Format

Send to

Choose Destination
J Clin Oncol. 2014 Jul 1;32(19):2001-9. doi: 10.1200/JCO.2013.53.6607. Epub 2014 Apr 14.

Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.

Author information

1
Allison W. Kurian, Meredith A. Mills, Kerry E. Kingham, Lisa McPherson, Alice S. Whittemore, Valerie McGuire, Uri Ladabaum, James M. Ford, Stanford University School of Medicine, Stanford; Emily E. Hare, Yuya Kobayashi, Stephen E. Lincoln, Michele Cargill, InVitae, San Francisco, CA.
2
Allison W. Kurian, Meredith A. Mills, Kerry E. Kingham, Lisa McPherson, Alice S. Whittemore, Valerie McGuire, Uri Ladabaum, James M. Ford, Stanford University School of Medicine, Stanford; Emily E. Hare, Yuya Kobayashi, Stephen E. Lincoln, Michele Cargill, InVitae, San Francisco, CA. jmf@stanford.edu.

Abstract

PURPOSE:

Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample.

METHODS:

Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at -80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants.

RESULTS:

In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes.

CONCLUSION:

Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients.

PMID:
24733792
PMCID:
PMC4067941
DOI:
10.1200/JCO.2013.53.6607
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center