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Somatic TP53 variants frequently confound germ-line testing results.
Weitzel, Jeffrey N; Chao, Elizabeth C; Nehoray, Bita; Van Tongeren, Lily R; LaDuca, Holly; Blazer, Kathleen R; Slavin, Thomas; Facmg, D A B M D; Pesaran, Tina; Rybak, Christina; Solomon, Ilana; Niell-Swiller, Mariana; Dolinsky, Jill S; Castillo, Danielle; Elliott, Aaron; Gau, Chia-Ling; Speare, Virginia; Jasperson, Kory.
Afiliação
  • Weitzel JN; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA. jweitzel@coh.org.
  • Chao EC; Ambry Genetics, Aliso Viejo, California, USA.
  • Nehoray B; Department of Pediatrics, University of California, Irvine, Irvine, California, USA.
  • Van Tongeren LR; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA.
  • LaDuca H; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA.
  • Blazer KR; Ambry Genetics, Aliso Viejo, California, USA.
  • Slavin T; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA.
  • Pesaran T; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA.
  • Rybak C; Ambry Genetics, Aliso Viejo, 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; Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA.
  • Castillo D; Ambry Genetics, Aliso Viejo, California, USA.
  • Elliott A; Division of Clinical Cancer Genomics, City of Hope, Duarte, 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.
Genet Med ; 20(8): 809-816, 2018 08.
Article em En | MEDLINE | ID: mdl-29189820
ABSTRACT

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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Testes Genéticos / Genes p53 Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Testes Genéticos / Genes p53 Idioma: En Ano de publicação: 2018 Tipo de documento: Article