Tumor mutational profile of triple negative breast cancer patients in Thailand revealed distinctive genetic alteration in chromatin remodeling gene
Tumor mutational profile of triple negative breast cancer patients in Thailand revealed distinctive genetic alteration in chromatin remodeling gene
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DOI：
10.7717/peerj.6501
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发表时间：
2019-02-25
期刊：
影响因子：
2.7
通讯作者：
Pithukpakorn, Manop
中科院分区：
文献类型：
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作者：
Niyomnaitham, Suvimol;Parinyanitikul, Napa;Pithukpakorn, Manop
背景：三阴性乳腺癌(TNBC)是一种以激素受体和人上皮生长因子受体2(HER2)缺失为特征的乳腺癌亚型。TNBC占乳腺癌的15%-20%。TNBC与更具侵袭性的疾病和更差的临床结局相关。尽管TNBC的发病机制目前尚不清楚，但不同人群临床特征的异质性可能与肿瘤突变谱的差异有关。已经有关于不同种族的TNBC基因突变的研究，但泰国TNBC患者的肿瘤基因组数据目前尚不清楚。本研究旨在调查泰国人TNBC的突变情况。方法：患者为2014-2017年间被诊断为原发性乳腺癌的泰国人。所有手术切除的原发肿瘤组织均由病理学家仔细检查，并存档为福尔马林固定的石蜡包埋肿瘤。采用免疫组织化学方法，以激素受体缺失和HER2定义为TNBC。提取基因组DNA，并对Illumina HiSeq上的所有外显子进行测序。然后通过生物信息学平台对基因组数据进行处理，以确定基因组变化和肿瘤突变负担。结果：共纳入116例TNBC患者。对TNBC样本的基因组分析确定了81,460个变异，其中5,906个变异存在于癌症相关基因中。结果表明，泰国TNBC的肿瘤突变负荷高于以往报道的数据。突变最频繁的癌症相关基因是TP53，与其他TNBC队列相似。同时，与以前的研究相比，KMT2C在泰国TNBC中的突变更常见。与其他西方TNBC队列相比，泰国TNBC患者的突变谱也显示出许多频繁突变的基因的差异。结论：这一结果支持了不同种族背景的TNBC乳腺癌患者表现出不同的基因组改变模式。虽然TP53是所有队列中最常见的突变基因，但泰国TNBC显示出不同的基因突变频率，特别是在KMT2C中。特别是，癌症基因突变在泰国TNBC患者中更为普遍。这一结果对TNBC的不同潜在遗传和表观遗传学机制提供了重要的见解，可能转化为该疾病患者的新治疗策略。
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.