Two types of sporadic multiple colorectal cancers with and without HNPCC-like genetic instability.
OBJECTIVE
Sporadic multiple colorectal cancers (MCCs) potentially have similar genetic alterations to hereditary nonpolyposis colorectal cancers (HNPCCs), but genetically unstable MCCs other than HNPCCs are not well characterized. We report the frequency of HNPCC-like sporadic multiple colon cancers and their characterization as for HNPCC-related gene mutations.


METHODS
Microsatellite instability (MSI) at 12 microsatellite loci was examined by a polymerase chain reaction in 19 cases each of MCC and single colorectal cancer (SCC). The target sequences of MSI, transforming growth factor beta type II receptor (TGF beta RII) gene, and the HNPCC genes, hMSH2 and hMLH1, were amplified and analyzed for mutations by sequencing.


RESULTS
In 5 of 19 cases with MCC, MSI was observed at more than 4 microsatellite loci, and the other cases including all SCCs showed no MSI or MSI(+) at a single locus. In 4 of the 5 severe MSI(+) cases, a 10-bp adenine tract at codons 125-128 of the TGF beta RII gene was mutated. In terms of the hMSH2 and hMLH1 genes, only silent mutations and non-critical amino acid substitutions were found.


CONCLUSIONS
We found severe MSI in 26% of sporadic multiple colorectal cancers. Mutations of the TGF beta RII gene are closely associated with severe MSI(+) MCCs as observed in HNPCC, suggesting that these MCCs develop by the similar carcinogenic process to HNPCC.
Komura
K
K
Third Department of Surgery, Nihon University School of Medicine, Tokyo, Japan.
Masuda
H
H
Esumi
M
M
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins; D003062:Codon; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins; D017354:Point Mutation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003062:Codon; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005819:Genetic Markers; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein