title: Germline Analysis from Tumor-Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings.
abstract: OBJECTIVE
  To evaluate germline variants in hereditary cancer susceptibility genes among unselected cancer patients undergoing tumor-germline sequencing.
  
  
  METHODS
  Germline sequence data from 439 individuals undergoing tumor-germline dyad sequencing through the LCCC1108/UNCseq™ (NCT01457196) study were analyzed for genetic variants in 36 hereditary cancer susceptibility genes. These variants were analyzed as an exploratory research study to determine whether pathogenic variants exist within the germline of patients undergoing tumor-germline sequencing. Patients were unselected with respect to indicators of hereditary cancer predisposition.
  
  
  RESULTS
  Variants indicative of hereditary cancer predisposition were identified in 19 (4.3%) patients. For about half (10/19), these findings represent new diagnostic information with potentially important implications for the patient and their family. The others were previously identified through clinical genetic evaluation secondary to suspicion of a hereditary cancer predisposition. Genes with pathogenic variants included ATM, BRCA1, BRCA2, CDKN2A, and CHEK2 In contrast, a substantial proportion of patients (178, 40.5%) had Variants of Uncertain Significance (VUS), 24 of which had VUS in genes pertinent to the presenting cancer. Another 143 had VUS in other hereditary cancer genes, and 11 had VUS in both pertinent and nonpertinent genes.
  
  
  CONCLUSIONS
  Germline analysis in tumor-germline sequencing dyads will occasionally reveal significant germline findings that were clinically occult, which could be beneficial for patients and their families. However, given the low yield for unexpected germline variation and the large proportion of patients with VUS results, analysis and return of germline results should adhere to guidelines for secondary findings rather than diagnostic hereditary cancer testing. Clin Cancer Res; 22(16); 4087-94. ©2016 AACRSee related commentary by Mandelker, p. 3987.
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Seifert
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Julianne M
authors.initials: JM
authors.lastname: O'Daniel
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Krunal
authors.initials: K
authors.lastname: Amin
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Marchuk
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.|Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Nirali M
authors.initials: NM
authors.lastname: Patel
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Hoyle
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Lisle E
authors.initials: LE
authors.lastname: Mose
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Andrew
authors.initials: A
authors.lastname: Marron
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Michele C
authors.initials: MC
authors.lastname: Hayward
authors.affiliation: Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bizon
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.|Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Kirk C
authors.initials: KC
authors.lastname: Wilhelmsen
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: James P
authors.initials: JP
authors.lastname: Evans
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Berg
mesh_terms: D014408:Biomarkers, Tumor; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D023281:Genomics / Q000379:methods; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009369:Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis / Q000235:genetics; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor