Oncogenic pathway of sporadic colorectal cancer with novel germline missense mutations in the hMSH2 gene.
The deficiency of the DNA mismatch repair (MMR) system is involved in tumorigenesis of either familial or sporadic colorectal cancers showing microsatellite instability (MSI). To investigate the involvement of the mutated hMSH2 gene in carcinogenesis, we searched for alteration of the gene in 15 MSI tumors of Japanese patients with sporadic colorectal cancer by a polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and DNA sequencing analyses. We found 20 alterations including 7 novel mutations, 6 germline and one somatic. To assume an oncogenic pathway of tumor of two patients carrying germline missense mutations, G40S located in an evolutionarily conserved amino-terminal motif and Y619C in a domain interacting with either hMSH3 or hMSH6, somatic mutations in 9 target genes of the MMR defect and in the p53 and K-ras genes and loss of heterozygosity (LOH) at the hMLH1 and p53 gene loci were then studied. In the tumor carrying G40S, other somatic hMSH2 mutations, G203R and 687delA in the (A)(7) repeat, and 5 one-bp deletions in the target genes were found, while no mutation in the p53 and K-ras genes. These results indicate that G40S may affect the hMSH2 function and the tumor may be developed by a typical MSI pathway. In another tumor with Y619C, LOH at the hMLH1 gene locus, no mutation in MMR target genes, and two-hit inactivation of the p53 gene were detected. This MSI tumor seems to be developed by another than MSI pathway. These results indicate that there are different oncogenic pathways in the MSI sporadic colorectal cancers with germline missense mutations in the hMSH2 gene. We conclude that familial colorectal cancer-suspected cases exist in a small population of sporadic colorectal cancers.
Yamada
Kanae
K
Department of Molecular Biology, Toho University School of Medicine, 5-21-16 Ohmori-Nishi, Ohta-ku, Tokyo 143-8540, Japan.
Zhong
Xiaoling
X
Kanazawa
Shinsaku
S
Koike
Junichi
J
Tsujita
Kazunori
K
Hemmi
Hiromichi
H
D000595:Amino Acid Sequence; D020137:Base Pair Mismatch; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins / Q000235:genetics; D016158:Genes, p53 / Q000502:physiology; D011905:Genes, ras / Q000502:physiology; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats / Q000235:genetics*; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D020125:Mutation, Missense / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein