The Landscape of Genetic Alterations Stratified Prognosis in Oriental Pancreatic Cancer Patients

Shiwei Guo; Xiaohan Shi; Suizhi Gao; Qunxing Hou; Lisha Jiang; Bo Li; Jing Shen; Huan Wang; Shuo Shen; GuoXiao Zhang; Yaqi Pan; Wuchao Liu; Xiongfei Xu; Kailian Zheng; Zhuo Shao; Wei Jing; Ling Lin; Gang Li; Gang Jin

doi:10.3389/fonc.2021.717989

The Landscape of Genetic Alterations Stratified Prognosis in Oriental Pancreatic Cancer Patients

Front Oncol. 2021 Jul 22:11:717989. doi: 10.3389/fonc.2021.717989. eCollection 2021.

Authors

Shiwei Guo¹, Xiaohan Shi^{1

2}, Suizhi Gao¹, Qunxing Hou³, Lisha Jiang³, Bo Li¹, Jing Shen¹, Huan Wang¹, Shuo Shen¹, GuoXiao Zhang¹, Yaqi Pan¹, Wuchao Liu¹, Xiongfei Xu¹, Kailian Zheng¹, Zhuo Shao¹, Wei Jing¹, Ling Lin³, Gang Li¹, Gang Jin¹

Affiliations

¹ Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Naval Military Medical University (Second Military Medical University), Shanghai, China.
² Department of General Surgery, Naval Medical Center of People's Liberation Army (PLA), Shanghai, China.
³ Zhangjiang Center for Translational Medicine, Shanghai Biotecan Medical Diagnostics Co., Ltd, Shanghai, China.

Abstract

Background: Pancreatic cancer is a life-threatening malignant disease with significant diversity among geographic regions and races leading to distinct carcinogenesis and prognosis. Previous studies mainly focused on Western patients, while the genomic landscape of Oriental patients, especially Chinese, remained less investigated.

Methods: A total of 408 pancreatic cancer patients were enrolled. A panel containing 436 cancer-related genes was used to detect genetic alterations in tumor samples.

Results: We profiled the genomic alteration landscape of pancreatic duct adenocarcinoma (PDAC), intraductal papillary mucinous neoplasm (IPMN), periampullary carcinoma (PVC), and solid-pseudopapillary tumor (SPT). Comparison with a public database revealed specific gene mutations in Oriental PDAC patients including higher mutation rates of DNA damage repair-related genes. Analysis of mutational signatures showed potential heterogenous carcinogenic factors caused by diabetes mellitus. KRAS mutation, especially KRAS G12D mutation, was associated with poor survival, while patients not harboring the 17 significant copy number variations (CNVs) had a better prognosis. We further identified multiple correlations between clinicopathologic variables and genetic mutations, as well as CNVs. Finally, by network-based stratification, three classes of PDAC patients were robustly clustered. Among these, class 1 (characterized by the Fanconi anemia pathway) achieved the best outcome, while class 2 (involved in the platinum drug resistance pathway) suffered from the worst prognosis.

Conclusions: In this study, we reported for the first time the genetic alteration landscape of Oriental PDAC patients identifying many Oriental-specific alterations. The relationship between genetic alterations and clinicopathological factors as well as prognosis demonstrated important genomic impact on tumor biology. This study will help to optimize clinical treatment of Oriental PDAC patients and improve their survival.

Keywords: clinicopathological variable; genetic alteration; network-based stratification; pancreatic ductal adenocarcinoma; prognosis.