Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer

Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency...

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Vydáno v:Journal of clinical oncology Ročník 37; číslo 4; s. 286
Hlavní autoři: Latham, Alicia, Srinivasan, Preethi, Kemel, Yelena, Shia, Jinru, Bandlamudi, Chaitanya, Mandelker, Diana, Middha, Sumit, Hechtman, Jaclyn, Zehir, Ahmet, Dubard-Gault, Marianne, Tran, Christina, Stewart, Carolyn, Sheehan, Margaret, Penson, Alexander, DeLair, Deborah, Yaeger, Rona, Vijai, Joseph, Mukherjee, Semanti, Galle, Jesse, Dickson, Mark A, Janjigian, Yelena, O'Reilly, Eileen M, Segal, Neil, Saltz, Leonard B, Reidy-Lagunes, Diane, Varghese, Anna M, Bajorin, Dean, Carlo, Maria I, Cadoo, Karen, Walsh, Michael F, Weiser, Martin, Aguilar, Julio Garcia, Klimstra, David S, Diaz, Jr, Luis A, Baselga, Jose, Zhang, Liying, Ladanyi, Marc, Hyman, David M, Solit, David B, Robson, Mark E, Taylor, Barry S, Offit, Kenneth, Berger, Michael F, Stadler, Zsofia K
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.02.2019
Témata:
Biomarkers, Tumor - genetics
Colorectal Neoplasms, Hereditary Nonpolyposis - epidemiology
Colorectal Neoplasms, Hereditary Nonpolyposis - genetics
Colorectal Neoplasms, Hereditary Nonpolyposis - pathology
DNA Mismatch Repair
Female
Genetic Predisposition to Disease
Humans
Male
Microsatellite Instability
Middle Aged
Mutation
New York City - epidemiology
Phenotype
Prevalence
Prospective Studies
Transcriptome
New York City
ISSN:1527-7755, 1527-7755
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Shrnutí:Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status. MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed. Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases. MSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.
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SourceType-Scholarly Journals-1
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ISSN:1527-7755
1527-7755
DOI:10.1200/JCO.18.00283