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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.

ABSTRACT: Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

SUBMITTER: Fernandez-Rozadilla C

PROVIDER: S-EPMC10094749 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.

Fernandez-Rozadilla Ceres C Timofeeva Maria M Chen Zhishan Z Law Philip P Thomas Minta M Schmit Stephanie S Díez-Obrero Virginia V Hsu Li L Fernandez-Tajes Juan J Palles Claire C Sherwood Kitty K Briggs Sarah S Svinti Victoria V Donnelly Kevin K Farrington Susan S Blackmur James J Vaughan-Shaw Peter P Shu Xiao-Ou XO Long Jirong J Cai Qiuyin Q Guo Xingyi X Lu Yingchang Y Broderick Peter P Studd James J Huyghe Jeroen J Harrison Tabitha T Conti David D Dampier Christopher C Devall Mathew M Schumacher Fredrick F Melas Marilena M Rennert Gad G Obón-Santacana Mireia M Martín-Sánchez Vicente V Moratalla-Navarro Ferran F Oh Jae Hwan JH Kim Jeongseon J Jee Sun Ha SH Jung Keum Ji KJ Kweon Sun-Seog SS Shin Min-Ho MH Shin Aesun A Ahn Yoon-Ok YO Kim Dong-Hyun DH Oze Isao I Wen Wanqing W Matsuo Keitaro K Matsuda Koichi K Tanikawa Chizu C Ren Zefang Z Gao Yu-Tang YT Jia Wei-Hua WH Hopper John J Jenkins Mark M Win Aung Ko AK Pai Rish R Figueiredo Jane J Haile Robert R Gallinger Steven S Woods Michael M Newcomb Polly P Duggan David D Cheadle Jeremy J Kaplan Richard R Maughan Timothy T Kerr Rachel R Kerr David D Kirac Iva I Böhm Jan J Mecklin Lukka-Pekka LP Jousilahti Pekka P Knekt Paul P Aaltonen Lauri L Rissanen Harri H Pukkala Eero E Eriksson Johan J Cajuso Tatiana T Hänninen Ulrika U Kondelin Johanna J Palin Kimmo K Tanskanen Tomas T Renkonen-Sinisalo Laura L Zanke Brent B Männistö Satu S Albanes Demetrius D Weinstein Stephanie S Ruiz-Narvaez Edward E Palmer Julie J Buchanan Daniel D Platz Elizabeth E Visvanathan Kala K Ulrich Cornelia C Siegel Erin E Brezina Stefanie S Gsur Andrea A Campbell Peter P Chang-Claude Jenny J Hoffmeister Michael M Brenner Hermann H Slattery Martha M Potter John J Tsilidis Konstantinos K Schulze Matthias M Gunter Marc M Murphy Neil N Castells Antoni A Castellví-Bel Sergi S Moreira Leticia L Arndt Volker V Shcherbina Anna A Stern Mariana M Pardamean Bens B Bishop Timothy T Giles Graham G Southey Melissa M Idos Gregory G McDonnell Kevin K Abu-Ful Zomoroda Z Greenson Joel J Shulman Katerina K Lejbkowicz Flavio F Offit Kenneth K Su Yu-Ru YR Steinfelder Robert R Keku Temitope T van Guelpen Bethany B Hudson Thomas T Hampel Heather H Pearlman Rachel R Berndt Sonja S Hayes Richard R Martinez Marie Elena ME Thomas Sushma S Corley Douglas D Pharoah Paul P Larsson Susanna S Yen Yun Y Lenz Heinz-Josef HJ White Emily E Li Li L Doheny Kimberly K Pugh Elizabeth E Shelford Tameka T Chan Andrew A Cruz-Correa Marcia M Lindblom Annika A Hunter David D Joshi Amit A Schafmayer Clemens C Scacheri Peter P Kundaje Anshul A Nickerson Deborah D Schoen Robert R Hampe Jochen J Stadler Zsofia Z Vodicka Pavel P Vodickova Ludmila L Vymetalkova Veronika V Papadopoulos Nickolas N Edlund Chistopher C Gauderman William W Thomas Duncan D Shibata David D Toland Amanda A Markowitz Sanford S Kim Andre A Chanock Stephen S van Duijnhoven Franzel F Feskens Edith E Sakoda Lori L Gago-Dominguez Manuela M Wolk Alicja A Naccarati Alessio A Pardini Barbara B FitzGerald Liesel L Lee Soo Chin SC Ogino Shuji S Bien Stephanie S Kooperberg Charles C Li Christopher C Lin Yi Y Prentice Ross R Qu Conghui C Bézieau Stéphane S Tangen Catherine C Mardis Elaine E Yamaji Taiki T Sawada Norie N Iwasaki Motoki M Haiman Christopher C Le Marchand Loic L Wu Anna A Qu Chenxu C McNeil Caroline C Coetzee Gerhard G Hayward Caroline C Deary Ian I Harris Sarah S Theodoratou Evropi E Reid Stuart S Walker Marion M Ooi Li Yin LY Moreno Victor V Casey Graham G Gruber Stephen S Tomlinson Ian I Zheng Wei W Dunlop Malcolm M Houlston Richard R Peters Ulrike U

Nature genetics 20221220 1

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We ...[more]

PMID: 36539618

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Project description:Background: Genomic instability is a significant hallmark of aging and has a major impact on aging biology. Mosaic loss of chromosome Y (mLOY) in blood cells is a common chromosomal abnormality in aging men and is considered an indicator of genomic instability. Previous studies have indicated a connection between mLOY and prostate cancer risk, but the causal relationship has not been fully established. Methods: To determine the causal effect of mLOY on prostate cancer, we conducted a Mendelian Randomization (MR) study in two ancestral groups. We utilized 125 and 42 mLOY-associated variants as instrumental variables (IVs) in European and East Asian GWAS of prostate cancer, respectively. Summary-level data on prostate cancer was obtained from the PRACTICAL consortium (79,148 cases and 61,106 controls of European ancestry) and the Biobank Japan consortium (5,408 cases and 103,939 controls of East Asian ancestry). A single population was used to assess the causal relationship in East Asian ancestry. Our main method for obtaining MR results was inverse-variance weighted (IVW), and we conducted sensitivity analyses to confirm the robustness of our results. Finally, we combined the estimates from both sources using a fixed-effects meta-analysis. Results: Our MR analysis using the IVW method showed that a one-unit increase in genetically predicted mLOY was associated with an increased risk of prostate cancer in the PRACTICAL consortium (OR = 1.09%, 95% CI: 1.05-1.13, p = 1.2 × 10-5), but not in the Biobank Japan consortium (OR = 1.13%, 95% CI: 0.88-1.45, p = 0.34). Sensitivity analyses robustly indicated increased odds ratios for prostate cancer with every one-unit increase in genetically predicted mLOY for the PRACTICAL consortium. Furthermore, mLOY was found to be associated with prostate cancer risk in a meta-analysis of both sources (OR = 1.09%, 95% CI: 1.05-1.13, p = 8.0 × 10-6). Conclusion: Our MR study provides strong evidence that higher mLOY increases the risk of prostate cancer. Preventing mLOY may be a means of reducing the risk of developing prostate cancer.

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Dataset Information

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.

Publications

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.

Similar Datasets

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