Utility of Assessing the Number of Mutated KRAS, CDKN2A, TP53, and SMAD4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer.

Abstract

OBJECTIVES:

KRAS, CDKN2A, TP53, and SMAD4 have been recognized as major driver genes in pancreatic carcinogenesis. We examined somatic mutations in 50 cancer-related genes, including the four above-mentioned driver genes, to identify genomic biomarkers for predicting the outcome of patients with pancreatic cancer.

METHODS:

Genomic DNA was extracted from fresh-frozen specimens obtained from 100 patients with pancreatic cancer who had undergone a pancreatectomy with curative intent. The mutation profile was obtained using a single targeted deep sequencing assay performed with a next-generation sequencer, and the associations with clinicopathological factors were analyzed.

RESULTS:

Mutations in the KRAS, CDKN2A, TP53, and SMAD4 genes were detected in 96% (96/100), 42% (42/100), 13% (13/100), and 7% (7/100) of all patients, respectively. Among the 71 patients who underwent a radical operation followed by adjuvant chemotherapy, patients with fewer mutations among the four driver genes tended to have a better outcome. A multivariate analysis using the Cox proportional hazard model showed that the presence of 0 to 2 mutated driver genes was an independent predictor of a better overall survival (hazard ratio for death, 0.20; P = 0.0040).

CONCLUSIONS:

The number of mutated driver genes assessed using a targeted deep sequencing assay was a promising prognostic biomarker for pancreatic cancer.

• Authors: Hideyuki Hayashi, Takashi Kohno, Hideki Ueno, Nobuyoshi Hiraoka, Shunsuke Kondo, Motonobu Saito, Yoko Shimada, Hitoshi Ichikawa, Mamoru Kato, Tatsuhiro Shibata, Chigusa Morizane, Yasunari Sakamoto, Kazuaki Shimada, Yoshito Komatsu, Naoya Sakamoto, Takuji Okusaka
• Journal: Pancreas (Pancreas) Vol. 46 Issue 3 Pg. 335-340 (03 2017) ISSN: 1536-4828 [Electronic] United States
• PMID: 28099251 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• Cyclin-Dependent Kinase Inhibitor p16
• KRAS protein, human
• Smad4 Protein
• Tumor Suppressor Protein p53
• Proto-Oncogene Proteins p21(ras)

Topics

• Biomarkers, Tumor (genetics)
• Combined Modality Therapy
• Cyclin-Dependent Kinase Inhibitor p16 (genetics)
• High-Throughput Nucleotide Sequencing (methods)
• Humans
• Multivariate Analysis
• Mutation
• Outcome Assessment, Health Care (methods, statistics & numerical data)
• Pancreatic Neoplasms (drug therapy, genetics, surgery)
• Prognosis
• Proportional Hazards Models
• Proto-Oncogene Proteins p21(ras) (genetics)
• Smad4 Protein (genetics)
• Survival Analysis
• Tumor Suppressor Protein p53 (genetics)