DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility

Barbara Pardini; Alda Corrado; Elisa Paolicchi; Giovanni Cugliari; Sonja I. Berndt; Stephane Bezieau; Stephanie A. Bien; Hermann Brenner; Bette J. Caan; Peter T. Campbell; Graham Casey; Andrew T. Chan; Jenny Chang-Claude; Michelle Cotterchio; Manish Gala; Steven J. Gallinger; Robert W. Haile; Tabitha A. Harrison; Richard B. Hayes; Michael Hoffmeister; John L. Hopper; Li Hsu; Jeroen Huyghe; Mark A. Jenkins; Loic Le Marchand; Yi Lin; Noralane M. Lindor; Hongmei Nan; Polly A. Newcomb; Shuji Ogino; John D. Potter; Robert E. Schoen; Martha L. Slattery; Emily White; Ludmila Vodickova; Veronika Vymetalkova; Pavel Vodicka; Federica Gemignani; Ulrike Peters; Alessio Naccarati; Stefano Landi

doi:10.1002/ijc.32516

DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility

Barbara Pardini, Alda Corrado, Elisa Paolicchi, Giovanni Cugliari, Sonja I. Berndt, Stephane Bezieau, Stephanie A. Bien, Hermann Brenner, Bette J. Caan, Peter T. Campbell, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Michelle Cotterchio, Manish Gala, Steven J. Gallinger, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael HoffmeisterJohn L. Hopper, Li Hsu, Jeroen Huyghe, Mark A. Jenkins, Loic Le Marchand, Yi Lin, Noralane M. Lindor, Hongmei Nan, Polly A. Newcomb, Shuji Ogino, John D. Potter, Robert E. Schoen, Martha L. Slattery, Emily White, Ludmila Vodickova, Veronika Vymetalkova, Pavel Vodicka, Federica Gemignani, Ulrike Peters, Alessio Naccarati, Stefano Landi

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10⁻⁶) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10⁻⁶). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10⁻⁶. Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

Original language	English (US)
Pages (from-to)	363-372
Number of pages	10
Journal	International Journal of Cancer
Volume	146
Issue number	2
DOIs	https://doi.org/10.1002/ijc.32516
State	Published - Jan 15 2020
Externally published	Yes

Keywords

cancer susceptibility
colon cancer
DNA repair
genome-wide association studies
rectal cancer
single nucleotide polymorphisms

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/ijc.32516

Cite this

Pardini, B., Corrado, A., Paolicchi, E., Cugliari, G., Berndt, S. I., Bezieau, S., Bien, S. A., Brenner, H., Caan, B. J., Campbell, P. T., Casey, G., Chan, A. T., Chang-Claude, J., Cotterchio, M., Gala, M., Gallinger, S. J., Haile, R. W., Harrison, T. A., Hayes, R. B., ... Landi, S. (2020). DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility. International Journal of Cancer, 146(2), 363-372. https://doi.org/10.1002/ijc.32516

Pardini, B, Corrado, A, Paolicchi, E, Cugliari, G, Berndt, SI, Bezieau, S, Bien, SA, Brenner, H, Caan, BJ, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Cotterchio, M, Gala, M, Gallinger, SJ, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, J, Jenkins, MA, Le Marchand, L, Lin, Y, Lindor, NM, Nan, H, Newcomb, PA, Ogino, S, Potter, JD, Schoen, RE, Slattery, ML, White, E, Vodickova, L, Vymetalkova, V, Vodicka, P, Gemignani, F, Peters, U, Naccarati, A & Landi, S 2020, 'DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility', International Journal of Cancer, vol. 146, no. 2, pp. 363-372. https://doi.org/10.1002/ijc.32516

