Get started
Work

KRAS, CDKN2A, TP53, And SMAD4 Alterations in Relation to Postoperative Survival and Recurrence Patterns Among Patients with Pancreatic Cancer

Year: 2022
Type: article
Study design: Observational Study
Abstract: Alterations in KRAS , CDKN2A ( p16 ), TP53 , and SMAD4 genes have been major drivers of pancreatic carcinogenesis. The clinical course of patients with pancreatic cancer in relation to these driver alterations has not been fully characterised in large populations. We hypothesised that pancreatic carcinomas with different combinations of KRAS mutation and aberrant expression of CDKN2A, p53, and SMAD4 might show distinctive recurrence patterns and post‐operative survival outcomes. To test this hypothesis, we utilised a multi‐institutional cohort of 1,146 resected pancreatic carcinomas and assessed KRAS mutations by droplet digital polymerase chain reaction and CDKN2A, p53, and SMAD4 expression by immunohistochemistry. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease‐free survival (DFS) and overall survival (OS) were computed according to each molecular alteration and the number of altered genes using the Cox regression models. Multivariable competing risks regression analyses were conducted to assess the associations of the number of altered genes with specific patterns of recurrence. Loss of SMAD4 expression was associated with short DFS (multivariable HR, 1.24; 95% CI, 1.09–1.43) and OS times (multivariable HR, 1.27; 95% CI, 1.10–1.46). Compared to cases with 0–2 altered genes, cases with three and four altered genes had multivariable HRs for OS of 1.28 (95% CI, 1.09–1.51) and 1.47 (95% CI, 1.22–1.78), respectively ( p trend < 0.001). Patients with an increasing number of altered genes were more likely to have short DFS time ( p trend = 0.003) and to develop liver metastasis ( p trend = 0.006) rather than recurrence at local or other distant sites. In conclusion, loss of SMAD4 expression and an increasing number of altered genes were associated with unfavourable outcomes in pancreatic cancer patients. This study suggests that the accumulation of the four major driver alterations can confer a high metastatic potential to the liver, thereby impairing post‐operative survival among patients with pancreatic cancer.
DOI: 10.1002/cjp2.323
Authors: Yohei Masugi, Manabu Takamatsu, Mariko Tanaka, Kensuke Hara, Yosuke Inoue, Tsuyoshi Hamada, Tatsunori Suzuki, Junichi Arita, Yuki Hirose, Yoshikuni Kawaguchi, Yousuke Nakai, Atsushi Oba, Naoki Sasahira, Gaku Shimane, Tsuyoshi Takeda, Keisuke Tateishi, Sho Uemura, Mitsuhiro Fujishiro, Kiyoshi Hasegawa, Minoru Kitago, Yu Takahashi, Tetsuo Ushiku, Kengo Takeuchi, Michiie Sakamoto, for the GTK Pancreatic Cancer Study Group in Japan
Institutions: Keio University, The Cancer Institute Hospital, Japanese Foundation For Cancer Research, The University of Tokyo, Akita University, University of Tokyo Hospital
Language: English
Subfield: Oncology
Field: Medicine
Open Access status: gold
Estimated APC paid: $2,700
Funders: Takeda Science Foundation, Japan Agency for Medical Research and Development, Pancreas Research Foundation of Japan, Keio University, University of Tokyo, Daiwa Securities Health Foundation, Japan Society for the Promotion of Science
Awards: Analysis of transcriptome in the tumor microenvironment to explore the pathogenesis and new treatment strategies of human pancreatic cancer., Mechanisms of pancreatic carcinogenesis by metabolic changes in human pancreatic epithelial cells with mutated kRas gene, G2105455229, Prognostic prediction and heterogenetic visualization of pancreatic cancer by histologic and genomic analysis, G5037146584, Heterogeneity of the desmoplastic stroma of human pancreatic cancer: Clinicopathological significance and molecular chanisms shaping the heterogeneity
OpenAlex ID: W4379967327
FWCI: 2.143
Cites: 70
Cited by: 24
Related to: 10