Whole Genome Sequencing Demonstrates Potential for Diagnosis and Discovery in the Cancer Genetics Clinic

This group comprised 176 patients with BRCA1/2 mutations and 82 without. BRCA2 and BRCA1 are normally expressed in the cells of breast and other tissues, where they help repair damaged DNA or destroy cells if DNA cannot be repaired. They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks. If BRCA1 or BRCA2 itself is damaged by a BRCA mutation, damaged DNA is not repaired properly, and this increases the risk for breast cancer as well as for ovarian, prostate, pancreatic, and other cancers.

Initial analysis of potentially pathogenic variants (PPVs) in 163 clinically-relevant genes suggested that WGS could provide useful clinical results despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). While expected BRCA1 and BRCA2 mutations were detected in the BRCA group, with at least 88.6% of mutations confidently detected, different cancer gene mutations were found in the cohort without BRCA mutations. Previously reported pathogenic missense variants did not always associate with their predicted diseases in the patients, which suggested that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants.

While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding the analysis to include data on 3209 [US] National Center for Biotechnology Information (Bethesda MD, USA) ClinVar genes. ClinVar is a freely accessible, public archive of reports of the relationships among human variations and phenotypes, with supporting evidence. ClinVar facilitates access to and communication about the relationships asserted between human variation and observed health status, and the history of that interpretation.

“Whole-genome sequencing is a new genetic tool that can determine more of a person’s DNA sequence than ever before. Our results show that nearly 90% of clinically identified mutations were confidently detected and additional cancer gene mutations were discovered, which together with the decreasing costs associated with whole-genome sequencing means that this method will improve patient care, as well as lead to discovery of new cancer genes,” said senior author Dr. Theodora Ross, professor of internal medicine at the University of Texas Southwestern Medical Center. “The results demonstrate that whole-genome sequencing can detect new cancer gene mutations in non-BRCA ‘mystery’ patients, demonstrating the added value whole-genome sequencing brings to the future cancer clinic although further investigation is needed in order to be able to interpret the precise clinical implications of the mutations found. Mystery patients are those who have a strong family history for cancer but after standard genetic testing, no genetic diagnoses are made. In our study, sequencing allowed us to discover novel candidate cancer gene mutations in mystery patients.”

The study was published in the December 18, 2014, online edition of the journal EBioMedicine.

Related Links:
University of Texas Southwestern Medical Center
ClinVar