Open Access

ARTICLE

Pathway Mutations in Breast Cancer Using Whole-Exome Sequencing

Ya-Sian Chang^*†‡§, Chieh-Min Chang^†‡, Chien-Yu Lin^¶#, Dy-San Chao^†, Hsi-Yuan Huang^†, Jan-Gowth Chang^{*†‡**††}

* Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
† Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan
‡ Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan
§ Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
¶ Graduate Institute of Clinical Medical Science and School of Medicine, China Medical University, Taichung, Taiwan
# Department of Laboratory Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan
** Graduate Institute of Biomedical Sciences, School of Medicine, China Medical University, Taichung, Taiwan
†† Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan

Oncology Research 2020, 28(2), 107-116. https://doi.org/10.3727/096504019X15698362825407

Abstract

The genomic landscape of breast cancer (BC) is complex. The purpose of this study was to decipher the mutational profiles of Taiwanese patients with BC using next-generation sequencing. We performed whole-exome sequencing on DNA from 24 tumor tissue specimens from BC patients. Sanger sequencing was used to validate the identified variants. Sanger sequencing was also performed on paired adjacent nontumor tissues. After genotype calling and algorithmic annotations, we identified 49 deleterious variants in canonical cancer-related genes in our BC cohort. The most frequently mutated genes were PIK3CA (16.67%), FKBP9 (12.5%), TP53 (12.5%), ATM (8.33%), CHEK2 (8.33%), FOXO3 (8.33%), NTRK1 (8.33%), and NUTM2B (8.33%). Seven mutated variants (ATR p.V1581fs, CSF1R p.R579Q, GATA3 p.T356delinsTMKS, LRP5 p.W389*, MAP3K1 p.T918fs, MET p.K1161fs, and MTR p.P1178S) were novel variants that are not present in any gene mutation database. After grouping the samples according to molecular subtype, we found that the cell cycle, MAPK, and chemokine signaling pathways in the luminal A subtype of BC; the focal adhesion, axon guidance, and endocytosis pathways in the luminal B subtype; and amyotrophic lateral sclerosis in the basal-like subtype were exclusively altered. Survival curve analysis showed that the presence of the MAPK signaling pathway and endocytosis mutations were correlated with a poor prognosis. These survival data were consistent with cBioPortal analyses of 2,051 BC cases. We discovered novel mutations in patients with BC. These results have implications for developing strategic, adjuvant, and gene-targeted therapies.

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