@article{187745d9d575416e85254ac0028f0a75,

title = "DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility",

abstract = "Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10−6. Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.",

keywords = "cancer susceptibility, colon cancer, DNA repair, genome-wide association studies, rectal cancer, single nucleotide polymorphisms",

author = "Barbara Pardini and Alda Corrado and Elisa Paolicchi and Giovanni Cugliari and Berndt, {Sonja I.} and Stephane Bezieau and Bien, {Stephanie A.} and Hermann Brenner and Caan, {Bette J.} and Campbell, {Peter T.} and Graham Casey and Chan, {Andrew T.} and Jenny Chang-Claude and Michelle Cotterchio and Manish Gala and Gallinger, {Steven J.} and Haile, {Robert W.} and Harrison, {Tabitha A.} and Hayes, {Richard B.} and Michael Hoffmeister and Hopper, {John L.} and Li Hsu and Jeroen Huyghe and Jenkins, {Mark A.} and {Le Marchand}, Loic and Yi Lin and Lindor, {Noralane M.} and Hongmei Nan and Newcomb, {Polly A.} and Shuji Ogino and Potter, {John D.} and Schoen, {Robert E.} and Slattery, {Martha L.} and Emily White and Ludmila Vodickova and Veronika Vymetalkova and Pavel Vodicka and Federica Gemignani and Ulrike Peters and Alessio Naccarati and Stefano Landi",

