FREQUENT SOMATIC MUTATIONS AND LOSS OF HETEROZYGOSITY OF THE VON HIPPEL-LINDAU TUMOR-SUPPRESSOR GENE IN PRIMARY HUMAN RENAL-CELL CARCINOMAS

We analyzed 47 primary sporadic human renal cell carcinomas (39 clear cell and 8 non-clear cell) for mutations of the von Hippel-Lindau (VHL ) tumor suppressor gene using the polymerase chain reaction and single strand conformational polymorphism analysis of DNA. All of the positi ve cases in single strand conformational polymorphism analyses were fu rther characterized by direct sequencing. Somatic mutations were detec ted in 22 (56%) of 39 clear cell renal carcinomas including 15 deletio ns, 3 insertions, 3 missense mutations, and 1 nonsense mutation. Ninet een of these mutations predicted to produce truncation of the VHL prot ein. These mutations mainly occurred in the last one-third region of e xons 1, 2, and 3. In addition, loss of heterozygosity of the VHL gene was observed in 16 (84%) of 19 informative clear cell renal carcinomas . No somatic mutations were detected in 8 non-clear cell carcinomas. T hese results show that the VHL tumor suppressor gene is one of the maj or tumor suppressor genes in human renal cell carcinomas, especially i n the clear cell subtype renal cell carcinoma. Clear cell carcinoma mi ght be distinguished from other pathological types of renal cell carci nomas by molecular genetic techniques.