Comprehensive Analysis of Somatic Mutations in Driver Genes of Resected Pancreatic Ductal Adenocarcinoma Reveals KRAS G12D and Mutant TP53 Combination as an Independent Predictor of Clinical Outcome

Shoucair, Sami; Pu, Ning; Kinny‐Köster, Benedict; Ooston, A. Floortje van; Javed, Ammar A.; Lafaro, Kelly J.; He, Jin; Wolfgang, Christopher L.; Yu, Jun

doi:10.1245/s10434-021-11081-z

Cited by 9 publications

(9 citation statements)

References 47 publications

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“… 55 Another retrospective study of 587 PDAC patients revealed that patient with more than one driver mutations had worse OS than those with one driver mutation (18.2 vs. 32.3 months, p = 0.033). 56 These results suggested that genomic profiling could provide important predictive information on the survival of PDAC patients.…”

Section: Discussionmentioning

confidence: 92%

“…A retrospective study of 111 PDAC patients showed that patients with KRAS G12R versus non‐G12R mutations had significantly longer OS (HR 0.55) and PFS (HR 0.58), respectively 55 . Another retrospective study of 587 PDAC patients revealed that patient with more than one driver mutations had worse OS than those with one driver mutation (18.2 vs. 32.3 months, p = 0.033) 56 . These results suggested that genomic profiling could provide important predictive information on the survival of PDAC patients.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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

Zhao

Li²,

Wang

et al. 2023

Cancer Medicine

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“…Several features that coexist with KRAS mutations also have an impact on the prognosis of patients. In a retrospective study of 587 resected PDAC patients, the co-mutation of TP53 and KRAS G12D is shown to be an independent predictor of better OS and recurrence-free survival (RFS) [ 48 ]. In a study of HER2-mutant advanced gastric cancer patients treated with trastuzumab, KRAS mutation was found to be a predictor of insufficient efficacy and poor prognosis [ 49 ].…”

Section: Kras Mutations In Cancersmentioning

confidence: 99%

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

Yang

Zhang

Huang

et al. 2023

JCM

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Kristen rat sarcoma (KRAS) gene is one of the most common mutated oncogenes in solid tumors. Yet, KRAS inhibitors did not follow suit with the development of targeted therapy, for the structure of KRAS has been considered as being implausible to target for decades. Chemotherapy was the initial recommended therapy for KRAS-mutant cancer patients, which was then replaced by or combined with immunotherapy. KRAS G12C inhibitors became the most recent breakthrough in targeted therapy, with Sotorasib being approved by the Food and Drug Administration (FDA) based on its significant efficacy in multiple clinical studies. However, the subtypes of the KRAS mutations are complex, and the development of inhibitors targeting non-G12C subtypes is still at a relatively early stage. In addition, the monotherapy of KRAS inhibitors has accumulated possible resistance, acquiring the exploration of combination therapies or next-generation KRAS inhibitors. Thus, other non-target, conventional therapies have also been considered as being promising. Here in this review, we went through the characteristics of KRAS mutations in cancer patients, and the prognostic effect that it poses on different therapies and advanced therapeutic strategy, as well as cutting-edge research on the mechanisms of drug resistance, tumor development, and the immune microenvironment.

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“…The median diameter of the PC was 25 mm (IQR [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. The median PD diameter was 2 mm (IQR 2-3.5) and communication of the cyst with the PD was defined in 23 patients (95.8%).…”

Section: Eus and Fluid Cytologymentioning

confidence: 99%

“…Similar to work in cyst fluid, of the four cysts diagnosed as "probable mucinous cyst" by a pathologist, two were not found to contain any KRAS or GNAS mutations. TP53 mutations were observed in three samples (1 at codon 85 and 2 at codon 217), neither of these sites are associated with pancreatic cancer in COSMIC, but somatic mutations in TP53 at any point have been shown to aid in prediction of outcome of pancreatic adenocarcinoma [32]. We endeavored to test matched cyst fluid samples from patients from whom samples could be obtained and sufficient DNA could be extracted.…”

Section: E988mentioning

confidence: 99%

Next-generation sequencing of pancreatic cyst wall specimens obtained using micro-forceps for improving diagnostic accuracy

Astbury,

Baskar,

Grove

et al. 2023

Endosc Int Open

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Background and study aims: Pancreatic cysts are common incidental findings, with an estimated prevalence of 13-15% in imaging done for other reasons. Diagnosis often relies on collection of cyst fluid, but tissue sampling using micro-forceps may allow for a more reliable diagnosis and higher yield of DNA for next-generation sequencing (NGS). The primary aim was to assess the performance of NGS in identifying mucinous cyst. The secondary aims were to assess DNA yield between the cyst fluid and cyst wall tissue, complication rate and performance of conventional investigations. Patients and methods: 24 patients referred for endoscopic ultrasound were recruited. Biopsies were taken using micro-forceps and the AmpliSeq Cancer Hotspot panel was used for NGS, a PCR assay targeting several hotspots within 50 genes, including GNAS, KRAS and VHL. Results: The concentration of DNA extracted from 24 cyst wall samples was significantly higher than in the 9/24 available matched cyst fluid samples. The sensitivity, specificity and diagnostic accuracy of NGS for diagnosing mucinous cyst was 93%, 50% and 84%, standard of care -66.6%, 50% and 63.1% and for standard of care with NGS was 100%, 50% and 89.4% respectively. Cyst wall biopsy was able to diagnose 19/24 cysts (4 high risk, 7 intraductal papillary mucinous neoplasm, 4 cysts of mucinous origin and 4 benign). Conclusions: NGS data correlates well with histology and may aid in diagnosis and risk stratification of pancreatic cysts. Cyst wall biopsy performs well in diagnosing cysts but was inadequate in 5/24 patients.

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Comprehensive Analysis of Somatic Mutations in Driver Genes of Resected Pancreatic Ductal Adenocarcinoma Reveals KRAS G12D and Mutant TP53 Combination as an Independent Predictor of Clinical Outcome

Cited by 9 publications

References 47 publications

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

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

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

Next-generation sequencing of pancreatic cyst wall specimens obtained using micro-forceps for improving diagnostic accuracy

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