Clinically actionable alterations in Indian breast cancer patients derived through whole transcriptome sequencing - Original Article

Sep 22, 2026

Genomic study needs in Indian breast cancer patients are addressed through whole transcriptome sequencing of primary tumor samples. mRNA was sequenced on an Illumina platform, intrinsic subtypes were assigned using PAM50 and AIMS classifiers, and somatic and non-synonymous variants were prioritized using multiple variant callers with ClinVar-based pathogenic annotations. Among 97 patients, 145 high-confidence somatic mutations were identified, TP53 and PIK3CA were most frequent, actionable mutations appeared in 52%, and recurrent fusions including novel ERBB2-related partners were detected.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages9

Reading Time23 min

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Background and objectives

Methods

Results

Interpretation and conclusions

Indian J Med Res 163, January 2026, pp 95-103 DOI: 10.25259/IJMR_ 1642_2024 Original Article Clinically actionable alterations in Indian breast cancer patients derived through whole transcriptome sequencing Nilesh Gardi,1,2,\# Rohan Chaubal,1,2,3,\# Khushboo A. Gandhi, 1,2 Anushree Kadam,1,2 Ankita Singh,1,2 Aishwarya Sabari Raja,1,2,4 Vaibhav Vanmali,3 Rohini Hawaldar,3 Suhani Sale,1,2 Shalaka Joshi,2,3 Rajendra Badwe2,3 & Sudeep Gupta1,2,4 1Clinician Scientist Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Tata Memorial Centre, 2Training School Complex, Homi Bhabha National Institute, Departments of 3Surgical Oncology, and 4Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, Maharashtra, India Received October 16, 2024; Accepted May 23, 2025; Published February 28, 2026 Background and objectives: Genomic studies are essential for identifying mutations that may influence key aspects of breast tumours, such as susceptibility, aggressiveness, and response to treatment. There are deficient molecular and genomic data from Indian breast cancer patients. Methods: mRNA from primary breast cancer samples were subjected to next-generation transcriptome (mRNA) sequencing on an Illumina platform, in duplicates and triplicates to generate 30–60 M reads/sample. PAM50, and absolute intrinsic molecular subtyping (AIMS) gene expression-based classifiers were used for intrinsic subtyping. Variants were called using, GATK, MuTect2, VarScan2, and VarDict, followed by filtering for somatic and non-synonymous changes. Germline variants were excluded using public databases. ClinVar annotations prioritised pathogenic variants, and the STRING algorithm was used for network analysis. Results: A total of 207 RNA-Seq datasets from 97 breast cancer patients were analysed. There was good concordance between the immunohistochemical receptor and AIMS classification for all subtypes, but there was discordance between immunohistochemical and PAM50 subtypes within the ER-positive/HER2-positive subgroup, wherein only 38.5%(n= 5) were classified as HER2-like by gene expression classification. Variant analysis identified 145 high-confidence somatic mutations, with TP53 (n=46, 47%) and PIK3CA (n=33, 34%) being the most frequent. Additional actionable mutations in BRCA1, BRCA2, FGFR2, PTEN, AKT1, and mTOR pathways were identified. At least one actionable mutation was found in 52% of patients. Fusion transcript analysis identified 91 recurrent fusions, including novel partners with ERBB2, MED1, and CDK12, suggesting the possibility of unique molecular events. Interpretation and conclusions: This study demonstrates that Indian breast cancer patients exhibit molecular subtypes and actionable mutations comparable to Caucasian cohorts. Keywords Breast cancer; Intrinsic subtype; PIK3CA; TP53; Transcriptome Identifying and characterising somatic mutations and gene fusions have provided important insights into intricate molecular mechanisms underlying breast cancer. These genetic alterations can lead to aberrant signalling pathways, disrupted cellular processes, and dysregulation of critical genes involved in tumour suppression or promotion. Understanding the underlying genetic aberrations in this disease has been shown to provide important input into patients’prognoses and suggest treatment strategies.1 There is a paucity of genome-wide molecular characterisation in Indian breast cancer patients. However, a few molecular studies have been reported. Thakkar et al1 identified 108 differentially expressed genes (DEG) in 31 ER-positive breast tumours, implicating mRNA transcription and cellular | \#Equal contribution | | --- | | How to cite this article: Gardi N, Chaubal R, Gandhi KA, Kadam A, Singh A, Raja AS, et al. Clinically actionable alterations in Indian breast cancer patients derived through whole transcriptome sequencing. Indian J Med Res. 2026;163:95-103 . DOI: 10.25259/IJMR_ 1642_2024.

FAQs

How were intrinsic molecular subtypes determined in this study?

Intrinsic subtypes were assigned using PAM50 and absolute intrinsic molecular subtyping (AIMS) gene-expression classifiers based on transcriptome data.

Which genes were most frequently mutated among the patients?

Variant analysis identified 145 high-confidence somatic mutations, with TP53 (46; 47%) and PIK3CA (33; 34%) as the most frequent.

What proportion of patients carried actionable mutations, and were gene fusions also assessed?

At least one actionable mutation was found in 52% of patients. The fusion transcript analysis detected 91 recurrent fusions, including novel partners with ERBB2, MED1, and CDK12.

Sep 22, 2026

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