Germline Analysis from Tumor-Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings

Abstract

Purpose: To evaluate germline variants in hereditary cancer susceptibility genes among unselected cancer patients undergoing tumor-germline sequencing.

Experimental design: 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.

Figure 1. Germline findings across all UNCseq™ patients

The percentages of patients with Pathogenic variants (light shading) or Variants of Uncertain Significance (VUS, dark shading) in genes that are concordant with the tumor type are depicted as stacked bar graphs. Numbers above the bars represent the sample size for the specific tumor type. Numbers in parentheses represent the number of patients with Variants of Uncertain Significance or Pathogenic variants. Here, Pathogenic variants include both Likely Pathogenic (LP) and Known Pathogenic (KP) variants. In both the ovarian and breast cancer groups, one patient in each group had a Variant of Uncertain Significance and a Pathogenic variant. Hence, 8 cases were found to have pathogenic variants in genes concordant with breast cancer, 3 cases were found with pathogenic variants in genes concordant with ovarian cancer, and 1 case was found to have a pathogenic variant in a gene concordant with pancreatic cancer.

Figure 2. Germline Pathogenic/Likely Pathogenic variants identified in all UNCseq™ patients

The numbers of Known Pathogenic (KP) and Likely Pathogenic (LP) variants across all UNCseq™ patients analyzed are depicted as a bar graph, divided by gene.

Figure 3. Germline Variants of Uncertain Significance across all UNCseq™ patients

A. Variants occurring in genes relevant to the patient's cancer diagnosis. B. Variants occurring in genes unrelated to the patient's cancer diagnosis. Numbers above the bars represent the frequency of patients with 0,1,2,3 or 4 variants. Percentages represent the percent of all UNCseq™ patients analyzed.