A single-nucleotide-polymorphism in the 5'-flanking region of MSX1 gene as a predictive marker candidate for platinum-based therapy of esophageal carcinoma

Takahiro Mori; Kazuko Ueno; Katsushi Tokunaga; Yosuke Kawai; Koichi Matsuda; Nao Nishida; Keigo Komine; Sakae Saito; Masao Nagasaki; BioBank Japan Project

doi:10.1177/17588359221080580

A single-nucleotide-polymorphism in the 5'-flanking region of MSX1 gene as a predictive marker candidate for platinum-based therapy of esophageal carcinoma

Ther Adv Med Oncol. 2022 Feb 24:14:17588359221080580. doi: 10.1177/17588359221080580. eCollection 2022.

Authors

Takahiro Mori¹, Kazuko Ueno², Katsushi Tokunaga², Yosuke Kawai², Koichi Matsuda³, Nao Nishida⁴, Keigo Komine⁵, Sakae Saito⁶, Masao Nagasaki⁷; BioBank Japan Project

Affiliations

¹ Departments of Clinical Oncology and Gastroenterological Surgery, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara 252-0392, Kanagawa, Japan.
² Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan.
³ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁴ Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan.
⁵ Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.
⁶ Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
⁷ Center for the Promotion of Interdisciplinary Education and Research, and nd Center for Genomic Midicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Abstract

Background: Platinum derivatives are important treatment options for patients with esophageal carcinoma (EC), and a predictive marker for platinum-based therapy is needed for precision medicine.

Patients and methods: This study contained two cohorts consisting of EC patients treated using platinum-based chemoradiation therapy (CRT) as the first-line and another external cohort of nationwide clinicogenomic data from the BioBank Japan (BBJ).

Results: Genome-wide association study (GWAS) of therapeutic outcomes, refractory disease or not, following platinum-based CRT as first-line in 94 patients in the first cohort suggested the association of 89 SNPs using p < 0.0001. The top 10 SNPs selected from each chromosomal region by odds ratio were evaluated for progression-free survival (PFS) and overall survival (OS) hazard ratios in the first cohort, resulting in four candidates (p < 0.0025). The four selected candidates were re-evaluated in another cohort of 24 EC patients, which included patients prospectively enrolled in this study to fulfill the sample size statistically suggested by the results of the first cohort, and of the four, only rs3815544 was replicated (p < 0.0125). Furthermore, this candidate genotype of rs3815544 proceeded to the re-evaluation study in an external cohort consisting of EC patients treated with platinum derivatives and/or by radiation therapy as the first-line treatment in BBJ, which confirmed that the alternative allele (G) of rs3815544 was statistically associated with non-response (SD or PD) to platinum-based therapy in EC patients (odds ratio = 1.801, p = 0.048). The methylation QTL database as well as online clinicogenomic databases suggested that the region including rs3815544 may regulate MSX1 expression through CpG methylation, and this down-regulation was statistically associated with poor prognosis after platinum-based therapies for EC.

Conclusion: rs3815544 is a novel candidate predictive marker for platinum-based EC therapy.

Keywords: MSX1; esophageal carcinoma; platinum-based therapy; predictive marker; single nucleotide polymorphism.