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Analysis of circulating cell-free DNA identifies KRAS copy number gain and mutation as a novel prognostic marker in Pancreatic cancer.

ABSTRACT: Serial biopsy of pancreatic ductal adenocarcinoma (PDAC), to chart tumour evolution presents a significant challenge. We examined the utility of circulating free DNA (cfDNA) as a minimally invasive approach across a cohort of 55 treatment-naïve patients with PDAC; 31 with metastatic and 24 with locally advanced disease. Somatic mutations in cfDNA were detected using next generation sequencing in 15/24 (62.5%) and 27/31 (87%) of patients with locally advanced and metastatic disease, respectively. Copy number changes were detected in cfDNA of 10 patients of whom 7 exhibited gain of chromosome 12p harbouring KRAS as well as a canonical KRAS codon 12 mutation. In multivariable Cox Regression analysis, we show for the first time that patients with KRAS copy number gain and KRAS mutation have significantly worse outcomes, suggesting that this may be linked to PDAC progression. The simple cfDNA assay we describe will enable determination of the presence of KRAS copy number gain and KRAS mutations in larger studies and clinical trials.

SUBMITTER: Mohan S

PROVIDER: S-EPMC6690979 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Analysis of circulating cell-free DNA identifies KRAS copy number gain and mutation as a novel prognostic marker in Pancreatic cancer.

Mohan Sumitra S Ayub Mahmood M Rothwell Dominic G DG Gulati Sakshi S Kilerci Bedirhan B Hollebecque Antoine A Sun Leong Hui H Smith Nigel K NK Sahoo Sudhakar S Descamps Tine T Zhou Cong C Hubner Richard A RA McNamara Mairéad G MG Lamarca Angela A Valle Juan W JW Dive Caroline C Brady Ged G

Scientific reports 20190812 1

Serial biopsy of pancreatic ductal adenocarcinoma (PDAC), to chart tumour evolution presents a significant challenge. We examined the utility of circulating free DNA (cfDNA) as a minimally invasive approach across a cohort of 55 treatment-naïve patients with PDAC; 31 with metastatic and 24 with locally advanced disease. Somatic mutations in cfDNA were detected using next generation sequencing in 15/24 (62.5%) and 27/31 (87%) of patients with locally advanced and metastatic disease, respectively. ...[more]

PMID: 31406261

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Project description:BackgroundAlthough the molecular features of pancreatic ductal adenocarcinoma (PDAC) have been well described, the impact of detailed gene mutation subtypes on disease progression remained unclear. This study aimed to evaluate the impact of different TP53 mutation subtypes on clinical characteristics and outcomes of patients with PDAC.MethodsWe included 639 patients treated with PDAC in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine between Jan 2019 and Jun 2021. The genomic alterations of PDAC were analyzed, and the association of TP53 mutation subtypes and other core gene pathway alterations with patients' clinical characteristics were evaluated by Chi-squared test, Kaplan-Meier method and Cox regression model.ResultsTP53 missense mutation was significantly associated with poor differentiation in KRASmut PDAC (50.7% vs. 36.1%, P = 0.001). In small-sized (≤ 2 cm) KRASmut tumors, significantly higher LNs involvement (54.8% vs. 23.5%, P = 0.010) and distal metastic rate (20.5% vs. 2.9%, P = 0.030) were observed in those with TP53 missense mutation instead of truncating mutation. Compared with TP53 truncating mutation, missense mutation was significantly associated with reduced DFS (6.6 [5.6-7.6] vs. 9.2 [5.2-13.3] months, HR 0.368 [0.200-0.677], P = 0.005) and OS (9.6 [8.0-11.1] vs. 18.3 [6.7-30.0] months, HR 0.457 [0.248-0.842], P = 0.012) in patients who failed to receive chemotherapy, while higher OS (24.2 [20.8-27.7] vs. 23.8 [19.0-28.5] months, HR 1.461 [1.005-2.124], P = 0.047) was observed in TP53missense cases after chemotherapy.ConclusionsTP53 missense mutation was associated with poor tumor differentiation, and revealed gain-of-function properties in small-sized KRAS transformed PDAC. Nonetheless, it was not associated with insensitivity to chemotherapy, highlighting the neoadjuvant therapy before surgery as the potential optimized strategy for the treatment of a subset of patients.

Dataset Information

Analysis of circulating cell-free DNA identifies KRAS copy number gain and mutation as a novel prognostic marker in Pancreatic cancer.

Publications

Analysis of circulating cell-free DNA identifies KRAS copy number gain and mutation as a novel prognostic marker in Pancreatic cancer.

Similar Datasets

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