The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8

The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8

^*Division of Medical Oncology, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262; ^§Department of Laboratory Medicine and Pathology, Mayo Foundation, Rochester, MN 55905; and Harvard School of Public Health, 44 Binney Street, Boston, MA 02115

Communicated by David Marshall Prescott, University of Colorado, Boulder, CO (received for review May 15, 1998)

Abstract

The 3;8 chromosomal translocation, t(3;8)(p14.2;q24.1), was described in a family with classical features of hereditary renal cell carcinoma. Previous studies demonstrated that the 3p14.2 breakpoint interrupts the fragile histidine triad gene (FHIT) in its 5′ noncoding region. However, evidence that FHIT is causally related to renal or other malignancies is controversial. We now show that the 8q24.1 breakpoint region encodes a 664-aa multiple membrane spanning protein, TRC8, with similarity to the hereditary basal cell carcinoma/segment polarity gene, patched. This similarity involves two regions of patched, the putative sterol-sensing domain and the second extracellular loop that participates in the binding of sonic hedgehog. In the 3;8 translocation, TRC8 is fused to FHIT and is disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed. In a series of sporadic renal carcinomas, an acquired TRC8 mutation was identified. By analogy to patched, TRC8 might function as a signaling receptor and other pathway members, to be defined, are mutation candidates in malignant diseases involving the kidney and thyroid.

Footnotes

↵ † To whom reprint requests should be addressed. e-mail: gemmill{at}loki.uchsc.edu.
↵ ‡ Present address: CuraGen Corporation, 12085 Research Drive, Alachua, FL 32615.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AF064800 and AF064801).
ABBREVIATIONS:

RCC,

renal cell carcinoma;

TSG,

tumor suppressor gene;

FHIT, fragile histidine triad gene,

RACE, rapid amplification of cDNA ends;

TRC8,

translocation in renal carcinoma, chromosome 8 gene;

TM,

transmembrane segment;

SSD,

sterol-sensing domain;

RT-PCR,

reverse transcriptase–PCR;

SSCP,

single-stranded conformational polymorphism analysis;

HMG,

hydroxymethylglutaryl;

YAC,

yeast artificial chromosome