Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy

M Kanai; T Kawaguchi; M Kotaka; D Manaka; J Hasegawa; A Takagane; Y Munemoto; T Kato; T Eto; T Touyama; T Matsui; K Shinozaki; S Matsumoto; T Mizushima; M Mori; J Sakamoto; A Ohtsu; T Yoshino; S Saji; F Matsuda

doi:10.1016/j.annonc.2021.08.1745

Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy

Ann Oncol. 2021 Nov;32(11):1434-1441. doi: 10.1016/j.annonc.2021.08.1745. Epub 2021 Aug 12.

Authors

M Kanai¹, T Kawaguchi², M Kotaka³, D Manaka⁴, J Hasegawa⁵, A Takagane⁶, Y Munemoto⁷, T Kato⁸, T Eto⁹, T Touyama¹⁰, T Matsui¹¹, K Shinozaki¹², S Matsumoto¹³, T Mizushima¹⁴, M Mori¹⁵, J Sakamoto¹⁶, A Ohtsu¹⁷, T Yoshino¹⁷, S Saji¹⁸, F Matsuda²

Affiliations

¹ Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: [email protected].
² Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
³ Gastrointestinal Cancer Center, Sano Hospital, Kobe, Japan.
⁴ Department of Surgery, Gastrointestinal Center, Kyoto-Katsura Hospital, Kyoto, Japan.
⁵ Department of Surgery, Osaka Rosai Hospital, Osaka, Japan.
⁶ Department of Surgery, Hakodate Goryoukaku Hospital, Hokkaido, Japan.
⁷ Department of Surgery, Fukui Ken Saiseikai Hospital, Fukui, Japan.
⁸ Department of Surgery, Kansai Rosai Hospital, Hyogo, Japan.
⁹ Department of Gastroenterology, Tsuchiura Kyodo General Hospital, Ibaraki, Japan.
¹⁰ Department of Surgery, Nakagami Hospital, Okinawa, Japan.
¹¹ Department of Gastroenterological Surgery, Aichi Cancer Center Aichi Hospital, Aichi, Japan.
¹² Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima, Japan.
¹³ Department of Real World Data Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁴ Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
¹⁵ Department of Surgery and Science, Kyushu University, Fukuoka, Japan.
¹⁶ Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan; Tokai Central Hospital, Kakamigahara, Japan.
¹⁷ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
¹⁸ Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan.

PMID: 34391895
DOI: 10.1016/j.annonc.2021.08.1745

Abstract

Background: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach.

Patients and methods: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored.

Results: No SNPs exceeded the genome-wide significance (P < 5.0 × 10^-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs.

Conclusion: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Keywords: colon cancer; genome-wide association study; oxaliplatin; peripheral sensory neuropathy; pharmacogenomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols
Chemotherapy, Adjuvant
Clinical Trials, Phase II as Topic
Clinical Trials, Phase III as Topic
Colonic Neoplasms* / drug therapy
Colonic Neoplasms* / genetics
Fluorouracil / therapeutic use
Genome-Wide Association Study*
Humans
Neoplasm Recurrence, Local
Oxaliplatin / adverse effects
Prospective Studies

Substances

Oxaliplatin
Fluorouracil