FOXC2 and CLIP4 : a potential biomarker for synchronous metastasis of ≤7-cm clear cell renal cell carcinomas.
Renal cell carcinomas (RCC) smaller than 7-cm are heterogeneous and exhibit metastatic potential in approximately 15% of cases. Although large-scale characterization of mutations in clear cell RCC (ccRCC), the most common RCC subtype, has been established, the genetic alterations related to ≤7-cm ccRCCs undergoing synchronous metastasis are poorly understood. To discover biomarkers that can be used to estimate the risk of synchronous metastasis in these ccRCC patients, we performed whole exome sequencing on the formalin-fixed paraffin-embedded (FFPE) samples of 10 ccRCC patients with ≤7-cm tumors and synchronous metastasis and expanded our study using The Cancer Genome Atlas (TCGA) ccRCC dataset (n = 201). Recurrent mutations were selected according to functional prediction and statistical significance. Mutations in three candidate genes, RELN (1 out of 10), FOXC2 (1 out of 10), and CLIP4 (2 out of 10) were found in expanded analysis using a TCGA cohort. Furthermore, siRNA-mediated target gene knockdown (FOXC2 and CLIP4) and overexpression (RELN) assays showed that FOXC2 and CLIP4 significantly increased cell migration and viability in ccRCCs. Our study demonstrated that FOXC2 and CLIP4 activity correlates to the presence of ≤7-cm ccRCCs with synchronous metastasis and may be potential molecular predictors of synchronous metastasis of ≤7-cm ccRCCs.
Department of Chemistry, Yonsei University, Seoul, Korea.
Jinwoo
J
Ahn
Department of Urology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea.
Kyung Seok
KS
Han
Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Jun Hyeok
JH
Heo
Department of Chemistry, Yonsei University, Seoul, Korea.
Duhee
D
Bang
Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
You Hyun
YH
Kang
Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Hyun A
HA
Jin
Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Sung Joon
SJ
Hong
Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, Korea.
Ji Hyun
JH
Lee
Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Won Sik
WS
Ham
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D000091042:Reelin Protein; D047368:Tumor Burden / Q000235:genetics*
D014408:Biomarkers, Tumor; C489394:CLIP4 protein, human; D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D000091042:Reelin Protein; C082078:mesenchyme fork head 1 protein; C000717127:RELN protein, human
CLIP4; FOXC2; clear cell renal cell carcinoma (ccRCC); metastasis; whole exome sequencing