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Published on: February 11, 2019
Heterogeneity of KRAS Mutations in Pancreatic Ductal Adenocarcinoma
Daisuke Hashimoto1, Kota Arima, Naomi Yokoyama
1From the *Department of Gastroenterological Surgery and †Institute of Resource Development and Analysis, Kumamoto University Graduate School of Medical Sciences; and ‡Department of Surgery, Kumamoto Regional Medical Center, Kumamoto, Japan.
Objectives:
Activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are the most common and frequent changes observed in pancreatic cancer. This study aimed to determine the frequency and extent of intratumoral and metastatic lymph node KRAS mutation heterogeneity of resected pancreatic ductal adenocarcinoma.
Methods:
Tumor tissues macrodissected from tumor centers, invasion fronts (n = 97), and lymph nodes (n = 11) were subjected to DNA extraction and mutation analysis of KRAS codons 12 and 13 by pyrosequencing.
Results:
Activating mutations in codon 12 of KRAS were detected in 90 (92.8%) tumor centers. No mutations were detected in KRAS codon 13 in any patient. After a comparison of tumor centers and invasion fronts, intratumoral heterogeneity of KRAS was observed only in 4 (4.1%) cases. Additional invasion front tumor analysis revealed the same mutation status consistent with each tumor center. No heterogeneity was observed between primary tumors and metastatic lymph nodes.
Conclusions:
Intratumoral heterogeneity of the KRAS mutational status is rare in pancreatic ductal adenocarcinoma. In addition, no KRAS heterogeneity between primary tumors and metastatic lymph nodes was detected in this study. This finding is consistent with the hypothesis that oncogenic activation of KRAS is the first driver mutation in pancreatic cancer.
Insights
KRAS mutations are common in pancreatic cancer. This study found rare KRAS mutation heterogeneity within tumors and no differences between primary tumors and lymph nodes, suggesting KRAS is an early driver mutation.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are frequent in pancreatic cancer.
- Understanding KRAS mutation heterogeneity is crucial for pancreatic ductal adenocarcinoma research.
Purpose of the Study:
- To determine the frequency and extent of KRAS mutation heterogeneity in pancreatic ductal adenocarcinoma.
- To investigate intratumoral and lymph node KRAS mutation status.
Main Methods:
- Analyzed KRAS codons 12 and 13 mutations in tumor centers, invasion fronts (n=97), and lymph nodes (n=11) using pyrosequencing.
- Utilized macrodissection for DNA extraction and mutation analysis.
Main Results:
- Activating KRAS mutations were found in 92.8% of tumor centers (codon 12).
- Intratumoral KRAS heterogeneity was rare (4.1%), with consistent mutation status between tumor centers and invasion fronts.
- No KRAS heterogeneity was observed between primary tumors and metastatic lymph nodes.
Conclusions:
- Intratumoral KRAS heterogeneity is uncommon in pancreatic ductal adenocarcinoma.
- The absence of KRAS heterogeneity between primary tumors and lymph nodes supports its role as an early driver mutation in pancreatic cancer development.
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