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Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic?
Hum Genet. 2003 Feb; 112(2):105-9.HG

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome. Germline mutations in five different mismatch repair (MMR) genes, MSH2, MSH6, MLH1, MLH3, and PMS2 are linked to HNPCC. Here, we describe two colon cancer families in which the index patients carry missense mutations in both MSH2 and MSH6. The MSH2 mutation, I145M, is the same in both families, whereas the MSH6 mutations are different (R1095H and L1354Q). The families do not fulfil the international criteria for HNPCC, one family comprising two and the other family four colon cancer patients, all in one generation, resembling a recessive rather than dominant inheritance characteristic of HNPCC. The tumors of the index patients showed microsatellite instability. Functional analysis was performed to determine which one of the mutations could primarily underlie the cancer susceptibility in the families. MSH2 and MSH6 are known to form a heterodimeric complex (MutSalpha) responsible for mismatch recognition. The interaction of each mutated protein with its wild-type partner and with its mutated partner present in the colon cancer patient, and the MMR function of the mutated MutSalpha complexes were determined. Since none of the three mutations affected the MSH2-MSH6 interaction or the function of MutSalpha in an in-vitro MMR assay, our results suggest that alone the mutations do not cause MMR deficiency typical of HNPCC. However, our results do not exclude the possible compound pathogenicity of the two mutations.

Authors+Show Affiliations

Department of Biosciences, Division of Genetics, University of Helsinki, Viikinkaari 5, 00014 Helsinki, Finland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12522549

Citation

Kariola, Reetta, et al. "Two Mismatch Repair Gene Mutations Found in a Colon Cancer Patient--which One Is Pathogenic?" Human Genetics, vol. 112, no. 2, 2003, pp. 105-9.
Kariola R, Otway R, Lönnqvist KE, et al. Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic? Hum Genet. 2003;112(2):105-9.
Kariola, R., Otway, R., Lönnqvist, K. E., Raevaara, T. E., Macrae, F., Vos, Y. J., Kohonen-Corish, M., Hofstra, R. M., & Nyström-Lahti, M. (2003). Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic? Human Genetics, 112(2), 105-9.
Kariola R, et al. Two Mismatch Repair Gene Mutations Found in a Colon Cancer Patient--which One Is Pathogenic. Hum Genet. 2003;112(2):105-9. PubMed PMID: 12522549.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic? AU - Kariola,Reetta, AU - Otway,Robyn, AU - Lönnqvist,Karin E, AU - Raevaara,Tiina E, AU - Macrae,Finlay, AU - Vos,Yvonne J, AU - Kohonen-Corish,Maija, AU - Hofstra,Robert M W, AU - Nyström-Lahti,Minna, Y1 - 2002/11/21/ PY - 2002/08/12/received PY - 2002/10/10/accepted PY - 2003/1/11/pubmed PY - 2003/2/27/medline PY - 2003/1/11/entrez SP - 105 EP - 9 JF - Human genetics JO - Hum. Genet. VL - 112 IS - 2 N2 - Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome. Germline mutations in five different mismatch repair (MMR) genes, MSH2, MSH6, MLH1, MLH3, and PMS2 are linked to HNPCC. Here, we describe two colon cancer families in which the index patients carry missense mutations in both MSH2 and MSH6. The MSH2 mutation, I145M, is the same in both families, whereas the MSH6 mutations are different (R1095H and L1354Q). The families do not fulfil the international criteria for HNPCC, one family comprising two and the other family four colon cancer patients, all in one generation, resembling a recessive rather than dominant inheritance characteristic of HNPCC. The tumors of the index patients showed microsatellite instability. Functional analysis was performed to determine which one of the mutations could primarily underlie the cancer susceptibility in the families. MSH2 and MSH6 are known to form a heterodimeric complex (MutSalpha) responsible for mismatch recognition. The interaction of each mutated protein with its wild-type partner and with its mutated partner present in the colon cancer patient, and the MMR function of the mutated MutSalpha complexes were determined. Since none of the three mutations affected the MSH2-MSH6 interaction or the function of MutSalpha in an in-vitro MMR assay, our results suggest that alone the mutations do not cause MMR deficiency typical of HNPCC. However, our results do not exclude the possible compound pathogenicity of the two mutations. SN - 0340-6717 UR - https://www.unboundmedicine.com/medline/citation/12522549/Two_mismatch_repair_gene_mutations_found_in_a_colon_cancer_patient__which_one_is_pathogenic L2 - https://dx.doi.org/10.1007/s00439-002-0866-4 DB - PRIME DP - Unbound Medicine ER -