Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome Journal Article
| Authors: | Liu, Y. L.; Cadoo, K. A.; Maio, A.; Patel, Z.; Kemel, Y.; Salo-Mullen, E.; Catchings, A.; Ranganathan, M.; Kane, S.; Soslow, R.; Ceyhan-Birsoy, O.; Mandelker, D.; Carlo, M. I.; Walsh, M. F.; Shia, J.; Markowitz, A. J.; Offit, K.; Stadler, Z. K.; Latham, A. |
| Article Title: | Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome |
| Abstract: | Purpose: This study aimed to characterize MSH6/PMS2-associated mismatch repair–deficient (MMR-D)/microsatellite instability-high (MSI-H) tumors, given revised guidelines suggesting more modest phenotypes. Methods: Patients who consented to Institutional Review Board–approved protocols of tumor/germline sequencing or Lynch syndrome registry at a single institution from February 2005 to January 2021 with germline, heterozygous MSH6/PMS2 pathogenic/likely pathogenic variants were identified. Clinical data were abstracted and correlated with MMR/microsatellite instability status using nonparametric tests. Results: We identified 243 patients (133 sequencing, 110 registry) with germline MSH6/PMS2 pathogenic/likely pathogenic variants; 186 (77%) had >1 cancer. Of 261 pooled tumors, colorectal cancer (CRC) and endometrial cancer (EC) comprised 55% and 43% of cancers in MSH6 and PMS2, respectively; 192 tumors underwent molecular assessments and 122 (64%) were MMR-D/MSI-H (77 in MSH6, 45 in PMS2). MMR-D/MSI-H cancers included CRC (n = 56), EC (n = 35), small bowel cancer (n = 6), ovarian cancer (n = 6), urothelial cancer (n = 5), pancreas/biliary cancer (n = 4), gastric/esophageal cancer (n = 3), nonmelanoma skin tumors (n = 3), prostate cancer (n = 2), breast cancer (n = 1), and central nervous system/brain cancer (n = 1). Among MMR-D/MSI-H CRC and EC, median age of diagnosis was 51.5 (range = 27-80) and 55 (range = 39-74) years, respectively; 9 of 56 (16%) MMR-D/MSI-H CRCs were diagnosed at age <35 years. Conclusion: MSH6/PMS2 heterozygotes remain at risk for a broad spectrum of cancers, with 16% of MMR-D/MSI-H CRCs presenting before upper threshold of initiation of colonoscopy per guidelines. © 2022 American College of Medical Genetics and Genomics |
| Keywords: | genetics; endometrial neoplasms; metabolism; colorectal neoplasms; colorectal tumor; mismatch repair; microsatellite instability; dna mismatch repair; onset age; age of onset; lynch syndrome; endometrium tumor; colorectal neoplasms, hereditary nonpolyposis; pms2 protein, human; mismatch repair protein pms2; hereditary nonpolyposis colorectal cancer; complication; mismatch repair deficiency; humans; human; male; female; mutl protein homolog 1; early-onset colorectal cancer; msh6 and pms2; mismatch repair endonuclease pms2 |
| Journal Title: | Genetics in Medicine |
| Volume: | 24 |
| Issue: | 6 |
| ISSN: | 1098-3600 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-06-01 |
| Start Page: | 1187 |
| End Page: | 1195 |
| Language: | English |
| DOI: | 10.1016/j.gim.2022.02.016 |
| PUBMED: | 35346574 |
| PROVIDER: | scopus |
| PMCID: | PMC9942243 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2022 -- Source: Scopus |
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