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Project Aims to Collect Data on Pathogenic Variants and VUS from Hereditary Cancer Panels


This story was originally published on Sept. 29.

NEW YORK (GenomeWeb) – Despite the proliferation of next-generation sequencing panel tests, many turn up results that are difficult to interpret — uncovering a known pathogenic variant whose penetrance is not understood or revealing a variant of unknown significance, for instance.

Now, researchers are attempting to solve some of these questions for patients that receive genetic testing for hereditary cancer in a project called Participants in the Prospective Registry of MultiPlex Testing (PROMPT).

Last week, researchers from Memorial Sloan Kettering, the Mayo Clinic, the Abramson Cancer Center of the University of Pennsylvania, and the Dana-Farber Cancer Institute announced that they have created an online registry for data from consenting patients who have received NGS-based hereditary cancer tests from commercial laboratories.

Specifically, the researchers will work with laboratories at Ambry Genetics, Myriad Genetics, GeneDx, and Quest, which will provide registry and enrollment information to patients whose test has indicated a pathogenic variant or a VUS.

The project has two aims: to better understand penetrance of variants known to be associated with cancer risk and to understand VUS.

The project was designed with the goal of generating information about genes associated with cancer risk, similar to what is known about the BRCA1 and BRCA2 genes. "We understand that someone's at an increased risk for breast and ovarian cancer due to BRCA1 and BRCA2, and that there are things we can do to significantly decrease that risk," Susan Domcheck, executive director of the Basser Research Center for BRCA at Penn's Abramson Cancer Center, told Clinical Sequencing News. The genes are good models for how genetic information can be used in clinical management, she added.

However, while there are now many other genes associated with cancer risk and advances in sequencing technology has enabled testing for all of those genes in a cost-efficient manner, "we don't have nearly as much information about the risks with those genes and what to do with the information," Domchek said.

For instance, according to Elizabeth Chao, chief medical officer at Ambry, the firm runs hundreds of panels per day. While approximately two-thirds of those panels are negative, the remaining patients have either known pathogenic variants or a VUS and would be eligible for the study. In the two and half years Ambry has been offering gene panels, the VUS rate has come down significantly, Chao said, but it is still around 25 percent or higher. "It's pretty significant," she said.

In addition, even when panels yield known pathogenic mutations, "it is hard to counsel patients" for many of the genes being tested for on hereditary cancer panels, Chao added. "We don't have precise numbers for risk or management guidelines in terms of what is appropriate to do in terms of screening and prevention."

PROMPT will attempt to build that information so risk profiles and clinical management guidelines can be developed. "We're at a place where the technology is here but our ability to readily translate it into clinical practice is lagging behind," Domchek said. "The purpose of the study is to catch up."

Patients that decide to enroll in the registry will also be able to choose how much data to provide. At the minimum, researchers will ask them to provide the data from their test result. But whether they choose to provide identifying information will be up to them. They can also opt to allow the researchers to contact them for additional information, including family data.

Domchek said that the registry will include a secure online portal to allow the researchers and participants to communicate without revealing identifying information about the participant. However, she said, ideally most participants would provide identifying information that allows the researchers to collect family data.

"It's extremely valuable to collect information about families," Domcheck said, adding that family data allows the researchers to do co-segregation studies to "figure out who has the variant and who doesn't, which allows you to develop risk estimates for cancer."

In addition, Domchek said, the researchers would also want to collect clinical data about the cancer — "what kind of cancer, the age of diagnosis, what it looked like under the microscope, features that can be helpful for understanding what kind of cancer people get with specific gene mutations."

While the goal of PROMPT is not to match patients with appropriate treatment or clinical trials, Domchek said that the technology would enable the researchers to provide that information when appropriate.

The researchers plan to eventually publish their findings in a manuscript to define penetrance, cancer risk, and potentially clinical management recommendations. In addition, all the data will be deposited into public databases like ClinVar so that other investigators can use it.