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 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
01.02.2019
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| Témata: | |
| ISSN: | 1527-7755, 1527-7755 |
| On-line přístup: | Zjistit podrobnosti o přístupu |
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| Abstract | 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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| AbstractList | 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.PURPOSEMicrosatellite 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.METHODSMSI 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.RESULTSAmong 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.CONCLUSIONMSI-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. 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. |
| Author | Bandlamudi, Chaitanya Walsh, Michael F Zhang, Liying Shia, Jinru Solit, David B Latham, Alicia Saltz, Leonard B Galle, Jesse Penson, Alexander Offit, Kenneth Hechtman, Jaclyn Janjigian, Yelena Cadoo, Karen Hyman, David M O'Reilly, Eileen M Vijai, Joseph Zehir, Ahmet Segal, Neil Robson, Mark E Reidy-Lagunes, Diane Varghese, Anna M Taylor, Barry S Tran, Christina Stewart, Carolyn Srinivasan, Preethi Baselga, Jose Weiser, Martin Berger, Michael F Aguilar, Julio Garcia Ladanyi, Marc Sheehan, Margaret Kemel, Yelena Bajorin, Dean Middha, Sumit Mandelker, Diana Carlo, Maria I Yaeger, Rona Dickson, Mark A Klimstra, David S Dubard-Gault, Marianne Diaz, Jr, Luis A DeLair, Deborah Mukherjee, Semanti Stadler, Zsofia K |
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Cancer Center, New York, NY – sequence: 8 givenname: Jaclyn surname: Hechtman fullname: Hechtman, Jaclyn organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 9 givenname: Ahmet surname: Zehir fullname: Zehir, Ahmet organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 10 givenname: Marianne surname: Dubard-Gault fullname: Dubard-Gault, Marianne organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 11 givenname: Christina surname: Tran fullname: Tran, Christina organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 12 givenname: Carolyn surname: Stewart fullname: Stewart, Carolyn organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 13 givenname: Margaret surname: Sheehan fullname: Sheehan, Margaret organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 14 givenname: Alexander surname: Penson fullname: Penson, Alexander organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 15 givenname: Deborah surname: DeLair fullname: DeLair, Deborah organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 16 givenname: Rona surname: Yaeger fullname: Yaeger, Rona organization: 2 Weill Cornell Medical College, New York, NY – sequence: 17 givenname: Joseph surname: Vijai fullname: Vijai, Joseph organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 18 givenname: Semanti surname: Mukherjee fullname: Mukherjee, Semanti organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 19 givenname: Jesse surname: Galle fullname: Galle, Jesse organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 20 givenname: Mark A surname: Dickson fullname: Dickson, Mark A organization: 2 Weill Cornell Medical College, New York, NY – sequence: 21 givenname: Yelena surname: Janjigian fullname: Janjigian, Yelena 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College, New York, NY – sequence: 29 givenname: Karen surname: Cadoo fullname: Cadoo, Karen organization: 2 Weill Cornell Medical College, New York, NY – sequence: 30 givenname: Michael F surname: Walsh fullname: Walsh, Michael F organization: 2 Weill Cornell Medical College, New York, NY – sequence: 31 givenname: Martin surname: Weiser fullname: Weiser, Martin organization: 2 Weill Cornell Medical College, New York, NY – sequence: 32 givenname: Julio Garcia surname: Aguilar fullname: Aguilar, Julio Garcia organization: 2 Weill Cornell Medical College, New York, NY – sequence: 33 givenname: David S surname: Klimstra fullname: Klimstra, David S organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 34 givenname: Luis A surname: Diaz, Jr fullname: Diaz, Jr, Luis A organization: 2 Weill Cornell Medical College, New York, NY – sequence: 35 givenname: Jose surname: Baselga fullname: Baselga, Jose organization: 2 Weill Cornell Medical College, New York, NY – sequence: 36 givenname: Liying surname: Zhang fullname: Zhang, Liying organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 37 givenname: Marc surname: Ladanyi fullname: Ladanyi, Marc organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 38 givenname: David M surname: Hyman fullname: Hyman, David M organization: 2 Weill Cornell Medical College, New York, NY – sequence: 39 givenname: David B surname: Solit fullname: Solit, David B organization: 2 Weill Cornell Medical College, New York, NY – sequence: 40 givenname: Mark E surname: Robson fullname: Robson, Mark E organization: 2 Weill Cornell Medical College, New York, NY – sequence: 41 givenname: Barry S surname: Taylor fullname: Taylor, Barry S organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 42 givenname: Kenneth surname: Offit fullname: Offit, Kenneth organization: 1 Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 43 givenname: Michael F surname: Berger fullname: Berger, Michael F organization: 2 Weill Cornell Medical College, New York, NY – sequence: 44 givenname: Zsofia K surname: Stadler fullname: Stadler, Zsofia K organization: 2 Weill Cornell Medical College, New York, NY |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30376427$$D View this record in MEDLINE/PubMed |
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| Title | Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer |
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