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. 2016 May;27(5):795-800.
doi: 10.1093/annonc/mdw018. Epub 2016 Jan 19.

Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol

F Meric-Bernstam  1 , L Brusco  2 , M Daniels  3 , C Wathoo  2 , A M Bailey  2 , L Strong  4 , K Shaw  2 , K Lu  3 , Y Qi  5 , H Zhao  5 , H Lara-Guerra  6 , J Litton  7 , B Arun  8 , A K Eterovic  9 , U Aytac  2 , M Routbort  10 , V Subbiah  11 , F Janku  11 , M A Davies  12 , S Kopetz  13 , J Mendelsohn  14 , G B Mills  15 , K Chen  16
Affiliations

Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol

F Meric-Bernstam et al. Ann Oncol. 2016 May.

Abstract

Background: Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic germline variants (PGVs).

Patients and methods: Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing.

Results: Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing.

Conclusions: In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancer-related genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling.

Keywords: BRCA1; genetics; hereditary cancer risk; incidental results; next-generation sequencing; personalized therapy.

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Figures

Figure 1.
Figure 1.
Frequency of likely pathogenic somatic and germline variants in selected genes. (A) Number of patients with likely pathogenic somatic variants in selected 18 genes (no alterations were found in TSC1). (B) The percentage of somatic versus germline variants was presented using all likely pathogenic variants in each gene as the denominator. (C) Pathogenic somatic versus germline mutant allele frequency (MAF) (unpaired t-test). (D) Clinical identification of germline pathogenic variants.
Figure 2.
Figure 2.
Clinical recognition of germline pathogenic variants.
See this image and copyright information in PMC

Comment in

References

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