Somatic TP53 variants frequently confound germ-line testing results.

Autor: Weitzel JN; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA. jweitzel@coh.org., Chao EC; Ambry Genetics, Aliso Viejo, California, USA.; Department of Pediatrics, University of California, Irvine, Irvine, California, USA., Nehoray B; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA., Van Tongeren LR; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA., LaDuca H; Ambry Genetics, Aliso Viejo, California, USA., Blazer KR; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA., Slavin T, Facmg DABMD; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA., Pesaran T; Ambry Genetics, Aliso Viejo, California, USA., Rybak C; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA., Solomon I; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA., Niell-Swiller M; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA., Dolinsky JS; Ambry Genetics, Aliso Viejo, California, USA., Castillo D; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA., Elliott A; Ambry Genetics, Aliso Viejo, California, USA., Gau CL; Ambry Genetics, Aliso Viejo, California, USA., Speare V; Ambry Genetics, Aliso Viejo, California, USA., Jasperson K; Ambry Genetics, Aliso Viejo, California, USA.
Jazyk: angličtina
Zdroj: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2018 Aug; Vol. 20 (8), pp. 809-816. Date of Electronic Publication: 2017 Nov 30.
DOI: 10.1038/gim.2017.196
Abstrakt: Purpose: Blood/saliva DNA is thought to represent the germ line in genetic cancer-risk assessment. Cases with pathogenic TP53 variants detected by multigene panel testing are often discordant with Li-Fraumeni syndrome, raising concern about misinterpretation of acquired aberrant clonal expansions (ACEs) with TP53 variants as germ-line results.
Methods: Pathogenic TP53 variants with abnormal next-generation sequencing metrics (e.g., decreased ratio (<25%) of mutant to wild-type allele, more than two detected alleles) were selected from a CLIA laboratory testing cohort. Alternate tissues and/or close relatives were tested to distinguish between ACE and germ-line status. Clinical data and Li-Fraumeni syndrome testing criteria were examined.
Results: Among 114,630 multigene panel tests and 1,454 TP53 gene-specific analyses, abnormal next-generation sequencing metrics were observed in 20% of 353 TP53-positive results, and ACE was confirmed for 91% of cases with ancillary materials, most of these due to clonal hematopoiesis. Only four met Chompret criteria. Individuals with ACE were older (50 years vs. 33.7; P = 0.02) and were identified more frequently in multigene panel tests (66/285; 23.2%) than in TP53 gene-specific tests (6/68; 8.8%, P = 0.005).
Conclusion: ACE confounds germ-line diagnosis, may portend hematologic malignancy, and may provoke unwarranted clinical interventions. Ancillary testing to confirm germ-line status should precede Li-Fraumeni syndrome management.
Databáze: MEDLINE
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