MLH1-methylated endometrial cancer under 60 years of age as the "sentinel" cancer in female carriers of high-risk constitutional MLH1 epimutation.

Autor: Hitchins MP; Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Medicine (Oncology), Stanford University, Stanford, CA, USA. Electronic address: megan.hitchins@cshs.org., Alvarez R; Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Zhou L; Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Aguirre F; Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Dámaso E; Department of Medicine (Oncology), Stanford University, Stanford, CA, USA; Hereditary Cancer Program, Catalan Institute of Oncology, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Av. Gran Via de l'Hospitalet, 199-203, 08908 L' Hospitalet de Llobregat, Barcelona, Spain; Molecular Genetics Unit, Elche University Hospital, Elche, Alicante. Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO), FISABIO- Elche Health Department, Spain., Pineda M; Molecular Genetics Unit, Elche University Hospital, Elche, Alicante. Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO), FISABIO- Elche Health Department, Spain; Consortium for Biomedical Research in Cancer - CIBERONC, Carlos III Institute of Health, Av. De Monforte de Lemos 5, 28029 Madrid, Spain., Capella G; Molecular Genetics Unit, Elche University Hospital, Elche, Alicante. Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO), FISABIO- Elche Health Department, Spain; Consortium for Biomedical Research in Cancer - CIBERONC, Carlos III Institute of Health, Av. De Monforte de Lemos 5, 28029 Madrid, Spain., Wong JJ; Epigenetics and RNA Biology Program Centenary Institute, and Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales 2050, Australia., Yuan X; Department of Pathology and Laboratory Medicine, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Ryan SR; Hereditary Cancer Assessment Program, University of New Mexico Comprehensive Cancer Center, NM, USA., Sathe DS; Precision Medicine and Genetics, Frederick Health, MD, USA., Baxter MD; Saint Francis Healthcare System, Cape Girardeau, MO, USA., Cannon T; Cancer Genetics Program, Inova Schar Cancer Institute, Inova Fairfax Hospital, VA, USA., Biswas R; Cancer Genetics Program, Inova Schar Cancer Institute, Inova Fairfax Hospital, VA, USA., DeMarco T; Cancer Genetics Program, Inova Schar Cancer Institute, Inova Fairfax Hospital, VA, USA., Grzelak D; Virginia Cancer Specialists, Fairfax, VA, USA., Hampel H; Department of Internal Medicine and the Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA; Division of Clinical Cancer Genomics, Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA., Pearlman R; Department of Internal Medicine and the Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
Jazyk: angličtina
Zdroj: Gynecologic oncology [Gynecol Oncol] 2023 Apr; Vol. 171, pp. 129-140. Date of Electronic Publication: 2023 Mar 08.
DOI: 10.1016/j.ygyno.2023.02.017
Abstrakt: 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 determine 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 Colorectal 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 (∼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 (∼17%) patients <50 years and one of 45 patients (∼2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three patients 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 synchronous/metachronous tumors (any age) displaying MLH1 methylation.
Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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