Tumor mutational profile of triple negative breast cancer patients in Thailand revealed distinctive genetic alteration in chromatin remodeling gene

Abstract

Background Triple negative breast cancer (TNBC) is a breast cancer subtype characterized by absence of both hormonal receptors and human epithelial growth factor receptor 2 (HER2). TNBC accounts for 15–20% of breast cancer. TNBC is associated with more aggressive disease and worse clinical outcome. Though the underlying mechanism of TNBC is currently unclear, the heterogeneity of clinical characteristics in various population may relate to the difference in tumor mutational profile. There were studies on TNBC gene mutations in various ethnic groups but the tumor genome data on Thai TNBC patients is currently unknown. This study aims to investigate mutational profile of Thai TNBC. Methods The patients were Thai individuals who were diagnosed with primary breast carcinoma between 2014 and 2017. All surgically removed primary tumor tissues were carefully examined by pathologists and archived as formalin-fixed paraffin-embedded tumor. TNBC was defined by absence of hormonal receptors and HER2 by immunohistochemistry. Genomic DNA was extracted, enriched and sequenced of all exomes on the Illumina HiSeq. Genomic data were then processed through bioinformatics platform to identify genomic alterations and tumor mutational burden. Results A total of 116 TNBC patients were recruited. Genomic analysis of TNBC samples identified 81,460 variants, of which 5,906 variants were in cancer-associated genes. The result showed that Thai TNBC has higher tumor mutation burden than previously reported data. The most frequently mutated cancer-associated gene was TP53 similar to other TNBC cohorts. Meanwhile KMT2C was found to be more commonly mutated in Thai TNBC than previous studies. Mutational profile of Thai TNBC patients also revealed difference in many frequently mutated genes when compared to other Western TNBC cohorts. Conclusion This result supported that TNBC breast cancer patients from various ethnic background showed diverse genome alteration pattern. Although TP53 is the most commonly mutated gene across all cohorts, Thai TNBC showed different gene mutation frequencies, especially in KMT2C. In particular, the cancer gene mutations are more prevalent in Thai TNBC patients. This result provides important insight on diverse underlying genetic and epigenetic mechanisms of TNBC that could translate to a new treatment strategy for patients with this disease.

Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients

“…In a South Korean cohort of 229 patients with ER+ and Her2-breast cancer, TP53 was found mutated in 10% of the patients [19], compared to 16.7% in 'luminal A and luminal B/Her2-combined' in our cohort. In a study of 116 triple-negative patients from Thailand [20], 76% were found to carry TP53 mutations, comparing to 92% in the same subtype in our cohort. Recapitulating, the high prevalence of mutations in TP53 implies a distinct molecular characteristic of EOBC and associated subtypes.…”

Association between tumor mutation profile and clinical outcomes among Hispanic Latina women with triple-negative breast cancer

“…TNBC represents a heterogeneous subtype of breast cancer with adverse clinical outcomes and inconsistent responses to current therapy, particularly in advanced-stage disease [3,4,8]. Data from previous studies revealed that the spectrum of mutation profiles is diverse between each patient and also differs amongst racial and ethnic groups [10,17,18,27,28]. Although there are multiple explanations for the diverse genomic landscape of TNBC patients, ethnicity could have a significant role in this discrepancy.…”

“…TP53 is widely considered to be a guardian of the genome because of its critical function in maintaining genome integrity, regulating the cell cycle, and initiating apoptosis. Multiple studies reported the frequency of TP53 mutation in human breast cancer ranged from 50% to 82% [17][18][19][20][21].…”

“…We compared the frequency of cancer gene mutations discovered in our study with previously published databases TCGA (The Cancer Genome Atlas), METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), and COSMIC (Catalogue of Somatic Mutations in Cancer), as well as Chinese [17], and Thai studies [18] using z-tests for proportions. The data were downloaded from the cBioPortal for Cancer Genomics (https://www.cbioportal.org/ study/summary?id=brca_metabric).…”

Prediction of Overall Survival for Early-stage Non-small Cell Lung Cancer via a Novel 7-gene Prognostic Signature and Allele Frequency Deviation (AFD)

“…patients. Non-synonymous and synonymous variants were included in this calculation, synonymous mutations were considerd purposefully to reduce sampling noise [36].…”