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

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 nextgeneration 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.

Original languageEnglish
Pages (from-to)335-340
Number of pages6
JournalPancreas
Volume46
Issue number3
DOIs
Publication statusPublished - 2017 Mar 1
Externally publishedYes

Fingerprint

High-Throughput Nucleotide Sequencing
p53 Genes
Pancreatic Neoplasms
Biomarkers
Mutation
Genes
Pancreatectomy
Neoplasm Genes
Adjuvant Chemotherapy
Proportional Hazards Models
Carcinogenesis
Multivariate Analysis
Survival
DNA

Keywords

  • Clinical sequencing
  • Driver mutation
  • Genomic biomarker
  • Next-generation sequencer
  • Precision medicine

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Endocrinology

Cite this

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. / Hayashi, Hideyuki; Kohno, Takashi; Ueno, Hideki; Hiraoka, Nobuyoshi; Kondo, Shunsuke; Saito, Motonobu; Shimada, Yoko; Ichikawa, Hitoshi; Kato, Mamoru; Shibata, Tatsuhiro; Morizane, Chigusa; Sakamoto, Yasunari; Shimada, Kazuaki; Komatsu, Yoshito; Sakamoto, Naoya; Okusaka, Takuji.

In: Pancreas, Vol. 46, No. 3, 01.03.2017, p. 335-340.

Research output: Contribution to journalArticle

Hayashi, H, Kohno, T, Ueno, H, Hiraoka, N, Kondo, S, Saito, M, Shimada, Y, Ichikawa, H, Kato, M, Shibata, T, Morizane, C, Sakamoto, Y, Shimada, K, Komatsu, Y, Sakamoto, N & Okusaka, T 2017, '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', Pancreas, vol. 46, no. 3, pp. 335-340. https://doi.org/10.1097/MPA.0000000000000760
Hayashi, Hideyuki ; Kohno, Takashi ; Ueno, Hideki ; Hiraoka, Nobuyoshi ; Kondo, Shunsuke ; Saito, Motonobu ; Shimada, Yoko ; Ichikawa, Hitoshi ; Kato, Mamoru ; Shibata, Tatsuhiro ; Morizane, Chigusa ; Sakamoto, Yasunari ; Shimada, Kazuaki ; Komatsu, Yoshito ; Sakamoto, Naoya ; Okusaka, Takuji. / 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. In: Pancreas. 2017 ; Vol. 46, No. 3. pp. 335-340.
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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 nextgeneration 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.",
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T1 - 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

AU - Hayashi, Hideyuki

AU - Kohno, Takashi

AU - Ueno, Hideki

AU - Hiraoka, Nobuyoshi

AU - Kondo, Shunsuke

AU - Saito, Motonobu

AU - Shimada, Yoko

AU - Ichikawa, Hitoshi

AU - Kato, Mamoru

AU - Shibata, Tatsuhiro

AU - Morizane, Chigusa

AU - Sakamoto, Yasunari

AU - Shimada, Kazuaki

AU - Komatsu, Yoshito

AU - Sakamoto, Naoya

AU - Okusaka, Takuji

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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 nextgeneration 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.

AB - 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 nextgeneration 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.

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KW - Driver mutation

KW - Genomic biomarker

KW - Next-generation sequencer

KW - Precision medicine

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