Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-05-01
|
| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.5871 |
| _version_ | 1797810419133317120 |
|---|---|
| author | Zhiming Zhao Xiaomo Li Fei Wang Yong Xu Si Liu Quanli Han Zhiying Yang Weiwei Huang Zhuzeng Yin Qu Liu Haidong Tan Tonghui Ma Shuang Si Jia Huang Hongling Yuan Wei Li Rong Liu |
| author_facet | Zhiming Zhao Xiaomo Li Fei Wang Yong Xu Si Liu Quanli Han Zhiying Yang Weiwei Huang Zhuzeng Yin Qu Liu Haidong Tan Tonghui Ma Shuang Si Jia Huang Hongling Yuan Wei Li Rong Liu |
| author_sort | Zhiming Zhao |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-13T07:07:29Z |
| format | Article |
| id | doaj.art-51b379596788480cb0b8b717dbd72b78 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-03-13T07:07:29Z |
| publishDate | 2023-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-51b379596788480cb0b8b717dbd72b782023-06-06T07:30:47ZengWileyCancer Medicine2045-76342023-05-011210116721168510.1002/cam4.5871Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implicationsZhiming Zhao0Xiaomo Li1Fei Wang2Yong Xu3Si Liu4Quanli Han5Zhiying Yang6Weiwei Huang7Zhuzeng Yin8Qu Liu9Haidong Tan10Tonghui Ma11Shuang Si12Jia Huang13Hongling Yuan14Wei Li15Rong Liu16Faculty of Hepatopancreatobiliary Surgery The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital Beijing ChinaHangzhou Jichenjunchuang Medical Laboratory, Co. Ltd Hangzhou ChinaFaculty of Hepatopancreatobiliary Surgery The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital Beijing ChinaFaculty of Hepatopancreatobiliary Surgery The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital Beijing ChinaHangzhou Jichenjunchuang Medical Laboratory, Co. Ltd Hangzhou ChinaDepartment of Medical Oncology The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital Beijing ChinaDepartment of Hepatobiliary Surgery China‐Japan Friendship Hospital Beijing ChinaHangzhou Jichenjunchuang Medical Laboratory, Co. Ltd Hangzhou ChinaFaculty of Hepatopancreatobiliary Surgery The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital Beijing ChinaFaculty of Hepatopancreatobiliary Surgery The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital Beijing ChinaDepartment of Hepatobiliary Surgery China‐Japan Friendship Hospital Beijing ChinaHangzhou Jichenjunchuang Medical Laboratory, Co. Ltd Hangzhou ChinaDepartment of Hepatobiliary Surgery China‐Japan Friendship Hospital Beijing ChinaDepartment of Hepatobiliary Surgery China‐Japan Friendship Hospital Beijing ChinaHangzhou Jichenjunchuang Medical Laboratory, Co. Ltd Hangzhou ChinaHangzhou Jichenjunchuang Medical Laboratory, Co. Ltd Hangzhou ChinaFaculty of Hepatopancreatobiliary Surgery The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital Beijing ChinaAbstract 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.https://doi.org/10.1002/cam4.5871cancer riskgenetic alterationsnext‐generation sequencingpancreatic cancerprecision therapy |
| spellingShingle | Zhiming Zhao Xiaomo Li Fei Wang Yong Xu Si Liu Quanli Han Zhiying Yang Weiwei Huang Zhuzeng Yin Qu Liu Haidong Tan Tonghui Ma Shuang Si Jia Huang Hongling Yuan Wei Li Rong Liu Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications Cancer Medicine cancer risk genetic alterations next‐generation sequencing pancreatic cancer precision therapy |
| title | Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications |
| title_full | Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications |
| title_fullStr | Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications |
| title_full_unstemmed | Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications |
| title_short | Pathogenic genomic alterations in Chinese pancreatic cancer patients and their therapeutical implications |
| title_sort | pathogenic genomic alterations in chinese pancreatic cancer patients and their therapeutical implications |
| topic | cancer risk genetic alterations next‐generation sequencing pancreatic cancer precision therapy |
| url | https://doi.org/10.1002/cam4.5871 |
| work_keys_str_mv | AT zhimingzhao pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT xiaomoli pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT feiwang pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT yongxu pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT siliu pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT quanlihan pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT zhiyingyang pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT weiweihuang pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT zhuzengyin pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT quliu pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT haidongtan pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT tonghuima pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT shuangsi pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT jiahuang pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT honglingyuan pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT weili pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications AT rongliu pathogenicgenomicalterationsinchinesepancreaticcancerpatientsandtheirtherapeuticalimplications |