title: Universal Screening for Mismatch-Repair Deficiency in Endometrial Cancers to Identify Patients With Lynch Syndrome and Lynch-like Syndrome.
abstract: Although consensus has yet to be reached on universal mismatch-repair (MMR) protein immunohistochemical (IHC) screening for Lynch syndrome (LS) in endometrial cancer (EC), an increasing number of institutions have adopted universal screening protocols similar to those used for colorectal carcinoma. Here we describe our institution's experience with a prospective universal screening protocol in which all ECs resected over a period of 19 months (n=242) were screened for MLH1, PMS2, MSH2, and MSH6 deficiencies using IHC, followed by MLH1 promoter methylation testing when appropriate. When consent was obtained, tumor samples underwent next-generation sequencing. A total of 11 unmethylated MMR-deficient cases (4.5% of cohort) were identified through IHC screening. Germline testing was performed in 10 cases and confirmed LS in 4 patients (1.7% of cohort). Of our 4 confirmed LS cases, 1 did not meet traditional LS screening criteria (eg, age below 50 y, Revised Bethesda criteria). In addition, universal screening identified 6 germline-negative MMR-deficient nonmethylated cases, 4 of which occurred in women older than 50. Although our next-generation sequencing data suggest somatic mutations in 4 of these cases, it is possible that these cases may represent cases of "Lynch-like syndrome." We conclude that a subset of LS cases could be missed using traditional screening guidelines. The value of screening for Lynch-like syndrome has yet to be determined. Although the cost-effectiveness of universal screening in EC has yet to be elucidated, we conclude that universal IHC screening is currently a reasonable, and arguably superior, approach to screening for LS.
authors.affiliation: Departments of Pathology (J.C.W., J.L.H., C.P.C, L.M.S., B.E.H.) Gynecologic Oncology (M.C.M., C.M.F., R.S.B., N.S.H.), Brigham And Women's Hospital Department of Medical Oncology (S.S., M.B.Y., A.C.), Dana-Farber Cancer Institute, Boston, MA Department of Pathology (E.J.Y.), Stanford University Medical Center, Palo Alto, CA.
authors.forename: Jaclyn C
authors.initials: JC
authors.lastname: Watkins
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Yang
authors.forename: Michael G
authors.initials: MG
authors.lastname: Muto
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Feltmate
authors.forename: Ross S
authors.initials: RS
authors.lastname: Berkowitz
authors.forename: Neil S
authors.initials: NS
authors.lastname: Horowitz
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Yurgelun
authors.forename: Anu
authors.initials: A
authors.lastname: Chittenden
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Howitt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000150:complications / Q000175:diagnosis*; D015179:Colorectal Neoplasms / Q000150:complications / Q000175:diagnosis*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications / Q000175:diagnosis*; D019175:DNA Methylation; D055088:Early Detection of Cancer / Q000379:methods*; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D008875:Middle Aged; D009386:Neoplastic Syndromes, Hereditary / Q000150:complications / Q000175:diagnosis*; D011446:Prospective Studies