A Pilot Study on BRCA1/2 and PI3K Mutations Across Subtypes of Triple Negative Breast Cancer in North Indian Population.

IF 1.3 4区 医学 Q3 ANATOMY & MORPHOLOGY Applied Immunohistochemistry & Molecular Morphology Pub Date : 2024-11-01 Epub Date: 2024-11-07 DOI:10.1097/PAI.0000000000001231
Parul Gupta, Tamanna Thakur, Anjali Chadda, Santosh Irinike, Siddhant Khare, Amanjit Bal
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Abstract

BRCA1/2 are tumor suppressor genes which regulate the DNA repair mechanism. Mutations in BRCA1/2 may increase the risk of breast cancer in patients. In the present study frequency of BRCA1/2 mutations in triple negative breast cancer (TNBC) patients was assessed and correlated with molecular subtypes of TNBC. Blood samples from 65 confirmed cases of TNBC were collected. DNA was isolated from whole blood and libraries were prepared using a BRCA1/2 custom panel. Sequencing was done on Ion torrent S5 sequencer and ion reporter was used for data analysis. Further molecular subtyping of mutation positive TNBC cases was done using immunohistochemistry markers CK5/6; CK4/14; Vimentin and E-Cadherin and androgen receptor (AR) using tissue microarray. Twenty five of 65 patients had heterozygous pathogenic mutations, alterations with conflicting interpretation of pathogenicity, variants of uncertain significance and variants of unknown significance. Nine patients had pathogenic mutation in BRCA 1 gene only and 2 patients had pathogenic mutations in BRCA2 gene. Two patients were transheterozygous for BRCA mutations, that is, had pathogenic mutations in both BRCA1/2 genes simultaneously and 5 were compound heterozygous (involving BRCA2 gene in all the cases). Prevalent subtypes among BRCA positive cases were unclassified subtype (n=4, 33%), Basal like (n=5, 41%), and mesenchymal subtype (n=3, 25%). None of the LAR subtype showed BRCA1/2 mutations. The present study observed that the BRCA1 mutation is more frequent than BRCA2 mutation in TNBC. BRCA1/2 mutations do not correspond to BRCAness or basal phenotype. Considering high incidence of breast cancer and lack of correlation of basal morphology with BRCA1/2 mutation, the molecular methods should be used for screening for BRCA1/2 mutations. This will not only help in familial screening but also in deciding targeted therapy with PARP (poly-ADP ribose polymerase) inhibitors.

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北印度人群三阴性乳腺癌亚型中 BRCA1/2 和 PI3K 基因突变的试点研究
BRCA1/2 是调节 DNA 修复机制的肿瘤抑制基因。BRCA1/2 基因突变可能会增加患者罹患乳腺癌的风险。本研究评估了三阴性乳腺癌(TNBC)患者中 BRCA1/2 基因突变的频率,并将其与 TNBC 的分子亚型相关联。研究收集了 65 例 TNBC 确诊病例的血液样本。从全血中分离出 DNA,并使用 BRCA1/2 定制面板制备文库。测序在 Ion torrent S5 测序仪上进行,数据分析使用离子报告器。利用免疫组化标记物CK5/6、CK4/14、波形蛋白和E-Cadherin以及组织芯片中的雄激素受体(AR)对突变阳性的TNBC病例进行了进一步的分子亚型鉴定。65 例患者中有 25 例存在杂合致病突变、致病性解释不一致的变异、意义不确定的变异和意义不明的变异。9 名患者仅有 BRCA 1 基因的致病突变,2 名患者有 BRCA2 基因的致病突变。两名患者是 BRCA 基因突变的跨杂合型,即 BRCA1/2 基因同时发生致病性突变,5 名患者是复合杂合型(所有病例都涉及 BRCA2 基因)。BRCA 阳性病例的常见亚型为未分类亚型(4 例,33%)、基底样亚型(5 例,41%)和间质亚型(3 例,25%)。LAR亚型均未发现BRCA1/2基因突变。本研究发现,在 TNBC 中,BRCA1 突变比 BRCA2 突变更常见。BRCA1/2突变与BRCAness或基础表型并不对应。考虑到乳腺癌的高发病率以及基底形态与 BRCA1/2 基因突变缺乏相关性,应采用分子方法筛查 BRCA1/2 基因突变。这不仅有助于家族性筛查,还有助于决定使用 PARP(聚-ADP 核糖聚合酶)抑制剂进行靶向治疗。
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来源期刊
Applied Immunohistochemistry & Molecular Morphology
Applied Immunohistochemistry & Molecular Morphology ANATOMY & MORPHOLOGY-MEDICAL LABORATORY TECHNOLOGY
CiteScore
3.20
自引率
0.00%
发文量
153
期刊介绍: ​Applied Immunohistochemistry & Molecular Morphology covers newly developed identification and detection technologies, and their applications in research and diagnosis for the applied immunohistochemist & molecular Morphologist. Official Journal of the International Society for Immunohistochemisty and Molecular Morphology​.
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