Positional Cloning of the Hereditary Renal Carcinoma 3;8 Chromosome Translocation Breakpoint

• Published in: Proceedings of the National Academy of Sciences - PNAS 1993-09, Vol.90 (18), p.8509-8513
• Main Authors: Boldog, Ferenc L., Gemmill, Robert M., Wilke, Charles M., Glover, Thomas W., Nilsson, Ann-Sofie, Chandrasekharappa, Settara C., Brown, Robert S., Li, Frederick P., Drabkin, Harry A.
• Format: Article
• Language: English
• Subjects: 550400 - Genetics; Animals; BASIC BIOLOGICAL SCIENCES; Biological and medical sciences; Blotting, Northern; BODY; breakpoints; carcinoma; Cell Line; Cell lines; CHROMOSOMAL ABERRATIONS; chromosome 3; chromosome 8; Chromosome Aberrations; CHROMOSOME BREAKAGE; Chromosome Mapping; Chromosome translocation; chromosome walking; CHROMOSOMES; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 8; Clone Cells; CLONING; Cloning, Molecular; Complementary DNA; Deoxyribonucleic acid; DISEASES; DNA; DNA - genetics; DNA - isolation & purification; DNA HYBRIDIZATION; DNA Probes; DNA-CLONING; Gene Library; Genes; Genetic loci; GENETIC MAPPING; Genomics; HEREDITARY DISEASES; HUMAN CHROMOSOME 3; HUMAN CHROMOSOME 8; HUMAN CHROMOSOMES; Humans; Hybrid Cells; Hybridity; HYBRIDIZATION; Kidney; KIDNEYS; man; MAPPING; Medical sciences; MRCA1 gene; MUTATIONS; NEOPLASMS; Nephrology. Urinary tract diseases; ORGANS; RNA - genetics; RNA - isolation & purification; translocation; Translocation, Genetic; Tumors; Tumors of the urinary system; Urinary Bladder Neoplasms - genetics; yeast artificial chromosomes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.18.8509

The chromosome (p14.2;q24.1) translocation t(3;8)has been associated with hereditary renal cancer in one family. Based on cytogenetic analyses and loss-of-heterozygosity experiments, the 3p14 region has been independently implicated as harboring a tumor suppressor gene critical to kidney and lung cancer development. The 3p14.2 region also contains FRA3B, the most sensitive fragile site induced by aphidicolin. A chromosome 3 probe, R7K145, derived from a radiation-reduced hybrid was positioned between the t(3;8) breakpoint and an aphidicolin-induced 3p14 breakpoint. A yeast artificial chromosome (YAC) contig containing R7K145 was developed that crossed the aphidicolin-induced breakpoint on its telomeric side. A subsequent chromosome walk identified a YAC that crossed the 3;8 translocation breakpoint. A λ sublibrary allowed isolation of clones spanning the rearrangement. Unique and evolutionarily conserved DNA sequences were used to screen a kidney cDNA library. We have identified a gene, referred to as HRCA1 (hereditary renal cancer associated 1), that maps immediately adjacent to the breakpoint. On the basis of its chromosomal position, HRCA1 may be a candidate tumor suppressor gene.