Study Finds Whole-Genome Sequencing Is Successful in Identifying Patients’ Risk for Inherited Cancers


Key Points

  • Whole-genome sequencing performed on patients with and without BRCA1/2 mutations has identified cancer-risk potentially pathogenic variants in the non-BRCA patients.
  • In the BRCA1/2 cohort, the researchers found that whole-genome sequencing correctly identified the majority of clinically diagnosed BRCA1 and BRCA2 mutations.
  • Whole-genome sequencing provided likely genetic cancer risk of potentially pathogenic variants in 20.7% of the non-BRCA1/2 clinic patients.

After performing whole-genome sequencing on patients found to have BRCA1or BRCA2 mutations as well as on those that were not carriers of either mutation, researchers found cancer risk–related potentially pathogenic variants in those without BRCA mutations. While the results highlight the potential for improving risk assessment in patients with a family history of cancer, they also raise concerns over how best to counsel them. The study by Foley et al is published in EBioMedicine.

Study Methodology

The researchers recruited 258 individuals from the cancer genetics clinics of the University of Texas Southwestern Medical Center and the Ohio State University cancer genetics programs. The researchers took blood samples from the patients and performed whole-genome sequencing on members of two cohorts of patients: those with BRCA1 (n = 88) or BRCA2 (n = 88) mutations and those who were not carriers of a BRCA1/2 mutation (n = 82). The genomes of 176 unrelated BRCA-mutation carriers at high risk for breast and ovarian cancer were first investigated to determine if whole-genome sequencing confirmed the clinically diagnosed mutations.

All statistical analyses were performed using the R statistical framework; 95% confidence intervals were determined from the binomial probability.

Study Findings

In the BRCA 1/2 cohort, the researchers found that whole-genome sequencing correctly identified the majority of clinically diagnosed BRCA1 and BRCA2 mutations, detecting 89.3% of the BRCA1 mutations and 88.6% of the BRCA2 mutations. Initial analysis of potentially pathogenic variants in 163 clinically relevant genes suggested that whole-genome sequencing will provide useful clinical results.

While loss-of-function variants represented only a small fraction of potentially pathogenic variants, whole-genome sequencing identified additional cancer risk loss-of-function potentially pathogenic variants in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of the non-BRCA cancer genetics patients after the researchers expanded their analysis to 3,209 ClinVar genes.

In total, report the researchers, whole-genome sequencing provided likely genetic cancer risk potentially pathogenic variants in 20.7% of the non-BRCA1/2 clinic patients. In contrast, according to the study abstract, “A recent report using targeted gene panel testing provided similar cancer risk potentially pathogenic variants in 10.6% of non-BRCA1/2 patients.”

“There are other major challenges involved in translating [whole-genome sequencing] into the clinic, including questions of mutation penetrance, better understanding of the genes about which we understand little, and how to counsel patients who test negative or positive for an identified familiar mutation in one of the less well understood genes (CHEK2, PALB2, or RAD51C, are good examples of this),” wrote the study authors.

“Right now, performing whole-genome sequencing in the cancer genetics clinic is inappropriate, but ultimately this is what is going to happen,” said Theodora Ross, MD, PhD, Professor of Internal Medicine and Director of the Cancer Genetics Program at UT Southwestern Medical Center in Dallas, Texas, and corresponding author of the study. She emphasized, however, that since there is the potential to identify not only genetic risks for the patient’s primary diagnosis, but also risks for other conditions, “genetic counseling is so important” for patients, she said.

The Next Steps

The researchers are submitting their whole-genome sequencing data to the NCBI dbGaP repository so other investigators can do their own analyses and publish their findings, said Dr. Ross. Dr. Ross also hopes to perform parallel whole-genome sequencing on the more than 2,000 patients that come into the UT Southwestern Medical Center’s cancer genetics clinic for testing each year. In addition, she plans to use whole-genome sequencing on “mystery” patients—those with cancer susceptibility syndromes—to attempt to identify their novel candidate cancer gene mutations.

Most importantly, said Dr. Ross, the study of single genes needs to be a top research priority. “The problem is there is not enough basic science being done on the genes in the genome. We are going to be finding all of these broken genes, and nobody is doing the research on them,” she said.

Dr. Ross is the corresponding author for the EBioMEdicine article.

The study was funded by the Burroughs Wellcome Fund Clinical Scientist Award, the Peter Bradley Carlson Charitable Trust, and the National Center for Advancing Translational Sciences of the National Institutes of Health. The authors declared no conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.