note = "Funding Information: PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Funding was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. Funding Information: Key words: colon cancer, rectal cancer, DNA repair, single nucleotide polymorphisms, cancer susceptibility, genome-wide association studies Abbreviations: BSGoF: binomial sequential goodness of fit; CCFR: Colon Cancer Family Registry; CI: confidence interval; eQTL: expression quantitative trait loci; FDR: false discovery rate; GECCO: Genetics and Epidemiology of Colorectal Cancer; GWAS: genome-wide association studies; HNPCC: hereditary nonpolyposis colorectal cancer; HR: homologous recombination; HRC: Haplotype Reference Consortium; htSNPs: haplotype tagging SNPs; HWE: Hardy–Weinberg Equilibrium; LD: linkage disequilibrium; MAF: minor allele frequency; MMR: mismatch repair pathway; MSI: microsatellite instability; NES: normalized effect size; OR: odds ratio; PARP: poly(ADP-ribose) polymerase; PCs: principal components; SNPs: single-nucleotide polymorphisms Additional Supporting Information may be found in the online version of this article. Conflict of interest: The authors declare no conflict of interests. Grant sponsor: Association Anne de Bretagne Genetique; Grant sponsor: California Department of Public Health; Grant number: HHSN261201000035C; Grant sponsor: Fondazione Umberto Veronesi; Grant sponsor: Fulbright Italy Research scholar grant 2018; Grant sponsor: German Federal Ministry of Education and Research; Grant numbers: 01ER0814, 01ER0815, 01ER1505A, 01ER1505B, 01KH0404; Grant sponsor: German Research Council; Grant numbers: HO 5117/2-1, BR 1704/17-1, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1; Grant sponsor: Grantov{\'a} Agentura Cesk{\'e}≤ Republiky; Grant number: 17-16857S; Grant sponsor: Groupement des Entreprises Fran{\c c}aises dans la Lutte contre le cancer (GEFLUC); Grant sponsor: Hawaii Department of Health; Grant numbers: N01-PC-67001, HHSN26120100037C, N01-PC-35137; Grant sponsor: Lega Italiana per La Lotta contro i Tumori; Grant sponsor: Ligue R{\'e}gionale Contre le Cancer; Grant sponsor: Ministerstvo Zdravotnictv{\'i} Cesk{\'e} Republiky; Grant numbers: AZV 15-27580, AZV 17-30920; Grant sponsor: National Cancer Institute; Grant numbers: HHSN2612013000121, K07 CA190673, N01-CN-67009, N01-PC-35142, P01 CA087969, P30 CA015704, P50 CA127003, R01 CA042182, R01 CA059045, R01 CA137178, R01 CA151993, R01 CA48998, R35 CA197735, U01 CA074778, U01 CA137088, U01 CA164930, U01 HG 004438, U01/U24 CA074783, U01/ U24 CA074794, U01/U24 CA074799, U01/U24 CA074800, U01/U24 CA074806, U01/U24 CA097735, U19 CA148107, UM1 CA186107, Z01 CP 010200; Grant sponsor: National Heart, Lung, and Blood Institute; Grant numbers: HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN268201100046C, HHSN271201100004C; Grant sponsor: National Institutes of Health; Grant numbers: K05 CA154337, P01 CA033619, P01 CA055075, R01 CA063464, R01 CA076366, R01 CA143247, R01 CA60987, R37 CA54281, U01 CA074783, U01 CA122839, U01 CA167551, U01 CA167552, U01 HG004446, UM1 CA167552; Grant sponsor: Regional Council of Pays de la Loire *B.P., A.C., U.P., A.N., and S.L. contributed equally to this work DOI: 10.1002/ijc.32516 History: Received 25 Feb 2019; Accepted 27 May 2019; Online 17 Jun 2019 Correspondence to: Alda Corrado, Department of Biology, University of Pisa, Via Derna 1, 56126 Pisa, Italy, Tel.: +390502211524, Fax: +390502211527, E-mail: corradoalda@gmail.com; or Barbara Pardini, Italian Institute for Genomic Medicine (IIGM), Via Nizza 52, 10126 Turin, Italy, Tel.: +390116709542, Fax: +390112365601, E-mail: barbara.pardini@iigm.it Funding Information: ASTERISK: a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Fran{\c c}aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne G{\'e}n{\'e}tique and the Ligue R{\'e}gionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (R01 CA60987). Funding Information: DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B). Funding Information: OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. Funding Information: WHI: The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A full listing of WHI investigators can be found at http://www.whi.org/ researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator% 20Short%20List.pdf The study was funded by the Italian Institute for Genomic Medicine (IIGM) and Compagnia di San Paolo Torino, Italy (to A. Naccarati, B. Pardini and G. Cugliari); Fondazione Umberto Veronesi “Post-doctoral fellowship Year 2014, 2015, 2016 and 2017” (to B. Pardini); Lega Italiana per La Lotta contro i Tumori (to B. Pardini and A. Naccarati), by the Grant Agency of the Czech Republic (17-16857S to A. Naccarati); by the Istituto Toscano Tumori (grant n. I56D15000010002 to S. Landi); by AZV Ministry of Health, Czech Republic (AZV 15-27580 and AZV 17-30920 to P. Vodicka and V. Vymetalkova). B. Pardini was supported by a Fulbright Research Scholarships (year 2018). Funding Information: WHI: The WHI program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN 268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN 268201100004C and HHSN271201100004C. Funding Information: The Colon Cancer Family Registry (CFR) Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (grant numbers U01 CA122839, R01 CA143247). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from National Cancer Institute, National Institutes of Health (grant number U19 CA148107 to S Gruber). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the National Cancer Institute, National Institutes of Health (grant number U01 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806), Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai{\textquoteright}i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137, and Contract No. HHSN26120100037C, and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: AZ, CO, MN, NC, NH, and by the Victoria Cancer Registry and Ontario Cancer Registry. Funding Information: Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673 and P50 CA127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673 and P50 CA127003) and PHS by the National Institutes of Health (R01 CA042182). Funding Information: ASTERISK: We are very grateful to Dr. Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. COLON CFR: CCFR: We graciously thank the generous contributions of our study participants, the dedication of our study staff, and the financial support from the U.S. National Cancer Institute, without which our important registry would not exist. DACHS: We thank all participants and cooperating clinicians, and Ute Handte-Daub, Utz Benscheid, Muhabbet Celik and Ursula Eilber for excellent technical assistance. Harvard cohorts: We would like to 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. PLCO: The authors thank the PLCO Cancer Screening Trial screening center investigators and the staff from Information Management Services Inc. and Westat Inc. Most importantly, we thank the study participants for their contributions that made this study possible. PMH: The authors would like to thank the study participants and staff of the Hormones and Colon Cancer study. WHI: The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A full listing of WHI investigators can be found at http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf The study was funded by the Italian Institute for Genomic Medicine (IIGM) and Compagnia di San Paolo Torino, Italy (to A. Naccarati, B. Pardini and G. Cugliari); Fondazione Umberto Veronesi ?Post-doctoral fellowship Year 2014, 2015, 2016 and 2017? (to B. Pardini); Lega Italiana per La Lotta contro i Tumori (to B. Pardini and A. Naccarati), by the Grant Agency of the Czech Republic (17-16857S to A. Naccarati); by the Istituto Toscano Tumori (grant n. I56D15000010002 to S. Landi); by AZV Ministry of Health, Czech Republic (AZV 15-27580 and AZV 17-30920 to P. Vodicka and V. Vymetalkova). B. Pardini was supported by a Fulbright Research Scholarships (year 2018). ASTERISK: a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Fran?aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne G?n?tique and the Ligue R?gionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (R01 CA60987). The Colon Cancer Family Registry (CFR) Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (grant numbers U01 CA122839, R01 CA143247). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from National Cancer Institute, National Institutes of Health (grant number U19 CA148107 to S Gruber). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the National Cancer Institute, National Institutes of Health (grant number U01 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806), Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai'i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137, and Contract No. HHSN26120100037C, and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: AZ, CO, MN, NC, NH, and by the Victoria Cancer Registry and Ontario Cancer Registry. DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B). DALS: National Institutes of Health (R01 CA48998 to M. L. Slattery). Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673 and P50 CA127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673 and P50 CA127003) and PHS by the National Institutes of Health (R01 CA042182). MEC: National Institutes of Health (R37 CA54281, P01 CA033619 and R01 CA063464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Funding was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. PMH: National Institutes of Health (R01 CA076366 to P.A. Newcomb). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. Publisher Copyright: {\textcopyright} 2019 UICC",

