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Detection of Circulating Cancer Cells with von Hippel-Lindau Gene Mutation in Peripheral Blood of Patients with Renal Cell Carcinoma¹

Department of Urology, Kochi Medical School, Kochi 783-8505 [S. A., H. O., T. S.]; Department of Urology, Kubokawa Hospital, Kochi 786-0002 [M. C.]; Department of Urology, Hatakenmin Hospital, Kochi 787-0785 [M. T.]; Department of Urology, Hosogi Hospital, Kochi 780-0926 [O. S.]; Department of Urology, Chikamori Hospital, Kochi 780-0052 [Y. Y.]; Department of Urology, Kochi Red Cross Hospital, Kochi 780-0062 [S. N.]; and Department of Urology, Yokohama Municipal Citizen’s Hospital, Kanagawa 240-0062 [M. M.], Japan

Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene have been detected in up to 60% of sporadic clear cell renal carcinomas (RCCs). Even patients with RCCs believed to be curable with radical nephrectomy sometimes develop distant metastasis 5–10 years after surgery, suggesting hematogenous circulation of cancer cells. Useful tumor markers have not yet been established for RCC. To detect patients at high risk of metastasis after surgery, we developed a highly sensitive and specific nested reverse transcription-PCR method using VHL gene mutation to detect circulating cancer cells. We screened 29 sporadic clear cell RCCs from patients for mutations of the VHL gene by direct sequencing. We next examined blood samples from patients with the VHL gene mutation using mutation-specific nested reverse transcription-PCR. Somatic mutations were detected in 20 of 29 (69.0%) sporadic clear cell RCCs. The VHL gene mutations were detected in peripheral and/or renal venous blood from 15 of 20 (75%) patients. The mutations were detected in the peripheral blood in 2 of 17 (11.8%) patients before surgery, 6 of 16 (37.5%) patients within 24 h after surgery, 3 of 16 (18.8%) patients on day 7 after surgery, and 2 of 11 (18.2%) patients on day 30 after surgery. In seven of nine (77.8%) patients, mutations were detected in renal venous blood during surgery. These findings indicate the presence of circulating cancer cells with VHL gene mutation. Although much larger studies are needed to determine the clinical significance, our study shows that this technique is feasible for detecting circulating RCC cells.

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