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Background <p>Cholangiocarcinoma (CCA) is a molecularly heterogeneous malignancy of the biliary tract with rising global incidence and distinct geographic variations in oncogenic drivers. Despite India’s significant cancer burden, genomic data on CCA in Indian patients remain sparse, limiting the development of targeted therapies.</p> Methods <p>This retrospective, multi-institutional study analyzed molecular data from 220 patients with cholangiocarcinoma (CCA), including 147 cases of cholangiocarcinoma not otherwise specified (CCA-unclassified), 63 intrahepatic cholangiocarcinomas (ICA), and 10 distal extrahepatic cholangiocarcinomas (dCCA). Samples were evaluated across three Indian institutions using multiple validated next-generation sequencing (NGS) platforms. The resulting genomic profiles were subsequently compared with international datasets available through cBioPortal. To minimize platform bias, mutation frequency comparisons were restricted to 42 DNA and 13 RNA genes present across all platforms. Statistical significance was assessed using Fisher’s exact test with false discovery rate (FDR) correction for multiple testing.</p> Results <p>Among 220 CCA cases, 147 (66.8%) were anatomically unclassified, 63 (28.6%) intrahepatic (ICA), and 10 (4.5%) distal extrahepatic (dCCA), with pronounced male predominance overall (M: F 1.7:1) and in ICA cases (2.2:1). In the unclassified cohort, the most frequent mutations were <i>TP53</i> (35.6%), <i>KRAS</i> (19.4%), <i>IDH1</i>(10.2% ) and <i>PIK3CA</i> (9.4%). Compared to international cBioPortal data, the Indian cohort showed significantly elevated <i>TP53</i> (35.8% vs. 24.2%; <i>P</i> = 0.0001), <i>KRAS</i> (19.4% vs. 13.0%; <i>P</i> = 0.009), and <i>PIK3CA</i> (9.4% vs. 4.1%; <i>P</i> = 0.001) mutations, but lower <i>BAP1</i> frequencies (5.0% vs. 13.2%; <i>P</i> = 0.007). IDH1 mutations were similar in both cohorts (10.2% vs. 11.1%; <i>p</i> = 0.74). Anatomically defined cases (<i>N</i> = 73) showed concordant patterns. Notably, a distinctive spectrum of non-fusion <i>FGFR2</i> alterations (8 alterations: 3 pathogenic mutations, 3 copy number amplifications, 1 VUS) was identified, distinct from the global pattern of <i>FGFR2</i> fusions. Tumor mutation burden was predominantly low (14/15 cases), and microsatellite instability-high was rare (1/29, 3.4%).</p> Interpretation <p>This study reveals region-specific genomic alterations in Indian CCA, including elevated <i>TP53</i>/<i>KRAS</i> mutations and a distinctive non-fusion <i>FGFR2</i> alteration pattern, distinct from global CCA registries. These ethnicity-stratified findings underscore the importance of population-specific genomic profiling for precision oncology and warrant prospective studies correlating these alterations with treatment response in Indian patients.</p>

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Genomic landscape of cholangiocarcinoma in India: ethnic variants and implications for targeted therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Moushumi Suryavanshi,
  • Vikas Ostwal,
  • Milind Javle,
  • Manoj Kumar,
  • Omshree Shetty,
  • Darshana Patil,
  • Shivani Sharma,
  • Sewanti Limaye,
  • Amol Patel,
  • Bhawna Sirohi,
  • Ankur Bahl,
  • Nitesh Rohtagi

摘要

Background

Cholangiocarcinoma (CCA) is a molecularly heterogeneous malignancy of the biliary tract with rising global incidence and distinct geographic variations in oncogenic drivers. Despite India’s significant cancer burden, genomic data on CCA in Indian patients remain sparse, limiting the development of targeted therapies.

Methods

This retrospective, multi-institutional study analyzed molecular data from 220 patients with cholangiocarcinoma (CCA), including 147 cases of cholangiocarcinoma not otherwise specified (CCA-unclassified), 63 intrahepatic cholangiocarcinomas (ICA), and 10 distal extrahepatic cholangiocarcinomas (dCCA). Samples were evaluated across three Indian institutions using multiple validated next-generation sequencing (NGS) platforms. The resulting genomic profiles were subsequently compared with international datasets available through cBioPortal. To minimize platform bias, mutation frequency comparisons were restricted to 42 DNA and 13 RNA genes present across all platforms. Statistical significance was assessed using Fisher’s exact test with false discovery rate (FDR) correction for multiple testing.

Results

Among 220 CCA cases, 147 (66.8%) were anatomically unclassified, 63 (28.6%) intrahepatic (ICA), and 10 (4.5%) distal extrahepatic (dCCA), with pronounced male predominance overall (M: F 1.7:1) and in ICA cases (2.2:1). In the unclassified cohort, the most frequent mutations were TP53 (35.6%), KRAS (19.4%), IDH1(10.2% ) and PIK3CA (9.4%). Compared to international cBioPortal data, the Indian cohort showed significantly elevated TP53 (35.8% vs. 24.2%; P = 0.0001), KRAS (19.4% vs. 13.0%; P = 0.009), and PIK3CA (9.4% vs. 4.1%; P = 0.001) mutations, but lower BAP1 frequencies (5.0% vs. 13.2%; P = 0.007). IDH1 mutations were similar in both cohorts (10.2% vs. 11.1%; p = 0.74). Anatomically defined cases (N = 73) showed concordant patterns. Notably, a distinctive spectrum of non-fusion FGFR2 alterations (8 alterations: 3 pathogenic mutations, 3 copy number amplifications, 1 VUS) was identified, distinct from the global pattern of FGFR2 fusions. Tumor mutation burden was predominantly low (14/15 cases), and microsatellite instability-high was rare (1/29, 3.4%).

Interpretation

This study reveals region-specific genomic alterations in Indian CCA, including elevated TP53/KRAS mutations and a distinctive non-fusion FGFR2 alteration pattern, distinct from global CCA registries. These ethnicity-stratified findings underscore the importance of population-specific genomic profiling for precision oncology and warrant prospective studies correlating these alterations with treatment response in Indian patients.