A novel germline mutation of hMLH1 in a Korean hereditary non-polyposis colorectal cancer family.
Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited disease caused by a germline mutation of the mismatch repair (MMR) genes, and the distinctive feature is that colorectal and extracolonic malignancies occur early in life. We report on the case of a Korean HNPCC family with endometrial cancer, with the goal of elucidating the involvement of an MMR deficiency. Although the family history did not fulfill the Amsterdam criteria II, blood samples were subjected to genetic testing by the revised Bethesda guidelines. Immunohistochemistry and direct sequencing of the genomic DNA identified a C insertion at the 1780th base in exon 16 of hMLH1, a pathogenic mutation that has not been reported before. By this mutation, premature termination at codon 592 resulted with an estimated deletion of 21% of the C-terminus of the hMLH1 protein. For early detection of the disease, the family was examined by colonoscopy and a gynecologic examination. The expression of hMLH1 in colon tissues was analyzed by Western blot analysis. We observed that the C-terminus portion of the hMLH1 protein was truncated in the HNPCC family members. Two young family members with no clinical symptoms were newly diagnosed with colorectal cancer by colonoscopy and a pathological examination. Hereby, we identified a novel pathogenic germline mutation of hMLH1 in a Korean HNPCC family. The loss of C-terminus of hMLH1 protein was thus considered to possibly play a role in the development of HNPCC with other tumors. Our findings might be useful for early diagnosis and management of the HNPCC family.
Department of Obstetrics and Gynecology, Eulji University School of Medicine, Daejeon 301-832, Korea.
Ki-Hwan
KH
Kim
Ju-Young
JY
Kim
Se-Ig
SI
Oh
Haing-Woon
HW
Baik
Dong-Wook
DW
Kang
Sung-Hee
SH
Jung
Jeong-Hoon
JH
Rho
In-Taek
IT
Hwang
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D018095:Germ-Line Mutation / Q000502:physiology; D006801:Humans; D007723:Korea; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009378:Neoplasms, Multiple Primary / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary / Q000235:genetics; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1