ArticleMolecular diagnosis & therapy2022
Methylation Analyses Reveal Promoter Hypermethylation as a Rare Cause of "Second Hit" in Germline BRCA1-Associated Pancreatic Ductal Adenocarcinoma.
Article in Molecular diagnosis & therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 10 citations in OpenAlex.
- A Phase II Trial of Niraparib in Patients with Advanced Pancreatic Cancer Harboring Pathogenic Variants in ATM, BRCA1, BRCA2, PALB2, and CHEK2.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Research progress in diagnosis and treatment of pancreatic cancer with mismatch repair and microsatellite instability.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Advances in pancreatic cancer epigenetics: From the mechanism to the clinic.World journal of gastrointestinal oncology · 2025Review
- A Rapid and Reliable Test forDiagnostics (Basel, Switzerland) · 2025Article
- BRCA1 & BRCA2 methylation as a prognostic and predictive biomarker in cancer: Implementation in liquid biopsy in the era of precision medicine.Clinical epigenetics · 2024Review
- Mutations in Mismatch Repair Genes and Microsatellite Instability Status in Pancreatic Cancer.Cancers · 2024Article
- Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review.Cancers · 2023Review
- BiallelicJCO precision oncology · 2023Article
- Prevalence of BRCA homopolymeric indels in an ION Torrent-based tumour-to-germline testing workflow in high-grade ovarian carcinoma.Scientific reports · 2023Article
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Authors and funding
20 authors at 4 institutions in 1 country.
Funding
Abstract
BACKGROUND AND
objectivePancreatic ductal adenocarcinoma (PDAC) is characterized by the occurrence of pathogenic variants in BRCA1/2 in 5-6% of patients. Biallelic loss of BRCA1/2 enriches for response to platinum agents and poly (ADP-ribose) polymerase 1 inhibitors. There is a dearth of evidence on the mechanism of inactivation of the wild-type BRCA1 allele in PDAC tumors with a germline BRCA1 (gBRCA1) pathogenic or likely pathogenic variant (P/LPV). Herein, we examine promotor hypermethylation as a "second hit" mechanism in patients with gBRCA1-PDAC.
methodsWe evaluated patients with PDAC who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) somatic and germline testing from an institutional database. DNA isolated from tumor tissue and matched normal peripheral blood were sequenced by MSK-IMPACT. In patients with gBRCA1-PDAC, we examined the somatic BRCA1 mutation status and promotor methylation status of the tumor BRCA1 allele via a methylation array analysis. In patients with sufficient remaining DNA, a second methylation analysis by pyrosequencing was performed.
resultsOf 1012 patients with PDAC, 19 (1.9%) were identified to harbor a gBRCA1 P/LPV. Fifteen patients underwent a methylation array and the mean percentage of BRCA1 promotor methylation was 3.62%. In seven patients in whom sufficient DNA was available, subsequent pyrosequencing confirmed an unmethylated BRCA1 promotor. Loss of heterozygosity was detected in 12 of 19 (63%, 95% confidence interval 38-84) patients, demonstrating loss of heterozygosity is the major molecular mechanism of BRCA1 inactivation in PDAC. Two (10.5%) cases had a somatic BRCA1 mutation.
conclusionsIn patients with gBRCA1-P/LPV-PDAC, loss of heterozygosity is the main inactivating mechanism of the wild-type BRCA1 allele in the tumor, and methylation of the BRCA1 promoter is a distinctly uncommon occurrence.
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