year = "2020",

month = jan,

day = "15",

doi = "10.1002/ijc.32516",

language = "English (US)",

volume = "146",

pages = "363--372",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "Wiley-Liss Inc.",

number = "2",

}

TY - JOUR

T1 - DNA repair and cancer in colon and rectum

T2 - Novel players in genetic susceptibility

AU - Pardini, Barbara

AU - Corrado, Alda

AU - Paolicchi, Elisa

AU - Cugliari, Giovanni

AU - Berndt, Sonja I.

AU - Bezieau, Stephane

AU - Bien, Stephanie A.

AU - Brenner, Hermann

AU - Caan, Bette J.

AU - Campbell, Peter T.

AU - Casey, Graham

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Cotterchio, Michelle

AU - Gala, Manish

AU - Gallinger, Steven J.

AU - Haile, Robert W.

AU - Harrison, Tabitha A.

AU - Hayes, Richard B.

AU - Hoffmeister, Michael

AU - Hopper, John L.

AU - Hsu, Li

AU - Huyghe, Jeroen

AU - Jenkins, Mark A.

AU - Le Marchand, Loic

AU - Lin, Yi

AU - Lindor, Noralane M.

AU - Nan, Hongmei

AU - Newcomb, Polly A.

AU - Ogino, Shuji

AU - Potter, John D.

AU - Schoen, Robert E.

AU - Slattery, Martha L.

