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KRAS Allelic Variants in Biliary Tract Cancers
Gordon Taylor Moffat1, Zishuo Ian Hu2, Funda Meric-Bernstam3
1Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Importance:
Biliary tract cancers (BTCs) contain several actionable molecular alterations, including FGFR2, IDH1, ERBB2 (formerly HER2), and KRAS. KRAS allelic variants are found in 20% to 30% of BTCs, and multiple KRAS inhibitors are currently under clinical investigation.
Objectives:
To describe the genomic landscape, co-sequence variations, immunophenotype, genomic ancestry, and survival outcomes of KRAS-mutated BTCs and to calculate the median overall survival (mOS) for the most common allelic variants.
Design, Setting, And Participants:
This retrospective, multicenter, pooled cohort study obtained clinical and next-generation sequencing data from multiple databases between January 1, 2017, and December 31, 2022. These databases included Princess Margaret Cancer Centre, MD Anderson Cancer Center, Foundation Medicine, American Association for Cancer Research Project GENIE, and cBioPortal for Cancer Genomics. The cohort comprised patients with BTCs who underwent genomic testing.
Main Outcome And Measure:
The main outcome was mOS, defined as date of diagnosis to date of death, which was measured in months.
Results:
A total of 7457 patients (n = 3773 males [50.6%]; mean [SD] age, 63 [5] years) with BTCs and genomic testing were included. Of these patients, 5813 had clinical outcome data available, in whom 1000 KRAS-mutated BTCs were identified. KRAS allelic variants were highly prevalent in perihilar cholangiocarcinoma (28.6%) and extrahepatic cholangiocarcinoma (36.1%). Thirty-six KRAS allelic variants were identified, and the prevalence rates in descending order were G12D (41%), G12V (23%), and Q61H (8%). The variant G12D had the highest mOS of 25.1 (95% CI, 22.0-33.0) months compared with 22.8 (95% CI, 19.6-31.4) months for Q61H and 17.8 (95% CI, 16.3-23.1) months for G12V variants. The majority of KRAS-mutated BTCs (98.9%) were not microsatellite instability-high and had low tumor mutational burden (ranging from a median [IQR] of 1.2 (1.2-2.5) to a mean [SD] of 3.3 [1.3]). Immune profiling through RNA sequencing of KRAS and NRAS-mutated samples showed a pattern toward a more immune-inflamed microenvironment with higher M1 macrophage activation (0.16 vs 0.12; P = .047) and interferon-γ expression compared with wild-type tumors. The G12D variant remained the most common KRAS allelic variant in all patient ancestries. Patients with admixed American ancestry had the highest proportion of G12D variant (45.0%).
Conclusions And Relevance:
This cohort study found that KRAS allelic variants were relatively common and may be potentially actionable genomic alterations in patients with BTCs, especially perihilar cholangiocarcinoma and extrahepatic cholangiocarcinoma. The findings add to the growing data on genomic and immune landscapes of KRAS allelic variants in BTCs and are potentially of value to the planning of specific therapies for this heterogeneous patient group.
Insights
KRAS allelic variants are common in biliary tract cancers (BTCs), particularly in perihilar and extrahepatic subtypes. The G12D variant showed the longest median overall survival, offering potential therapeutic targets for this patient group.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Biliary tract cancers (BTCs) exhibit actionable molecular alterations, including KRAS variants, which are present in 20-30% of cases.
- Multiple KRAS inhibitors are under clinical investigation, highlighting the therapeutic potential of targeting these mutations.
Purpose of the Study:
- To characterize the genomic landscape, immunophenotype, and survival outcomes of KRAS-mutated BTCs.
- To determine the median overall survival (mOS) for common KRAS allelic variants in BTC patients.
Main Methods:
- A retrospective, multicenter cohort study analyzed clinical and next-generation sequencing data from 7457 BTC patients (2017-2022).
- Median overall survival was calculated for patients with KRAS-mutated BTCs, with specific analysis of common allelic variants.
Main Results:
- KRAS mutations were prevalent in perihilar (28.6%) and extrahepatic (36.1%) cholangiocarcinoma.
- The G12D variant (41% of KRAS mutations) had the highest mOS (25.1 months), followed by Q61H (22.8 months) and G12V (17.8 months).
- KRAS-mutated BTCs generally had low tumor mutational burden and a more immune-inflamed microenvironment compared to wild-type tumors.
Conclusions:
- KRAS allelic variants are common and potentially actionable genomic alterations in BTCs, especially in perihilar and extrahepatic subtypes.
- These findings contribute to understanding the genomic and immune profiles of KRAS-mutated BTCs, aiding in personalized therapy planning.
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