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. 2016 Jan;2(1):104-11.
doi: 10.1001/jamaoncol.2015.5208.

Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA

Kasmintan A Schrader  1 , Donavan T Cheng  2 , Vijai Joseph  3 , Meera Prasad  2 , Michael Walsh  4 , Ahmet Zehir  2 , Ai Ni  5 , Tinu Thomas  6 , Ryma Benayed  2 , Asad Ashraf  7 , Annie Lincoln  7 , Maria Arcila  2 , Zsofia Stadler  8 , David Solit  9 , David M Hyman, Liying Zhang  2 , David Klimstra  2 , Marc Ladanyi  10 , Kenneth Offit  11 , Michael Berger  12 , Mark Robson  13
Affiliations

Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA

Kasmintan A Schrader et al. JAMA Oncol. 2016 Jan.

Erratum in

Abstract

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.

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.

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Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1
Figure 1. Individuals With at Least 1 Presumed Pathogenic Germline Variant in OMIM Genes, Including the Cancer and ACMG Subsets
The number of genes in the entire Online Mendelian Inheritance in Man (OMIM) subset is 187 (http://omim.org), which includes the Cancer subset of 93 genes and the partially overlapping American College of Medical Genetics (ACMG) subset of 26 genes (eTable 4 in the Supplement).
Figure 2
Figure 2. Total Presumed Pathogenic Germline Variants (PPGVs) Identified in 61 Genes
Results of germline analysis of 187 Mendelian disease-associated genes from a 341-gene panel (MSK-IMPACT) in 246 of 1566 individuals. AD indicates autosomal dominant (127 genes); AR, autosomal recessive (27 genes); CX, mixed patterns of inheritance (17 genes); SM, frequently associated with somatic mosaicism (4 genes); XD, X-linked dominant (4 genes); and XR, X-linked recessive (8 genes).
Figure 3
Figure 3. Aggregate Data Showing Presumed Pathogenic Germline Variants (PPGVs) in ACMG Genes by Tumor Type
Phenotypes are designated as expected to be secondary to pathogenic PPGVs based on common presentations of the known syndromes and gene associations (dark beige) or unexpected (light beige). ACMG indicates American College of Medical Genetics (ACMG).
See this image and copyright information in PMC

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