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Dana-Farber-Cancer Institute Inc.

Oregon Health & Science University

C Eric Bronner

Richard D Kolodner

Roni J Bollag

Robert M Liskay

Sean M Baker

Genomic sequences of human mismatch repair genes and gene products are described, as are methods of detecting mutations and/or polymorphisms in those genes. Also described are methods of diagnosing cancer susceptibility in a subject, and methods of identifying and classifying mismatch-repair-defective tumors. In particular, sequences and methods relating to human mutL homologs, hMLH1 and hPMS1 genes and gene products are provided.

Compositions and methods relating to DNA mismatch repair genes

Genomic sequences of human mismatch repair genes are described, as are methods of detecting mutations and/or polymorphisms in those genes. Also described are methods of diagnosing cancer susceptibility in a subject, and methods of identifying and classifying mismatch-repair-defective tumors. In particular, sequences and methods relating to human mutL homologs, hMLH1 and hPMS1 genes are provided.

Composition and methods relating to DNA mismatch repair genes

We have discovered two human genes, hMLH1 and hPMS1, each of which apparently encodes for a protein involved in DNA mismatch repair. The hMLH1 gene encodes for a protein which is homologous to the bacterial DNA mismatch repair protein MutL, and is located on human chromosome 3p21.3-23. We believe that mutations in the hMLH1 gene cause hereditary non-polyposis colon cancer (HNPCC) in some individuals based upon the similarity of the hMLH1 gene product to the yeast DNA mismatch repair protein MLH1, the coincident location of the hMLH1 gene and the HNPCC locus on chromosome 3, and hMLH1 missense mutations in affected individuals from a chromosome 3-linked HNPCC family. The human hPMS1 gene is homologous to the yeast DNA mismatch repair gene PMS1, and is located on human chromosome 7q. We believe that the hPMS1 gene is a strong candidate for HNPCC testing because the yeast proteins MLH1 and PMS1 have been shown to be involved in the same DNA repair pathway and because hMLH1 and hMSH2 have both been implicated in HNPCC families. The most immediate use for hMLH1 and hPMS1 will be in screening tests on individuals who are members of families which exhibit high frequencies of early onset cancer. We have also isolated and sequenced mouse MLH1 and PMS1 genes. We have produced chimeric mice with a mutant form of the PMS1 gene that will enable us to derive mice that are heterozygous or homozygous for mutation in mPMS1. These mice will be useful for cancer research. We have also produced and isolated antibodies directed to hPMS1 which are useful in assays to detect the presence of protein in tumor samples.

Growing community of inventors

Portland, OR, United States of America

C Eric Bronner