Germline variants in targeted tumor sequencing using matched normal DNA Journal Article


Authors: Schrader, K. A.; Cheng, D. T.; Joseph, V.; Prasad, M.; Walsh, M.; Zehir, A.; Ni, A.; Thomas, T.; Benayed, R.; Ashraf, A.; Lincoln, A.; Arcila, M.; Stadler, Z.; Solit, D.; Hyman, D.; Zhang, L.; Klimstra, D.; Ladanyi, M.; Offit, K.; Berger, M.; Robson, M.
Article Title: Germline variants in targeted tumor sequencing using matched normal DNA
Abstract: DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced cancer diagnoses eligible for studies of targeted agents at Memorial Sloan Kettering Cancer Center are offered tumor-normal sequencing with MSK-IMPACT, a 341-gene panel. We surveyed the germline variants seen in 187 overlapping genes with Mendelian disease associations in 1566 patients who had undergone tumor profiling between March and October 2014. MAIN OUTCOMES AND MEASURES: The number of presumed pathogenic germline variants (PPGVs) and variants of uncertain significance per person in 187 genes associated with single-gene disorders and the proportions of individuals with PPGVs in clinically relevant gene subsets, in genes consistent with known tumor phenotypes, and in genes with evidence of second somatic hits in their tumors. RESULTS: The mean age of the 1566 patients was 58 years, and 54% were women. Presumed pathogenic germline variants in known Mendelian disease-associated genes were identified in 246 of 1566 patients (15.7%; 95% CI, 14.0%-17.6%), including 198 individuals with mutations in genes associated with cancer susceptibility. Germline findings in cancer susceptibility genes were concordant with the individual's cancer type in only 81 of 198 cases (40.9%; 95% CI, 34.3%-47.9%). In individuals with PPGVs retained in the tumor, somatic alteration of the other allele was seen in 39 of 182 cases (21.4%; 95% CI, 16.1%-28.0%), of which 13 cases did not show a known correlation of the germline mutation and a known syndrome. Mutations in non-cancer-related Mendelian disease genes were seen in 55 of 1566 cases (3.5%; 95% CI, 27.1%-45.4%). Almost every individual had more than 1 variant of uncertain significance (1565 of 1566 patients; 99.9%; 95% CI, 99.6%-99.9%). CONCLUSIONS AND RELEVANCE: Germline variants are common in individuals undergoing tumor-normal sequencing and may reveal otherwise unsuspected syndromic associations. IMPORTANCE: Tumor genetic sequencing identifies potentially targetable genetic alterations with therapeutic implications. Analysis has concentrated on detecting tumor-specific variants, but recognition of germline variants may prove valuable as well. OBJECTIVE: To estimate the burden of germline variants identified through routine clinical tumor sequencing.
Keywords: adult; aged; aged, 80 and over; middle aged; genetics; neoplasms; phenotype; genetic predisposition to disease; biological model; gene expression profiling; risk factors; pathology; tumor marker; risk factor; risk assessment; predictive value of tests; new york city; models, genetic; dna mutational analysis; new york; genetic predisposition; germ-line mutation; predictive value; personalized medicine; germline mutation; procedures; very elderly; humans; prognosis; human; male; female; precision medicine; biomarkers, tumor
Journal Title: JAMA Oncology
Volume: 2
Issue: 1
ISSN: 2374-2437
Publisher: American Medical Association  
Date Published: 2016-01-01
Start Page: 104
End Page: 111
Language: English
DOI: 10.1001/jamaoncol.2015.5208
PUBMED: 26556299
PROVIDER: scopus
PMCID: PMC5477989
DOI/URL:
Notes: Article -- Export Date: 1 July 2016 -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    521 Offit
  2. Mark E Robson
    372 Robson
  3. David Solit
    440 Solit
  4. Liying Zhang
    89 Zhang
  5. Zsofia Kinga Stadler
    153 Stadler
  6. David S Klimstra
    857 Klimstra
  7. Marc Ladanyi
    885 Ladanyi
  8. David Hyman
    197 Hyman
  9. Ahmet Zehir
    159 Zehir
  10. Vijai Joseph
    120 Joseph
  11. Michael Forman Berger
    393 Berger
  12. Maria Eugenia Arcila
    350 Arcila
  13. Tinu Mary Thomas
    16 Thomas
  14. Donavan Tai Suan Cheng
    51 Cheng
  15. Rym Benayed
    79 Benayed
  16. Meera   Prasad
    11 Prasad
  17. Anne Gunning Lincoln
    14 Lincoln
  18. Asad   Ashraf
    6 Ashraf
  19. Michael Francis Walsh
    49 Walsh
  20. Ai   Ni
    53 Ni