Genomic analysis of cancer tissue reveals that somatic mutations commonly occur in a specific motif.
Somatic mutations are hallmarks of cancer progression. We sequenced 26 matched human prostate tumor and constitutional DNA samples for somatic alterations in the SRD5A2, HPRT, and HSD3B2 genes, and identified 71 nucleotide substitutions. Of these substitutions, 79% (56/71) occur within a WKVnRRRnVWK sequence (a novel motif we call THEMIS [from the ancient Greek goddess of prophecy]: W=A/T, K=G/T, V=G/A/C, R=purine (A/G), and n=any nucleotide), with one mismatch allowed. Literature searches identified this motif with one mismatch allowed in 66% (37/56) of the somatic prostate cancer mutations and in 74% (90/122) of the somatic breast cancer mutations found in all human genes analyzed. We also found the THEMIS motif with one allowed mismatch in 88% (23/26) of the ras1 gene somatic mutations formed in the sensitive to skin carcinogenesis (SENCAR) mouse model, after induction of error-prone DNA repair following mutagenic treatment. The high prevalence of the motif in each of the above mentioned cases cannot be explained by chance (P<0.046). We further identified 27 somatic mutations in the error-prone DNA polymerase genes pol eta, pol kappa, and pol beta in these prostate cancer patients. The data suggest that most somatic nucleotide substitutions in human cancer may occur in sites that conform to the THEMIS motif. These mutations may be caused by "mutator" mutations in error-prone DNA polymerase genes.
Makridakis
Nick M
NM
Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California (USC), Los Angeles, California, USA. nmakrida@tulane.edu
Caldas Ferraz
Lúcio Fábio
LF
Reichardt
Juergen K V
JK
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics; D020816:Amino Acid Motifs / Q000235:genetics; D004252:DNA Mutational Analysis; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008297:Male; D009154:Mutation; D011375:Progesterone Reductase / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*
C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D007041:Hypoxanthine Phosphoribosyltransferase; D004259:DNA-Directed DNA Polymerase