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.
Highlights
Pancreatic cancer is a devastating malignant disease with a median survival of 6–12 months and a 5-year survival rate of less than 9% [1, 2]
A total of 502 pancreatic and periampullary neoplasm specimens were submitted for targeted genomic profiling during clinical care
After further removing 31 samples from patients who had neoadjuvant therapy as well as 11 samples diagnosed as rare subtypes, 302 cases of pancreatic duct adenocarcinoma (PDAC), 74 cases of periampullary carcinoma (PAC), 24 cases of intraductal papillary mucinous neoplasm (IPMN), and 8 cases of solidpseudopapillary tumor (SPT) had credible sequencing results (Figure 1)
Summary
Pancreatic cancer is a devastating malignant disease with a median survival of 6–12 months and a 5-year survival rate of less than 9% [1, 2]. Current studies are mainly based on Western patients, and there is a lack of comparative studies on Oriental pancreatic cancer patients, especially among the largest patient population in China. Heterogeneity brings significant differences in biological behaviors of pancreatic cancer, including malignant proliferation [10], metastasis potential [11], and chemotherapy sensitivity [12], and these differences can affect prognosis [13, 14]. Defining the mutation landscape of pancreatic cancer in Oriental patients by comparing the characteristics between Eastern and Western patients may aid in identifying possible causes of differences in pathogenesis and prognosis. 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
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