction. Results: The association between minor allele of rs7200950 (ACD) with colorectal cancer–specific survival varied significantly by smoking pack-years (corrected P ¼ 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer–specific survival in women but not in men. Conclusions: Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted. Impact: Our study found a gene–smoking and gene–sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.
AB - Background: Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated. Methods: We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer–specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction. Results: The association between minor allele of rs7200950 (ACD) with colorectal cancer–specific survival varied significantly by smoking pack-years (corrected P ¼ 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer–specific survival in women but not in men. Conclusions: Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted. Impact: Our study found a gene–smoking and gene–sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.
UR - http://www.scopus.com/inward/record.url?scp=85091746303&partnerID=8YFLogxK
U2 - 10.1158/1055-9965.EPI-19-1507
DO - 10.1158/1055-9965.EPI-19-1507
M3 - Article
C2 - 32586834
AN - SCOPUS:85091746303
SN - 1055-9965
VL - 29
SP - 1817
EP - 1824
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 9
ER -