Details

Autor(en) / Beteiligte

• 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

Titel

Somatic TP53 variants frequently confound germ-line testing results

Ist Teil von

• Genetics in medicine, 2018-08, Vol.20 (8), p.809-816

Ort / Verlag

United States: Elsevier Limited

Erscheinungsjahr

2018

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. 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. 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). 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.