Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications

Zhao, Zhiming; Li, Xiaomo; Wang, Fei; Xu, Yong; Liu, Si; Han, Qi; Yang, Zhao; Huang, Weiwei; Yin, Zhongyuan; Liu, Qu; Tan, Haidong; Ma, Tonghui; Si, Shuang; Huang, Jia; Yuan, Hongling; Li, Wei; Liu, Rong

doi:10.1002/cam4.5871

Cited by 8 publications

(1 citation statement)

References 62 publications

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“…Somatic mutation testing for alterations like BRCA, KRAS, HER2, PALB2 and mismatch repair proteins, for PDA patients is recommended in the NCCN guidelines ( 4 ). Around 10% of PDA patients express alterations that are potentially targetable ( 5 ). PDA can be highly heterogenous in both biology and clinical behavior ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma

et al. 2023

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IntroductionKRAS mutation is a common occurrence in Pancreatic Ductal Adenocarcinoma (PDA) and is a driver mutation for disease development and progression. KRAS wild-type PDA may constitute a distinct molecular and clinical subtype. We used the Foundation one data to analyze the difference in Genomic Alterations (GAs) that occur in KRAS mutated and wild-type PDA.MethodsComprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed.Results and discussionOur cohort had 9444 cases of advanced PDA. 8723 (92.37%) patients had KRAS mutation. 721 (7.63%) patients were KRAS wild-type. Among potentially targetable mutations, GAs more common in KRAS wild-type included ERBB2 (mutated vs wild-type: 1.7% vs 6.8%, p <0.0001), BRAF (mutated vs wild-type: 0.5% vs 17.9%, p <0.0001), PIK3CA (mutated vs wild-type: 2.3% vs 6.5%, p <0.001), FGFR2 (mutated vs wild-type: 0.1% vs 4.4%, p <0.0001), ATM (mutated vs wild-type: 3.6% vs 6.8%, p <0.0001). On analyzing untargetable GAs, the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001), CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001), CDKN2B (mutated vs wild-type: 28.9% vs 23%, p =0.007), SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001) and MTAP (mutated vs wild-type: 21.7% vs 18%, p =0.02). ARID1A (mutated vs wild-type: 7.7% vs 13.6%, p <0.0001 and RB1(mutated vs wild-type: 2% vs 4%, p =0.01) were more prevalent in the wild-type subgroup. Mean TMB was higher in the KRAS wild-type subgroup (mutated vs wild-type: 2.3 vs 3.6, p <0.0001). High TMB, defined as TMB > 10 mut/mB (mutated vs wild-type: 1% vs 6.3%, p <0.0001) and very-high TMB, defined as TMB >20 mut/mB (mutated vs wild-type: 0.5% vs 2.4%, p <0.0001) favored the wild-type. PD-L1 high expression was similar between the 2 groups (mutated vs wild-type: 5.7% vs 6%,). GA associated with immune checkpoint inhibitors (ICPIs) response including PBRM1 (mutated vs wild-type: 0.7% vs 3.2%, p <0.0001) and MDM2 (mutated vs wild-type: 1.3% vs 4.4%, p <0.0001) were more likely to be seen in KRAS wild-type PDA.

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Section: Introductionmentioning

confidence: 99%

Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma

et al. 2023

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Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications

Zhao

Li²,

Wang

et al. 2023

Cancer Medicine

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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.

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Fusion genes in pancreatic tumors

Gkountakos,

Singhi,

Westphalen

et al. 2024

Trends in Cancer

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Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications

Cited by 8 publications

References 62 publications

Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma

Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma

Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications

Fusion genes in pancreatic tumors

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