Mosaicism in Tumor Suppressor Gene Syndromes: Prevalence, Diagnostic Strategies, and Transmission Risk

Jillian L Chen; David T Miller; Laura S Schmidt; David Malkin; Bruce R Korf; Charis Eng; David J Kwiatkowski; Krinio Giannikou

doi:10.1146/annurev-genom-120121-105450

Mosaicism in Tumor Suppressor Gene Syndromes: Prevalence, Diagnostic Strategies, and Transmission Risk

Annu Rev Genomics Hum Genet. 2022 Aug 31:23:331-361. doi: 10.1146/annurev-genom-120121-105450.

Authors

Jillian L Chen^{1

2}, David T Miller³, Laura S Schmidt^{4

5}, David Malkin^{6

7}, Bruce R Korf⁸, Charis Eng^{9

10

11

12}, David J Kwiatkowski¹, Krinio Giannikou^{1

13}

Affiliations

¹ Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine and Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; email: kgiannikou@bwh.harvard.edu.
² Boston University School of Medicine, Boston, Massachusetts, USA.
³ Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁴ Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
⁶ Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁷ Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁹ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹⁰ Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹¹ Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
¹² Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
¹³ Division of Hematology and Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, California, USA; email: kgiannikou@chla.usc.edu.

PMID: 36044908
DOI: 10.1146/annurev-genom-120121-105450

Abstract

A mosaic state arises when pathogenic variants are acquired in certain cell lineages during postzygotic development, and mosaic individuals may present with a generalized or localized phenotype. Here, we review the current state of knowledge regarding mosaicism for eight common tumor suppressor genes-NF1, NF2, TSC1, TSC2, PTEN, VHL, RB1, and TP53-and their related genetic syndromes/entities. We compare and discuss approaches for comprehensive diagnostic genetic testing, the spectrum of variant allele frequency, and disease severity. We also review affected individuals who have no mutation identified after conventional genetic analysis, as well as genotype-phenotype correlations and transmission risk for each tumor suppressor gene in full heterozygous and mosaic patients. This review provides new insight into similarities as well as marked differences regarding the appreciation of mosaicism in these tumor suppressor syndromes.

Keywords: NF1; NF2; PTEN; RB1; TP53; TSC1; TSC2; VHL; mosaicism; tumor suppressor.

Publication types

Review
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural

MeSH terms

Genes, Tumor Suppressor*
Humans
Mosaicism*
Mutation
Phenotype
Prevalence

Grants and funding

HHSN261200800001E/CA/NCI NIH HHS/United States