Prevalence of Mutations in Discoidin Domain-Containing Receptor Tyrosine Kinase 2 (DDR2) in Squamous Cell Lung Cancers in Korean Patients.
OBJECTIVE
The discoidin domain-containing receptor tyrosine kinase 2 (DDR2) is known to contain mutations in a small subset of patients with squamous cell carcinomas (SCC) of the lung. Studying the DDR2 mutations in patients with SCC of the lung would advance our understanding and guide the development of therapeutic strategies against lung cancer.


METHODS
We selected 100 samples through a preliminary genetic screen, including specimens from biopsies and surgical resection, and confirmed SCC by histologic examination. DDR2 mutations on exons 6, 15, 16, and 18 were analyzed by Sanger sequencing of formalin-fixed, paraffin-embedded tissue samples. The functional effects of novel DDR2 mutants were confirmed by in vitro assays.


RESULTS
We identified novel somatic mutations of DDR2 in two of the 100 SCC samples studied. One mutation was c.1745T>A (p.V582E) and the other was c.1784T>C (p.L595P), and both were on exon 15. Both patients were smokers and EGFR/KRAS/ALK-triple negative. The expression of the mutant DDR2 induced activation of DDR2 by the collagen ligand and caused enhanced cell growth and tumor progression. Moreover, dasatinib, a DDR2 inhibitor, showed potential efficacy against DDR2 L595P mutant-bearing cells.


CONCLUSIONS
Our results suggest that a mutation in DDR2 occurs naturally with a frequency of about 2% in Korean lung SCC patients. In addition, we showed that each of the novel DDR2 mutations were located in a kinase domain and induced an increase in cell proliferation rate.
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea.|Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Seoul, Korea.
Mi-Sook
MS
Lee
Department of Pathology, Seoul Medical Center, Seoul, Korea.
Eun Ah
EA
Jung
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea.|Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Seoul, Korea.
Sung Bin
SB
An
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea.|Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Seoul, Korea.
Yu Jin
YJ
Kim
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea.|Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Seoul, Korea.
Doo-Yi
DY
Oh
Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Seoul, Korea.
Ji-Young
JY
Song
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Sang-Won
SW
Um
Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea.
Joungho
J
Han
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea.|Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Seoul, Korea.|Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea.
Yoon-La
YL
Choi
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D044466:Asian People / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology* / Q000235:genetics*; D002460:Cell Line; D000070820:Discoidin Domain Receptor 2 / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D015995:Prevalence; D056910:Republic of Korea / Q000453:epidemiology; D017422:Sequence Analysis, DNA; D014057:Tomography, X-Ray Computed; D047368:Tumor Burden
D000070820:Discoidin Domain Receptor 2
Discoidin domain receptor 2; Lung neoplasms; Somatic mutations; Squamous cell carcinoma