AU - White, Emily

AU - Vodickova, Ludmila

AU - Vymetalkova, Veronika

AU - Vodicka, Pavel

AU - Gemignani, Federica

AU - Peters, Ulrike

AU - Naccarati, Alessio

AU - Landi, Stefano

N1 - Funding Information: PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Funding was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. Funding Information: Key words: colon cancer, rectal cancer, DNA repair, single nucleotide polymorphisms, cancer susceptibility, genome-wide association studies Abbreviations: BSGoF: binomial sequential goodness of fit; CCFR: Colon Cancer Family Registry; CI: confidence interval; eQTL: expression quantitative trait loci; FDR: false discovery rate; GECCO: Genetics and Epidemiology of Colorectal Cancer; GWAS: genome-wide association studies; HNPCC: hereditary nonpolyposis colorectal cancer; HR: homologous recombination; HRC: Haplotype Reference Consortium; htSNPs: haplotype tagging SNPs; HWE: Hardy–Weinberg Equilibrium; LD: linkage disequilibrium; MAF: minor allele frequency; MMR: mismatch repair pathway; MSI: microsatellite instability; NES: normalized effect size; OR: odds ratio; PARP: poly(ADP-ribose) polymerase; PCs: principal components; SNPs: single-nucleotide polymorphisms Additional Supporting Information may be found in the online version of this article. Conflict of interest: The authors declare no conflict of interests. Grant sponsor: Association Anne de Bretagne Genetique; Grant sponsor: California Department of Public Health; Grant number: HHSN261201000035C; Grant sponsor: Fondazione Umberto Veronesi; Grant sponsor: Fulbright Italy Research scholar grant 2018; Grant sponsor: German Federal Ministry of Education and Research; Grant numbers: 01ER0814, 01ER0815, 01ER1505A, 01ER1505B, 01KH0404; Grant sponsor: German Research Council; Grant numbers: HO 5117/2-1, BR 1704/17-1, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1; Grant sponsor: Grantová Agentura Ceské≤ Republiky; Grant number: 17-16857S; Grant sponsor: Groupement des Entreprises Françaises dans la Lutte contre le cancer (GEFLUC); Grant sponsor: Hawaii Department of Health; Grant numbers: N01-PC-67001, HHSN26120100037C, N01-PC-35137; Grant sponsor: Lega Italiana per La Lotta contro i Tumori; Grant sponsor: Ligue Régionale Contre le Cancer; Grant sponsor: Ministerstvo Zdravotnictví Ceské Republiky; Grant numbers: AZV 15-27580, AZV 17-30920; Grant sponsor: National Cancer Institute; Grant numbers: HHSN2612013000121, K07 CA190673, N01-CN-67009, N01-PC-35142, P01 CA087969, P30 CA015704, P50 CA127003, R01 CA042182, R01 CA059045, R01 CA137178, R01 CA151993, R01 CA48998, R35 CA197735, U01 CA074778, U01 CA137088, U01 CA164930, U01 HG 004438, U01/U24 CA074783, U01/ U24 CA074794, U01/U24 CA074799, U01/U24 CA074800, U01/U24 CA074806, U01/U24 CA097735, U19 CA148107, UM1 CA186107, Z01 CP 010200; Grant sponsor: National Heart, Lung, and Blood Institute; Grant numbers: HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN268201100046C, HHSN271201100004C; Grant sponsor: National Institutes of Health; Grant numbers: K05 CA154337, P01 CA033619, P01 CA055075, R01 CA063464, R01 CA076366, R01 CA143247, R01 CA60987, R37 CA54281, U01 CA074783, U01 CA122839, U01 CA167551, U01 CA167552, U01 HG004446, UM1 CA167552; Grant sponsor: Regional Council of Pays de la Loire *B.P., A.C., U.P., A.N., and S.L. contributed equally to this work DOI: 10.1002/ijc.32516 History: Received 25 Feb 2019; Accepted 27 May 2019; Online 17 Jun 2019 Correspondence to: Alda Corrado, Department of Biology, University of Pisa, Via Derna 1, 56126 Pisa, Italy, Tel.: +390502211524, Fax: +390502211527, E-mail: corradoalda@gmail.com; or Barbara Pardini, Italian Institute for Genomic Medicine (IIGM), Via Nizza 52, 10126 Turin, Italy, Tel.: +390116709542, Fax: +390112365601, E-mail: barbara.pardini@iigm.it Funding Information: ASTERISK: a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (R01 CA60987). Funding Information: DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B). Funding Information: OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. Funding Information: WHI: The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A full listing of WHI investigators can be found at http://www.whi.org/ researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator% 20Short%20List.pdf The study was funded by the Italian Institute for Genomic Medicine (IIGM) and Compagnia di San Paolo Torino, Italy (to A. Naccarati, B. Pardini and G. Cugliari); Fondazione Umberto Veronesi “Post-doctoral fellowship Year 2014, 2015, 2016 and 2017” (to B. Pardini); Lega Italiana per La Lotta contro i Tumori (to B. Pardini and A. Naccarati), by the Grant Agency of the Czech Republic (17-16857S to A. Naccarati); by the Istituto Toscano Tumori (grant n. I56D15000010002 to S. Landi); by AZV Ministry of Health, Czech Republic (AZV 15-27580 and AZV 17-30920 to P. Vodicka and V. Vymetalkova). B. Pardini was supported by a Fulbright Research Scholarships (year 2018). Funding Information: WHI: The WHI program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN 268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN 268201100004C and HHSN271201100004C. Funding Information: The Colon Cancer Family Registry (CFR) Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (grant numbers U01 CA122839, R01 CA143247). