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

Abstract

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

Characterization of the genomic landscape in large-scale Chinese patients with pancreatic cancer

“… 19 , 20 , 21 Recently, studies have reported the genomic characteristics of Chinese pancreatic cancer patients, however, lack of blood paired germline or based on small cases, which is difficult to reflect the real-world genomic characteristics of pancreatic cancer from China. 22 , 23 …”

Copy Number Variations in Pancreatic Cancer: From Biological Significance to Clinical Utility

“…REG4 overexpression was associated with poor prognosis and resistance to gemcitabine treatment in one study, suggesting that adjuvant therapies that target reg4 could enhance the usual gemcitabine-based treatment of pancreatic cancer [75,116,117]. ASAP2 (2p25.1) amplification has been associated with lower overall survival (OS) as well as lower relapse-free survival (RFS) [134,135]. FHIT (3p14.2) and ATR (3q23) deletions were mostly reported in both sporadic familial cases, indicating their possible role in PDAC susceptibility as well as progression [77,110,118,133,136].…”

“…ASAP2 (2p25.1) amplification has been associated with lower overall survival (OS) as well as lower relapse-free survival (RFS) [ 134 , 135 ]. FHIT (3p14.2) and ATR (3q23) deletions were mostly reported in both sporadic familial cases, indicating their possible role in PDAC susceptibility as well as progression [ 77 , 110 , 118 , 133 , 136 ].…”

“…No deletions were reported on chromosome 11, but there were amplifications on 11q13.3 (CCND1, TMEM16H), 11q13.5 (EMSY), and 11p14.1 (LGR4), of which the CCND1 gene was the most recurrent amplification [ 118 , 120 , 132 , 134 , 137 ]. One study showed that the presence of elevated EMSY copy numbers in relatively large, clustered cells surrounded by tumor cells expressing normal copy numbers suggests that the mutation occurred later in the carcinogenesis process rather than at an early stage.…”

The distinct genetic features of pancreatic cancer in Chinese population

“…Guo et al. 4 profiled the genomic alteration of PDAC with 408 Chinese patients, showing a relatively higher mutation rates of DNA damage repair-related genes.…”