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Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.
Gastroenterology. 2014 Dec; 147(6):1308-1316.e1.G

Abstract

BACKGROUND & AIMS

Patients with Lynch syndrome carry germline mutations in single alleles of genes encoding the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing.

METHODS

We analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, and POLD1 with ColoSeq and mutation frequencies were established.

RESULTS

Twenty-two of 32 patients (69%) were found to have 2 somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 remaining tumors 3 had one somatic mutation in a MMR gene, with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had only one mutation in a MMR gene and remained unexplained. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/megabase); 6 had mutation frequencies >200/megabase, and 5 of these had somatic mutations in POLE, which encodes a DNA polymerase.

CONCLUSIONS

Some patients are found to have tumors with MMR defects during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to a hypermutated phenotype of tumor cells. Patients with colon or endometrial cancers with MMR deficiency not explained by germline mutations might undergo analysis for tumor mutations in MMR genes to guide future surveillance guidelines.

Authors+Show Affiliations

Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. Electronic address: sigurdis.haraldsdottir@osumc.edu.Department of Internal Medicine, Division of Human Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.Department of Microbiology, Virology, Immunology, and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.Department of Pathology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.Department of Internal Medicine, Division of Human Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.Department of Microbiology, Virology, Immunology, and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.Department of Laboratory Medicine, University of Washington, Seattle, Washington.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25194673

Citation

Haraldsdottir, Sigurdis, et al. "Colon and Endometrial Cancers With Mismatch Repair Deficiency Can Arise From Somatic, Rather Than Germline, Mutations." Gastroenterology, vol. 147, no. 6, 2014, pp. 1308-1316.e1.
Haraldsdottir S, Hampel H, Tomsic J, et al. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology. 2014;147(6):1308-1316.e1.
Haraldsdottir, S., Hampel, H., Tomsic, J., Frankel, W. L., Pearlman, R., de la Chapelle, A., & Pritchard, C. C. (2014). Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology, 147(6), 1308-e1. https://doi.org/10.1053/j.gastro.2014.08.041
Haraldsdottir S, et al. Colon and Endometrial Cancers With Mismatch Repair Deficiency Can Arise From Somatic, Rather Than Germline, Mutations. Gastroenterology. 2014;147(6):1308-1316.e1. PubMed PMID: 25194673.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. AU - Haraldsdottir,Sigurdis, AU - Hampel,Heather, AU - Tomsic,Jerneja, AU - Frankel,Wendy L, AU - Pearlman,Rachel, AU - de la Chapelle,Albert, AU - Pritchard,Colin C, Y1 - 2014/09/03/ PY - 2014/06/13/received PY - 2014/08/05/revised PY - 2014/08/27/accepted PY - 2014/9/8/entrez PY - 2014/9/10/pubmed PY - 2015/2/5/medline KW - Colon Cancer KW - Genomic Instability KW - MSI KW - dMMR SP - 1308 EP - 1316.e1 JF - Gastroenterology JO - Gastroenterology VL - 147 IS - 6 N2 - BACKGROUND & AIMS: Patients with Lynch syndrome carry germline mutations in single alleles of genes encoding the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing. METHODS: We analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, and POLD1 with ColoSeq and mutation frequencies were established. RESULTS: Twenty-two of 32 patients (69%) were found to have 2 somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 remaining tumors 3 had one somatic mutation in a MMR gene, with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had only one mutation in a MMR gene and remained unexplained. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/megabase); 6 had mutation frequencies >200/megabase, and 5 of these had somatic mutations in POLE, which encodes a DNA polymerase. CONCLUSIONS: Some patients are found to have tumors with MMR defects during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to a hypermutated phenotype of tumor cells. Patients with colon or endometrial cancers with MMR deficiency not explained by germline mutations might undergo analysis for tumor mutations in MMR genes to guide future surveillance guidelines. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/25194673/Colon_and_endometrial_cancers_with_mismatch_repair_deficiency_can_arise_from_somatic_rather_than_germline_mutations_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(14)01080-4 DB - PRIME DP - Unbound Medicine ER -