Gut and Liver https://doi.org/10.5009/gnl18355 Comprehensive Cancer Panel Sequencing Defines Genetic Diversity and Changes in the Mutational Characteristics of Pancreatic Cancer Patients Receiving Neoadjuvant Treatment
Author Information
Kyong-Ah Yoon1, Sang Myung Woo2,3 , Yun-Hee Kim3, Sun-Young Kong3,4, Min Kyoung Lee3, Sung-Sik Han2, Tae Hyun Kim2, Woo Jin Lee2, and Sang-Jae Park2
1College of Veterinary Medicine, Konkuk University, Seoul, 2Center for Liver Cancer, Hospital, National Cancer Center, 3Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, and 4Center for Diagnostic Oncology, Hospital, National Cancer Center, Goyang, Korea

Sang Myung Wooa and Sang-Jae Parkb
Center for Liver Cancer, Hospital, National Cancer Center, Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea
aTel: +82-31-920-1733, Fax: +82-31-920-2798, E-mail: wsm@ncc.re.kr
bTel: +82-31-920-1640, Fax: +82-31-920-1640, E-mail: spark@ncc.re.kr
© The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer. All rights reserved.

Abstract
Background/Aims: Pancreatic ductal adenocarcinoma (PDA) is associated with an extremely poor prognosis. This study assessed the genetic diversity among patients with PDA and compared their mutational profiles before and after treatment. Methods: Tumors and matched blood samples were obtained from 22 PDA patients treated with neoadjuvant chemoradiation therapy. The somatic mutations were analyzed with a comprehensive cancer gene panel (CCP), and the biopsy samples obtained at diagnosis and the surgically resected samples after treatment were compared for seven patients. The CCP provided formalin-fixed paraffin-embedded sample-compatible multiplexed target selection for 409 genes implicated in cancer. Results: Assessments of the MLH1, MLH3, MSH2, and PMS2 genes showed that the four patients with the highest relative burdens of mutations harbored somatic mutations in at least three of these genes. Genes in the histone-lysine N-methyltransferase 2 (KMT2) family, such as KMT2D, KMT2A, and KMT2C, were frequently mutated in tumor samples. Survival was worse in patients with than without ARID1A gene mutations. Mutation patterns were compared between tissue samples before and after neoadjuvant treatment in seven patients who underwent surgical resection. The allelic fraction of mutations in KRAS codon 12 was lower in the surgically resected samples than in the endoscopic ultrasonography-guided fine needle aspiration biopsy samples of six patients. The number of mutant alleles of the histone lysine methyltransferase gene WHSC1 also decreased after treatment. Conclusions: These results indicate that tumor tissue from PDA patients is genetically diverse and suggest that ARID1A mutations may be a potential prognostic marker for PDA.
Keywords: Pancreatic neoplasms; ARID1A; Histone-lysine N-methyltransferase
Abstract
Background/Aims: Pancreatic ductal adenocarcinoma (PDA) is associated with an extremely poor prognosis. This study assessed the genetic diversity among patients with PDA and compared their mutational profiles before and after treatment. Methods: Tumors and matched blood samples were obtained from 22 PDA patients treated with neoadjuvant chemoradiation therapy. The somatic mutations were analyzed with a comprehensive cancer gene panel (CCP), and the biopsy samples obtained at diagnosis and the surgically resected samples after treatment were compared for seven patients. The CCP provided formalin-fixed paraffin-embedded sample-compatible multiplexed target selection for 409 genes implicated in cancer. Results: Assessments of the MLH1, MLH3, MSH2, and PMS2 genes showed that the four patients with the highest relative burdens of mutations harbored somatic mutations in at least three of these genes. Genes in the histone-lysine N-methyltransferase 2 (KMT2) family, such as KMT2D, KMT2A, and KMT2C, were frequently mutated in tumor samples. Survival was worse in patients with than without ARID1A gene mutations. Mutation patterns were compared between tissue samples before and after neoadjuvant treatment in seven patients who underwent surgical resection. The allelic fraction of mutations in KRAS codon 12 was lower in the surgically resected samples than in the endoscopic ultrasonography-guided fine needle aspiration biopsy samples of six patients. The number of mutant alleles of the histone lysine methyltransferase gene WHSC1 also decreased after treatment. Conclusions: These results indicate that tumor tissue from PDA patients is genetically diverse and suggest that ARID1A mutations may be a potential prognostic marker for PDA.
Keywords: Pancreatic neoplasms; ARID1A; Histone-lysine N-methyltransferase
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