University of Texas Southwestern Medical Center researchers report they have used whole-genome sequencing (WGS) to identify patients' risk for hereditary cancer, which can potentially lead to improvements in cancer prevention, diagnosis, and care. They say this is the first study that has used WGS to evaluate a series of 258 cancer patients' genomes to improve the ability to diagnose cancer-predisposing mutations.

The study “Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic” is published online in EBioMedicine.

“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 percent 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 Theodora Ross, M.D., Ph.D., professor of internal medicine and director of UT Southwestern's Cancer Genetics Program.

About 5-10% of all cancers are caused by known inherited gene mutations. These mutations are passed down from generation to generation. Mutations in the BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer. BRCA gene mutations are best known for their breast cancer risk, but they also cause increased risk for ovarian, prostate, pancreatic, and other cancers.

In addition, there are many different genes, including ATM, CDH1, CHEK2, PALB2, PTEN, and TP53, that are associated with an increased risk for breast cancer, and researchers are continually discovering additional genes that may affect cancer predisposition.

In this study, researchers developed new methods to analyze the large amount of data generated by WGS. Specifically, Dr. Ross’ team devised a method to compare the group of patients with BRCA1 or BRCA2 mutations to a group of patients without BRCA mutations. All expected BRCA1 and BRCA2 mutations were detected in the BRCA group, with at least 88.6% of mutations confidently detected. In contrast, different cancer gene mutations were found in the cohort without BRCA mutations.

“While loss-of-function (LoF) variants represented only a small fraction of PPVs [potentially pathogenic variants], WGS identified additional cancer risk LoF [loss-of-function] PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes [from the National Center for Biotechnology Information],” wrote the investigators. “These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks.”

“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,” added Dr. Ross, although further investigation is needed in order to be able to interpret the precise clinical implications of the mutations found.