Pachuau Lalawmpuii, Lalremmawia H, Ralte Lalengkimi, Vanlalpeka Johan, Pautu Jeremy Lalrinsanga, Chenkual Saia, Zomuana Thomas, Lalruatfela Sailo Tlau, Zohmingthanga John, Chhakchhuak Lalchhandama, Varma Ashok K, Kumar Nachimuthu Senthil
Department of Biotechnology, Mizoram University, Tanhril, Aizawl, Mizoram, 796004, India.
Department of Pathology, Department of Health & Family Welfare, Civil Hospital Aizawl, Government of Mizoram, Dawrpui, Aizawl, Mizoram, 796001, India.
Breast Cancer Res Treat. 2025 Jan;209(2):375-387. doi: 10.1007/s10549-024-07501-9. Epub 2024 Oct 9.
The incidence of triple-negative breast cancer (TNBC) in India is higher compared to Western populations. The objective of this study is to identify novel and less reported variants in TNBC in Mizoram, a state with a high cancer incidence in India.
We analysed whole exome sequencing data from triple-negative breast cancer (TNBC) patients in the Mizo population to identify key and novel variants. Moreover, we analysed reported breast cancer-related genes and pathway alterations.
Somatic mutation analysis revealed that TP53 was the most frequently mutated gene and TP53, CACNA1E, IGSF3, RYR1, and FAM155A as significantly mutated driver genes. Based on the ACMG guidelines, we identified a rare pathogenic germline variant of BRCA1 (p.C1697R) in 13% and a likely pathogenic frameshift insertion in RBMX (p.P106Ffs) in 73% of the patients. We also found that the ATM, STK11, and CDKN2A genes were significantly mutated in germline TNBC samples compared to healthy samples. Moreover, we identified novel somatic variants in CHEK2 (p.K182M) and NF1 (p.C245X), and novel germline variants RB1 (p.D111G), CDH1 (p.A10Gfs), CDKN2A (p.V96G), CDKN2A (p.S12Afs*22), MAP3K1 (CAAdelins0), MSH6 (p.L1226_L1230del), and PMS2 (TTCdelins0). Pathway analysis revealed that most somatic mutations were highly associated with PI3K-Akt signalling pathway and MAPK signalling pathways in TNBC.
These findings identified novel variants and key genes contributing to disease development and progression. Further analysis of less studied genes, including RBMX, MRC1, ATM, CTNNB1, and CDKN2A, in TNBC may reveal new potential genes for targeted therapeutic strategies and contribute to clinical advancements in the treatment of TNBC.
与西方人群相比，印度三阴性乳腺癌（TNBC）的发病率更高。本研究的目的是在印度癌症发病率较高的米佐拉姆邦，鉴定TNBC中未被充分报道的新变异。
我们分析了米佐人群中三阴性乳腺癌（TNBC）患者的全外显子测序数据，以鉴定关键和新的变异。此外，我们分析了已报道的乳腺癌相关基因和通路改变。
体细胞突变分析显示，TP53是最常发生突变的基因，TP53、CACNA1E、IGSF3、RYR1和FAM155A为显著突变的驱动基因。根据美国医学遗传学与基因组学学会（ACMG）指南，我们在13%的患者中鉴定出一种罕见的BRCA1致病种系变异（p.C1697R），在73%的患者中鉴定出RBMX中一种可能致病的移码插入（p.P106Ffs）。我们还发现，与健康样本相比，ATM、STK11和CDKN2A基因在种系TNBC样本中发生了显著突变。此外，我们鉴定出CHEK2（p.K182M）和NF1（p.C245X）中的新体细胞变异，以及RB1（p.D111G）、CDH1（p.A10Gfs）、CDKN2A（p.V96G）、CDKN2A（p.S12Afs*22）、MAP3K1（CAAdelins0）、MSH6（p.L1226_L1230del）和PMS2（TTCdelins0）中的新种系变异。通路分析显示，大多数体细胞突变与TNBC中的PI3K-Akt信号通路和MAPK信号通路高度相关。
这些发现鉴定出了有助于疾病发生和发展的新变异和关键基因。对TNBC中研究较少的基因（包括RBMX、MRC1、ATM、CTNNB1和CDKN2A）进行进一步分析，可能会揭示出靶向治疗策略的新潜在基因，并有助于TNBC治疗的临床进展。
