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Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications
Zhiming Zhao1, Xiaomo Li2, Fei Wang1
1Faculty of Hepatopancreatobiliary Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.
Background:
Approximately 90% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by the untargetable non-G12C KRAS mutations, and only a small subset of patients are eligible for FDA-approved precision therapies. The practice of precision therapy in pancreatic cancer was limited by the paucity of targetable genetic alterations, especially in the Asian population.
Methods:
To explore therapeutic targets in 499 Chinese PDAC patients, a deep sequencing panel (OncoPanscan™, Genetron health) was used to characterize somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants.
Results:
We performed genomic profiling in 499 Chinese PDAC patients, which revealed somatic driver mutations in KRAS, TP53, CDKN2A, SMAD4, ARID1A, RNF43, and pathogenic germline variants (PGVs) in cancer predisposition genes including BRCA2, PALB2, and ATM. Overall, 20.4% of patients had targetable genomic alterations. About 8.4% of patients carried inactivating germline and somatic variants in BRCA1/2 and PALB2, which were susceptible to platinum and PARP inhibitors therapy. Patients with KRAS wild-type disease and early-onset pancreatic cancer (EOPC) harbored actionable mutations including BRAF, EGFR, ERBB2, and MAP2K1/2. Compared to PGV-negative patients, PGV-positive patients were younger and more likely to have a family history of cancer. Furthermore, PGVs in PALB2, BRCA2, and ATM were associated with high PDAC risk in the Chinese population.
Conclusions:
Our results demonstrated that a genetic screen of actionable genomic variants could facilitate precision therapy and cancer risk reduction in pancreatic cancer patients of Asian ethnicity.
Insights
Genomic profiling of 499 Chinese pancreatic cancer patients revealed actionable targets in 20.4%. This study highlights the potential for precision therapy and risk reduction in Asian populations with pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is often driven by untargetable KRAS mutations, limiting precision therapy options, especially in Asian populations.
- A significant unmet need exists for identifying targetable alterations in diverse patient groups.
Purpose of the Study:
- To identify actionable genomic alterations and pathogenic germline variants in Chinese PDAC patients.
- To explore the potential for precision therapy and genetic risk assessment in this population.
Main Methods:
- Deep sequencing of 499 Chinese PDAC patients using the OncoPanscan™ panel.
- Characterization of somatic alterations (point mutations, indels, CNAs, fusions) and pathogenic germline variants (PGVs).
Main Results:
- Identified driver mutations in KRAS, TP53, CDKN2A, SMAD4, ARID1A, RNF43, and PGVs in BRCA2, PALB2, ATM.
- 20.4% of patients had targetable genomic alterations; 8.4% had BRCA1/2/PALB2 variants actionable by platinum/PARP inhibitors.
- KRAS wild-type and early-onset PDAC patients showed actionable mutations (BRAF, EGFR, ERBB2, MAP2K1/2).
- PGV-positive patients were younger, had a family cancer history, and PGVs in PALB2, BRCA2, ATM were linked to high PDAC risk in Chinese individuals.
Conclusions:
- Genetic screening can guide precision therapy for pancreatic cancer in Asian patients.
- Identifying PGVs aids in cancer risk reduction strategies for individuals and families.
