Pipette Petri Dish DNA
Credit: Andrew Brookes / Getty Images

A new process tested at University of Kentucky (UK) expands access to germline genetic testing for cancer patients by reporting research-grade germline sequencing to the clinical oncology team. Over a third of pathogenic/likely pathogenic germline variants (PGVs) identified using a universal testing strategy would have been missed by a guideline-based approach, the team reports.

The study was published in JCO Precision Oncology. Jill Kolesar, PharmD, is the senior author. She directs the UK Markey Cancer Center’s Precision Medicine Clinic and co-directs the Center’s Molecular Tumor Board (MTB).

“These findings not only demonstrate the feasibility of expanded germline testing but also its potential to bring lifesaving benefits to even more patients and improve personalized cancer care,” said Kolesar.

Germline testing detects inherited genetic mutations that increase the risk for cancer and other diseases. For cancer patients, the tests can point to potential therapies and identify family members who would benefit from risk reduction strategies and early screening. 

To determine if a patient is at inherited risk, clinicians typically consider phenotype and family history. The inherited risk for epithelial ovarian, exocrine pancreatic, high-grade prostate, metastatic human epidermal growth factor receptor 2–negative breast, medullary thyroid, and adrenocortical carcinomas is sufficient that a universal approach to germline genetic testing for these diseases is standard of care. 

While patients with cancer frequently undergo research-grade germline sequencing, clinically actionable results are not routinely disclosed to their treating physicians. And, there is evidence that more patients should receive such testing, including adolescents and young adults with cancer, those with advanced cancer, and patients with certain other cancers.  

In fact, it’s been proposed that a pan-cancer approach to germline testing may be best. Mayo Clinic researchers, for example, reported 13.3% (397/2,984) of unselected patients with cancer harbored a pathogenic/likely pathogenic germline variant (PGV) using a universal germline testing strategy. 

This study aimed to evaluate the feasibility of reporting clinically relevant secondary findings (SFs) identified in germline research sequencing using MTB) and the treating oncology physician.

The study included participants from a single cancer center who had any type of the disease. They underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments–certified laboratory to verify PGVs listed among the American College of Medical Genomics and Genetics Secondary Finding v2.0 genes (updated here). 

In consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing. MTB reviewed germline research test results from a group of patients with various cancers. Findings were then communicated to patients’ oncologists, along with recommendations for genetic counseling and confirmatory testing. 

Among 781 participants, more than four percent had genetic mutations related to inherited cancers. More than a third of those cases would have been missed by the existing guidelines. The team also identified 14 patients at risk for other hereditary diseases not typically covered by standard germline testing for cancer risk.  

The findings also suggest expanding germline testing for patients with other cancers including, endometrial, lung, and head or neck cancer. 

Also of Interest