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Showing content from https://www.ncbi.nlm.nih.gov/pubmed/29189820 below:

Somatic TP53 variants frequently confound germ-line testing results

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Editorial

. 2018 Aug;20(8):809-816. doi: 10.1038/gim.2017.196. Epub 2017 Nov 30. Somatic TP53 variants frequently confound germ-line testing results Elizabeth C Chao^{2 3}, Bita Nehoray⁴, Lily R Van Tongeren⁴, Holly LaDuca², Kathleen R Blazer⁴, Thomas Slavin, D A B M D Facmg⁴, Tina Pesaran², Christina Rybak⁴, Ilana Solomon⁴, Mariana Niell-Swiller⁴, Jill S Dolinsky², Danielle Castillo⁴, Aaron Elliott², Chia-Ling Gau², Virginia Speare², Kory Jasperson²

Affiliations

¹ Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA. jweitzel@coh.org.
² Ambry Genetics, Aliso Viejo, California, USA.
³ Department of Pediatrics, University of California, Irvine, Irvine, California, USA.
⁴ Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA.

PMID: 29189820
PMCID: PMC5976505
DOI: 10.1038/gim.2017.196

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Editorial

Somatic TP53 variants frequently confound germ-line testing results

Jeffrey N Weitzel et al. Genet Med. 2018 Aug.

. 2018 Aug;20(8):809-816. doi: 10.1038/gim.2017.196. Epub 2017 Nov 30. Authors Jeffrey N Weitzel¹, Elizabeth C Chao^{2 3}, Bita Nehoray⁴, Lily R Van Tongeren⁴, Holly LaDuca², Kathleen R Blazer⁴, Thomas Slavin, D A B M D Facmg⁴, Tina Pesaran², Christina Rybak⁴, Ilana Solomon⁴, Mariana Niell-Swiller⁴, Jill S Dolinsky², Danielle Castillo⁴, Aaron Elliott², Chia-Ling Gau², Virginia Speare², Kory Jasperson² Affiliations

¹ Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA. jweitzel@coh.org.
² Ambry Genetics, Aliso Viejo, California, USA.
³ Department of Pediatrics, University of California, Irvine, Irvine, California, USA.
⁴ Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA.

PMID: 29189820
PMCID: PMC5976505
DOI: 10.1038/gim.2017.196

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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.

Keywords: Li-Fraumeni syndrome; TP53; aberrant clonal expansion; clonal hematopoiesis; somatic variant.

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Conflict of interest statement

Conflict of Interest

Dr. Weitzel, Ms. Nehoray, Ms. Van Tongeren, Dr. Blazer, Dr. Slavin, Ms. Rybak, Ms. Solomon, Ms. Niell-Swiller, and Ms. Castillo have nothing to disclose. Dr. Chao was a full-time salaried employee of Ambry Genetics during a portion of the time of work on the project (until January of 2016), and continues to be a minority shareholder in the corporation. Ms. LaDuca, Ms. Pesaran, Ms. Dolinksy, Dr. Elliott, Dr. Gau, Dr. Speare, and Mr. Jasperson are full-time salary employees of Ambry Genetics.

Figures
Figure 1

Consort Diagram of the Clinical…

Figure 1

Consort Diagram of the Clinical Study; The total sample of cases evaluated at…

Figure 1

Consort Diagram of the Clinical Study; The total sample of cases evaluated at the genetic testing laboratory is indicated followed by the respective subsets of MGPT and single-gene TP53 tests and the subsets meeting eligibility criteria. Cases with and without ancillary testing are noted, as is the final assignment of aberrant clonal expansion status based on consideration of the data. Abbreviations: NGS, Next-Generation Sequencing; SSA, Single Site Analyses; MGPT, Multigene Panel Test; VLP, Variant Likely Pathogenic; P, Pathogenic; Aberrant Clonal Expansions, ACE

Figure 2

Figure 2a. Spectrum of cancers…

Figure 2

Figure 2a. Spectrum of cancers among TP53 cases suspected to be due to…

Figure 2

Figure 2a. Spectrum of cancers among TP53 cases suspected to be due to ACE; The cancer subtypes and their respective proportions are indicated in the pie chart. Note that in some cases (n=18) some individuals had multiple tumor types. Abbreviations: MDS, Myelodysplastic syndrome Figure 2b. Spectrum of cancers among relatives of cases suspected to be due to ACE; The cancer subtypes (excluding non-melanoma skin cancers) reported among first and second degree relatives and their respective proportions are indicated in the pie chart. ^aUrothelial & Kidney: Bladder, Kidney, Renal Pelvis ^bHead & Neck: Esophageal, Laryngeal, Nose, Throat

Figure 2

Figure 2a. Spectrum of cancers…

Figure 2

Figure 2a. Spectrum of cancers among TP53 cases suspected to be due to…

Figure 2