An OncogenicALKFusion and anRRASMutation inKRASMutation-Negative Pancreatic Ductal Adenocarcinoma.
Oncogenic mutations in theKRASgene are a well-known driver event, occurring in >95% of pancreatic cancers. The objective of this study was to identify driver oncogene aberrations in pancreatic cancers without theKRASmutation.



Whole-exome and transcriptome sequencing was performed on four cases ofKRASmutation-negative pancreatic ductal adenocarcinoma, which were identified in a cohort of 100 cases.



One case harbored an oncogenicDCTN1-ALKfusion. The fusion gene enabled interleukin-3-independent growth of Ba/F3 cells and rendered them susceptible to the anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib and alectinib. The structure of the breakpoint junction indicated that the fusion was generated by nonhomologous end joining between a segment ofDCTN1exon DNA and a segment ofALKintron DNA, resulting in the generation of a cryptic splicing site. Another case harbored an oncogenicRRASmutation that activated the GTPase of the RRAS protein.



Rare oncogenic aberrations, such as theALKfusion andRRASmutation, may drive pancreatic carcinogenesis independent of theKRASmutation.The Oncologist2017;22:158-164Implications for Practice:The oncogenicDCTN1-ALKfusion and theRRASmutation were associated with the development of pancreatic ductal adenocarcinoma (PDAC) in the absence of theKRASmutation. Constitutional activation ofDCTN1-ALKfusion protein was suppressed by the anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib and alectinib. Thus, a small subset of PDAC patients might benefit from therapy using these inhibitors.
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
Yoko
Y
Shimada
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan tkkohno@ncc.go.jp.
Takashi
T
Kohno
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Hideki
H
Ueno
Division of Analytical Pathology, National Cancer Center Research Institute, Tokyo, Japan.
Yoshinori
Y
Ino
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Hideyuki
H
Hayashi
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
Takashi
T
Nakaoku
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Yasunari
Y
Sakamoto
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Shunsuke
S
Kondo
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Chigusa
C
Morizane
Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan.
Kazuaki
K
Shimada
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Takuji
T
Okusaka
Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
Nobuyoshi
N
Hiraoka
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D018631:ras Proteins
ALK; Gene fusion; KRAS; Pancreatic adenocarcinoma; RRAS