Journal Article

DKFZ-2020-02227

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Identifying novel susceptibility genes for colorectal cancer risk from a transcriptome-wide association study of 125,478 subjects.

Guo, X. ; Lin, W. ; Wen, W. ; Huyghe, J. ; Bien, S. ; Cai, Q. ; Harrison, T. ; Chen, Z. ; Qu, C. ; Bao, J. ; Long, J. ; Yuan, Y. ; Wang, F. ; Bai, M. ; Abecasis, G. R. ; Albanes, D. ; Berndt, S. I. ; Bézieau, S. ; Bishop, D. T. ; Brenner, H.DKFZ* ; Buch, S. ; Burnett-Hartman, A. ; Campbell, P. T. ; Castellví-Bel, S. ; Chan, A. T. ; Chang-Claude, J.DKFZ* ; Chanock, S. J. ; Cho, S. H. ; Conti, D. V. ; de la Chapelle, A. ; Feskens, E. J. ; Gallinger, S. J. ; Giles, G. G. ; Goodman, P. J. ; Gsur, A. ; Guinter, M. ; Gunter, M. J. ; Hampe, J. ; Hampel, H. ; Hayes, R. B. ; Hoffmeister, M.DKFZ* ; Kampman, E. ; Kang, H. M. ; Keku, T. O. ; Kim, H. R. ; Le Marchand, L. ; Lee, S. C. ; Li, C. I. ; Li, L. ; Lindblom, A. ; Lindor, N. ; Milne, R. L. ; Moreno, V. ; Murphy, N. ; Newcomb, P. A. ; Nickerson, D. A. ; Offit, K. ; Pearlman, R. ; Pharoah, P. D. P. ; Platz, E. A. ; Potter, J. D. ; Rennert, G. ; Sakoda, L. C. ; Schafmayer, C. ; Schmit, S. L. ; Schoen, R. E. ; Schumacher, F. R. ; Slattery, M. L. ; Su, Y.-R. ; Tangen, C. M. ; Ulrich, C. M. ; van Duijnhoven, F. J. ; Van Guelpen, B. ; Visvanathan, K. ; Vodicka, P. ; Vodickova, L. ; Vymetalkova, V. ; Wang, X. ; White, E. ; Wolk, A. ; Woods, M. O. ; Casey, G. ; Hsu, L. ; Jenkins, M. A. ; Gruber, S. B. ; Peters, U. ; Zheng, W.

2021
Saunders Philadelphia, Pa. [u.a.]

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Please use a persistent id in citations: doi:10.1053/j.gastro.2020.08.062

Abstract: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (TCGA, n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in four novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In nine known GWAS-identified loci, we uncovered nine genes that have not been previously reported, whereas four genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < 0.01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

Note: 2021 Mar;160(4):1164-1178.e6

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Contributing Institute(s):

1. C070 Klinische Epidemiologie und Alternf. (C070)
2. Präventive Onkologie (C120)
3. C020 Epidemiologie von Krebs (C020)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 15 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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