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from National Cancer Institute, National Institutes of Health (grant number U19 CA148107 to S Gruber). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the National Cancer Institute, National Institutes of Health (grant number U01 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806), Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai’i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137, and Contract No. HHSN26120100037C, and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: AZ, CO, MN, NC, NH, and by the Victoria Cancer Registry and Ontario Cancer Registry. Funding Information: Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673 and P50 CA127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673 and P50 CA127003) and PHS by the National Institutes of Health (R01 CA042182). Funding Information: ASTERISK: We are very grateful to Dr. Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. COLON CFR: CCFR: We graciously thank the generous contributions of our study participants, the dedication of our study staff, and the financial support from the U.S. National Cancer Institute, without which our important registry would not exist. DACHS: We thank all participants and cooperating clinicians, and Ute Handte-Daub, Utz Benscheid, Muhabbet Celik and Ursula Eilber for excellent technical assistance. Harvard cohorts: We would like to 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. PLCO: The authors thank the PLCO Cancer Screening Trial screening center investigators and the staff from Information Management Services Inc. and Westat Inc. Most importantly, we thank the study participants for their contributions that made this study possible. PMH: The authors would like to thank the study participants and staff of the Hormones and Colon Cancer study. WHI: The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A full listing of WHI investigators can be found at http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf The study was funded by the Italian Institute for Genomic Medicine (IIGM) and Compagnia di San Paolo Torino, Italy (to A. Naccarati, B. Pardini and G. Cugliari); Fondazione Umberto Veronesi ?Post-doctoral fellowship Year 2014, 2015, 2016 and 2017? (to B. Pardini); Lega Italiana per La Lotta contro i Tumori (to B. Pardini and A. Naccarati), by the Grant Agency of the Czech Republic (17-16857S to A. Naccarati); by the Istituto Toscano Tumori (grant n. I56D15000010002 to S. Landi); by AZV Ministry of Health, Czech Republic (AZV 15-27580 and AZV 17-30920 to P. Vodicka and V. Vymetalkova). B. Pardini was supported by a Fulbright Research Scholarships (year 2018). ASTERISK: a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Fran?aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne G?n?tique and the Ligue R?gionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (R01 CA60987). The Colon Cancer Family Registry (CFR) Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (grant numbers U01 CA122839, R01 CA143247). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from National Cancer Institute, National Institutes of Health (grant number U19 CA148107 to S Gruber). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the National Cancer Institute, National Institutes of Health (grant number U01 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806), Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai'i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137, and Contract No. HHSN26120100037C, and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: AZ, CO, MN, NC, NH, and by the Victoria Cancer Registry and Ontario Cancer Registry. DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B). DALS: National Institutes of Health (R01 CA48998 to M. L. Slattery). Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673 and P50 CA127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673 and P50 CA127003) and PHS by the National Institutes of Health (R01 CA042182). MEC: National Institutes of Health (R37 CA54281, P01 CA033619 and R01 CA063464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Funding was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. PMH: National Institutes of Health (R01 CA076366 to P.A. Newcomb). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. Publisher Copyright: © 2019 UICC

PY - 2020/1/15

Y1 - 2020/1/15

N2 - Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10−6. Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

AB - Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10−6. Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

KW - cancer susceptibility

KW - colon cancer

KW - DNA repair

KW - genome-wide association studies

KW - rectal cancer

KW - single nucleotide polymorphisms

UR - http://www.scopus.com/inward/record.url?scp=85068514355&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068514355&partnerID=8YFLogxK

U2 - 10.1002/ijc.32516

DO - 10.1002/ijc.32516

M3 - Article

C2 - 31209889

AN - SCOPUS:85068514355

VL - 146

SP - 363

EP - 372

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 2

ER -

DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility

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