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Clinical Updates and Surveillance Recommendations for DNA Replication Repair Deficiency Syndromes in Children and Young Adults.

Authors :
Das A
MacFarland SP
Meade J
Hansford JR
Schneider KW
Kuiper RP
Jongmans MCJ
Lesmana H
Schultz KAP
Nichols KE
Durno C
Zelley K
Porter CC
States LJ
Ben-Shachar S
Savage SA
Kalish JM
Walsh MF
Scott HS
Plon SE
Tabori U
Source :
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Aug 15; Vol. 30 (16), pp. 3378-3387.
Publication Year :
2024

Abstract

Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by abnormalities in the DNA mismatch repair (MMR) system due to pathogenic variants in the PMS2, MSH6, MSH2, or MLH1 genes, and/or in the polymerase-proofreading genes POLE and POLD1. RRD predisposition syndromes (constitutional MMR deficiency, Lynch, and polymerase proofreading-associated polyposis) share overlapping phenotypic and biological characteristics. Moreover, cancers stemming from germline defects of one mechanism can acquire somatic defects in another, leading to complete RRD. Here we describe the recent advances in the diagnostics, surveillance, and clinical management for children with RRD syndromes. For patients with constitutional MMR deficiency, new data combining clinical insights and cancer genomics have revealed genotype-phenotype associations and helped in the development of novel functional assays, diagnostic guidelines, and surveillance recommendations. Recognition of non-gastrointestinal/genitourinary malignancies, particularly aggressive brain tumors, in select children with Lynch and polymerase proofreading-associated polyposis syndromes harboring an RRD biology have led to new management considerations. Additionally, universal hypermutation and microsatellite instability have allowed immunotherapy to be a paradigm shift in the treatment of RRD cancers independent of their germline etiology. These advances have also stimulated a need for expert recommendations about genetic counseling for these patients and their families. Future collaborative work will focus on newer technologies such as quantitative measurement of circulating tumor DNA and functional genomics to tailor surveillance and clinical care, improving immune surveillance; develop prevention strategies; and deliver these novel discoveries to resource-limited settings to maximize benefits for patients globally.<br /> (©2024 American Association for Cancer Research.)

Details

Language :
English
ISSN :
1557-3265
Volume :
30
Issue :
16
Database :
MEDLINE
Journal :
Clinical cancer research : an official journal of the American Association for Cancer Research
Publication Type :
Academic Journal
Accession number :
38860976
Full Text :
https://doi.org/10.1158/1078-0432.CCR-23-3994