MLH1-methylated endometrial cancer under 60 years of age as the ?sentinel? cancer in female carriers of high-risk constitutional<i> MLH1</i> epimutation

Objective. Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (ep...

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Autores: Hitchins MP, Alvarez R, Zhou L, Aguirre F, Dámaso E, Pineda M, Capella G, Wong JJ, Yuan X, Ryan SR, Sathe DS, Baxter MD, Cannon T, Biswas R, DeMarco T, Grzelak D, Hampel H, Pearlman R
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:oai:fisabio.fundanetsuite.com:p14970
Acceso en línea:https://fisabio.portalinvestigacion.com/publicaciones/14970
Access Level:acceso abierto
Palabra clave:Endometrial cancer
MLH1 methylation
Constitutional MLH1 epimutation
Lynch syndrome
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spelling MLH1-methylated endometrial cancer under 60 years of age as the ?sentinel? cancer in female carriers of high-risk constitutional<i> MLH1</i> epimutationHitchins MPAlvarez RZhou LAguirre FDámaso EPineda MCapella GWong JJYuan XRyan SRSathe DSBaxter MDCannon TBiswas RDeMarco TGrzelak DHampel HPearlman REndometrial cancerMLH1 methylationConstitutional MLH1 epimutationLynch syndromeObjective. Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to de-termine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1- methylated tumors.Methods. We screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4, <60 years), and (ii) two population-based cohorts; "Columbus-area" (n = 68, all ages) and "Ohio Colo-rectal Cancer Prevention Initiative (OCCPI)" (n = 24, <60 years).Results. Constitutional MLH1 methylation was identified in three out of four patients diagnosed between 36 and 59 years from cancer clinics. Two had mono-/hemiallelic epimutation (similar to 50% alleles methylated). One with multiple primaries had low-level mosaicism in normal tissues and somatic "second-hits" affecting the unmethylated allele in all tumors, demonstrating causation. In the population-based cohorts, all 68 cases from the Columbus-area cohort were negative and low-level mosaic constitutional MLH1 methylation was identified in one patient aged 36 years out of 24 from the OCCPI cohort, representing one of six (similar to 17%) patients <50 years and one of 45 patients (similar to 2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three pa-tients with underlying constitutional MLH1 methylation.Conclusions. A correct diagnosis at first presentation of cancer is important as it will significantly alter clinical management. Screening for constitutional MLH1 methylation is warranted in patients with early-onset EC or syn-chronous/metachronous tumors (any age) displaying MLH1 methylation.(c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).ACADEMIC PRESS INC ELSEVIER SCIENCE2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/14970Gynecologic OncologyISSN: 00908258ISSNe: 10956859reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglésinfo:eu-repo/semantics/openAccessoai:fisabio.fundanetsuite.com:p149702026-06-11T12:45:17Z
dc.title.none.fl_str_mv MLH1-methylated endometrial cancer under 60 years of age as the ?sentinel? cancer in female carriers of high-risk constitutional<i> MLH1</i> epimutation
title MLH1-methylated endometrial cancer under 60 years of age as the ?sentinel? cancer in female carriers of high-risk constitutional<i> MLH1</i> epimutation
spellingShingle MLH1-methylated endometrial cancer under 60 years of age as the ?sentinel? cancer in female carriers of high-risk constitutional<i> MLH1</i> epimutation
Hitchins MP
Endometrial cancer
MLH1 methylation
Constitutional MLH1 epimutation
Lynch syndrome
title_short MLH1-methylated endometrial cancer under 60 years of age as the ?sentinel? cancer in female carriers of high-risk constitutional<i> MLH1</i> epimutation
title_full MLH1-methylated endometrial cancer under 60 years of age as the ?sentinel? cancer in female carriers of high-risk constitutional<i> MLH1</i> epimutation
title_fullStr MLH1-methylated endometrial cancer under 60 years of age as the ?sentinel? cancer in female carriers of high-risk constitutional<i> MLH1</i> epimutation
title_full_unstemmed MLH1-methylated endometrial cancer under 60 years of age as the ?sentinel? cancer in female carriers of high-risk constitutional<i> MLH1</i> epimutation
title_sort MLH1-methylated endometrial cancer under 60 years of age as the ?sentinel? cancer in female carriers of high-risk constitutional<i> MLH1</i> epimutation
dc.creator.none.fl_str_mv Hitchins MP
Alvarez R
Zhou L
Aguirre F
Dámaso E
Pineda M
Capella G
Wong JJ
Yuan X
Ryan SR
Sathe DS
Baxter MD
Cannon T
Biswas R
DeMarco T
Grzelak D
Hampel H
Pearlman R
author Hitchins MP
author_facet Hitchins MP
Alvarez R
Zhou L
Aguirre F
Dámaso E
Pineda M
Capella G
Wong JJ
Yuan X
Ryan SR
Sathe DS
Baxter MD
Cannon T
Biswas R
DeMarco T
Grzelak D
Hampel H
Pearlman R
author_role author
author2 Alvarez R
Zhou L
Aguirre F
Dámaso E
Pineda M
Capella G
Wong JJ
Yuan X
Ryan SR
Sathe DS
Baxter MD
Cannon T
Biswas R
DeMarco T
Grzelak D
Hampel H
Pearlman R
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Endometrial cancer
MLH1 methylation
Constitutional MLH1 epimutation
Lynch syndrome
topic Endometrial cancer
MLH1 methylation
Constitutional MLH1 epimutation
Lynch syndrome
description Objective. Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to de-termine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1- methylated tumors.Methods. We screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4, <60 years), and (ii) two population-based cohorts; "Columbus-area" (n = 68, all ages) and "Ohio Colo-rectal Cancer Prevention Initiative (OCCPI)" (n = 24, <60 years).Results. Constitutional MLH1 methylation was identified in three out of four patients diagnosed between 36 and 59 years from cancer clinics. Two had mono-/hemiallelic epimutation (similar to 50% alleles methylated). One with multiple primaries had low-level mosaicism in normal tissues and somatic "second-hits" affecting the unmethylated allele in all tumors, demonstrating causation. In the population-based cohorts, all 68 cases from the Columbus-area cohort were negative and low-level mosaic constitutional MLH1 methylation was identified in one patient aged 36 years out of 24 from the OCCPI cohort, representing one of six (similar to 17%) patients <50 years and one of 45 patients (similar to 2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three pa-tients with underlying constitutional MLH1 methylation.Conclusions. A correct diagnosis at first presentation of cancer is important as it will significantly alter clinical management. Screening for constitutional MLH1 methylation is warranted in patients with early-onset EC or syn-chronous/metachronous tumors (any age) displaying MLH1 methylation.(c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fisabio.portalinvestigacion.com/publicaciones/14970
url https://fisabio.portalinvestigacion.com/publicaciones/14970
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ACADEMIC PRESS INC ELSEVIER SCIENCE
publisher.none.fl_str_mv ACADEMIC PRESS INC ELSEVIER SCIENCE
dc.source.none.fl_str_mv Gynecologic Oncology
ISSN: 00908258
ISSNe: 10956859
reponame:r-FISABIO. Repositorio Institucional de Producción Científica
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str r-FISABIO. Repositorio Institucional de Producción Científica
collection r-FISABIO. Repositorio Institucional de Producción Científica
repository.name.fl_str_mv
repository.mail.fl_str_mv
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