Characteristics of mismatch repair-deficient colon cancer in relation to mismatch repair protein loss, hypermethylation silencing, and constitutional and biallelic somatic mismatch repair gene pathogenic variants Journal Article
| Authors: | Keshinro, A.; Ganesh, K.; Vanderbilt, C.; Firat, C.; Kim, J. K.; Chen, C. T.; Yaeger, R.; Segal, N. H.; Gonen, M.; Shia, J.; Stadler, Z. K.; Weiser, M. R. |
| Article Title: | Characteristics of mismatch repair-deficient colon cancer in relation to mismatch repair protein loss, hypermethylation silencing, and constitutional and biallelic somatic mismatch repair gene pathogenic variants |
| Abstract: | BACKGROUND: Mismatch repair-deficient colon cancer is heterogeneous. Differentiating inherited constitutional variants from somatic genetic alterations and gene silencing is important for surveillance and genetic counseling. OBJECTIVE: This study aimed to determine the extent to which the underlying mechanism of loss of mismatch repair influences molecular and clinicopathologic features of microsatellite instability-high colon cancer. DESIGN: This is a retrospective analysis. SETTINGS: This study was conducted at a comprehensive cancer center. PATIENTS: Patients with microsatellite instability-high colon cancer of stage I, II, or III were included. INTERVENTION: Patients underwent a curative surgical resection. MAIN OUTCOME MEASURES: The main outcome measures were hypermethylation of the MLH1 promoter, biallelic inactivation, constitutional pathogenic variants, and loss of specific mismatch repair proteins. RESULTS: Of the 157 identified tumors with complete genetic analysis, 66% had hypermethylation of the MLH1 promoter, 18% had constitutional pathogenic variants, (Lynch syndrome), 11% had biallelic somatic mismatch repair gene pathogenic variants, and 6% had unexplained high microsatellite instability. The distribution of mismatch repair loss was as follows: MLH1 and PMS2 co-loss, 79% of the tumors; MSH2 and MSH6 co-loss, 10%; MSH6 alone, 3%; PMS2 alone, 2%; other combinations, 2%; no loss, 2%. Tumor mutational burden was lowest in MLH1- and PMS2-deficient tumors. MSH6-deficient tumors had the lowest levels of tumor-infiltrating lymphocytes, lowest MSI scores, and fewest frameshift deletions. Patients with MLH1 promoter hypermethylation were significantly more likely to be older and female and to have right-sided colon lesions than patients with biallelic inactivation. Mutation was the most prevalent second hit in tumors with biallelic inactivation and tumors of patients with Lynch syndrome. LIMITATIONS: This study was limited by potential selection or referral bias, missing data for some patients, and relatively small sizes of some subgroups. CONCLUSIONS: Clinical characteristics of mismatch repair-deficient colon cancer vary with the etiology of microsatellite instability, and its molecular characteristics vary with the affected mismatch repair protein. See Video Abstract at http://links.lww.com/DCR/B984. © 2023 Lippincott Williams and Wilkins. All rights reserved. |
| Keywords: | adult; controlled study; protein expression; aged; cancer surgery; retrospective studies; human cell; major clinical study; promoter region; somatic mutation; frameshift mutation; genetics; outcome assessment; genetic analysis; protein depletion; colonic neoplasms; retrospective study; dna methylation; cancer center; colon cancer; mismatch repair; colon tumor; microsatellite instability; dna mismatch repair; family history; gene loss; gene silencing; heterozygosity loss; lynch syndrome; mismatch repair protein; protein msh6; colorectal neoplasms, hereditary nonpolyposis; muts homolog 2 protein; mismatch repair protein pms2; genetic counseling; hereditary nonpolyposis colorectal cancer; hypermethylation; medical history; mismatch repair deficiency; colon injury; high throughput sequencing; lymph vessel metastasis; humans; human; male; female; article; mutl protein homolog 1; dna mismatch repair protein msh2; tumor mutational burden; mismatch repair endonuclease pms2; constitutional mismatch repair deficiency syndrome; biallelic somatic pathogenic variants; constitutional pathogenic variants |
| Journal Title: | Diseases of the Colon and Rectum |
| Volume: | 66 |
| Issue: | 4 |
| ISSN: | 0012-3706 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2023-04-01 |
| Start Page: | 549 |
| End Page: | 558 |
| Language: | English |
| DOI: | 10.1097/dcr.0000000000002452 |
| PUBMED: | 35724254 |
| PROVIDER: | scopus |
| PMCID: | PMC9763548 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Martin R. Weiser -- Source: Scopus |
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