Journal Article

DKFZ-2023-01581

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients.

Park, H. A. (First author)DKFZ* ; Edelmann, D.DKFZ* ; Canzian, F.DKFZ* ; Seibold, P.DKFZ* ; Harrison, T. A. ; Hua, X. ; Shi, Q. ; Silverman, A. ; Benner, A.DKFZ* ; Macauda, A.DKFZ* ; Schneider, M. ; Goldberg, R. M. ; Alberts, S. R. ; Hoffmeister, M.DKFZ* ; Brenner, H.DKFZ* ; Chan, A. T. ; Peters, U. ; Newcomb, P. A. ; Chang-Claude, J. (Last author)DKFZ*

2023
Wiley-Liss Bognor Regis

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Please use a persistent id in citations: doi:10.1002/ijc.34663

Abstract: We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10-8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10-7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10-6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.

Keyword(s): adjuvant chemotherapy ; colorectal cancer prognosis ; genome-wide association study ; oxaliplatin-based treatment ; single nucleotide polymorphism

Note: #EA:C020#LA:C020# / 2023 Nov 1;153(9):1623-1634

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Contributing Institute(s):

1. C020 Epidemiologie von Krebs (C020)
2. C060 Biostatistik (C060)
3. C055 Genomische Epidemiologie (C055)
4. C070 Klinische Epidemiologie und Alternf. (C070)
5. Präventive Onkologie (C120)
6. DKTK HD zentral (HD01)

Research Program(s):

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

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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