Background

Breast cancers exhibit genetic heterogeneity which causes differential responses to various chemotherapy agents. Given the unique demographic and genomic background in South Asia, genetic architecture in breast cancers is not fully explored.

Methods and results

In this study, we determined the genetic landscape of our previously established luminal-A subtype breast cancer cell line (BC-PAK1), and compared it with a Caucasian origin MCF7 breast cancer cell line of the same molecular subtype. Deep whole-exome sequencing (100X) was performed from early passages of the primary cancer cells using the Illumina NextSeq500. Data analysis with in silico tools showed novel non-silent somatic mutations previously not described in breast cancers, including a frameshift insertion (p.Ala1591AlafsTer28) in CIC, and a frameshift deletion (p.Lys333LysfsTer21) in PABPC1. Five genes CDC27, PIK3CG, ARAP3, RAPGEF1, and EFNA3, related with cell cycle pathway (hsa04110), ErbB signaling pathway (hsa04012), Ras signaling pathway (hsa04014), and Rap1 signaling pathway (hsa04015) were found to have recurrent non-silent somatic mutations. Further, the major contribution of COSMIC signatures 3 (failure of DNA double-strand break repair by homologous recombination), and 12 (transcriptional strand-bias for T>C substitutions) was observed. Also, the somatic mutations landscape in BC-PAK1 was found to be different as compared to the MCF7 cell line. The unique genetic landscape of BC-PAK1 might be responsible for significantly reduced response to doxorubicin than the MCF7 cell line.

Conclusion

This study presents a distinct genetic architecture in luminal-A breast cancer potentially responsible for differential response to chemotherapy. Further studies on large cohorts of breast cancer patients are suggested for implementation in personalized medicine.

中文翻译：

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巴基斯坦来源的 luminal-A 乳腺癌细胞系中独特的遗传景观和对阿霉素的低反应

背景

乳腺癌表现出遗传异质性，导致对各种化疗药物的不同反应。鉴于南亚独特的人口统计学和基因组背景，尚未充分探索乳腺癌的遗传结构。

方法和结果

在这项研究中，我们确定了我们先前建立的 luminal-A 亚型乳腺癌细胞系 (BC-PAK1) 的遗传图谱，并将其与相同分子亚型的高加索来源 MCF7 乳腺癌细胞系进行了比较。使用 Illumina NextSeq500 从原代癌细胞的早期传代中进行深度全外显子组测序 (100X)。使用计算机工具进行的数据分析显示了以前未在乳腺癌中描述的新型非沉默体细胞突变，包括CIC 中的移码插入 (p.Ala1591Ala fs Ter28)和 PABPC1 中的移码缺失 (p.Lys333Lys fs Ter21 ) 。五个基因CDC27、PIK3CG、ARAP3、RAPGEF1和EFNA3发现与细胞周期通路（hsa04110）、ErbB信号通路（hsa04012）、Ras信号通路（hsa04014）和Rap1信号通路（hsa04015）相关的复发性非沉默体细胞突变。此外，观察到 COSMIC 特征 3（通过同源重组修复 DNA 双链断裂失败）和 12（T>C 取代的转录链偏差）的主要贡献。此外，发现 BC-PAK1 中的体细胞突变景观与 MCF7 细胞系相比是不同的。与 MCF7 细胞系相比，BC-PAK1 独特的遗传景观可能导致对阿霉素的反应显着降低。

结论

这项研究提出了一种独特的 Luminal-A 乳腺癌遗传结构，可能导致对化疗的不同反应。建议对大量乳腺癌患者进行进一步研究，以实施个性化医疗。