Researchers are concerned about the lesser-known genes included in the test and also point out that little published research exists to support use of these genes for clinical laboratory testing

Gene-panel tests for inherited cancers were scrutinized by a group of 17 prominent international genetic researchers in a study published by the New England Journal of Medicine (NEJM) this summer titled “Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk.” These experts pointed out that, for many of the genes included in these test panels, there remains much uncertainty about their role in various cancers and other diseases.

What will be of greatest interest to pathologist, Ph.D.s, and medical laboratory professionals currently performing molecular diagnostics assays and genetics is that these experts proposed greater regulation of unvalidated gene-panel tests for inherited cancers. In the NEJM, the authors provided some examples of genetic tests, such as those offered by Myriad Genetics, Inc. (NASDAQ:MYGN), Ambry Genetics, Invitae (NYSE:NVTA), and Illumina, Inc. (NASDAQ:ILMN) and noted that risks posed by many mutations occurring on these panels are unknown.

These panel tests can include more than 100 genes, 21 of which are an indication of breast cancer, including BRCA1 and BRCA2, stated the paper.

Government Wants to Increase Oversight of LDTs

The FDA has been considering how to regulate laboratory-developed tests (LTDs) for some time, stated a Reuters report. The report also noted that LTDs currently fall under guidelines established by the Clinical Laboratory Improvement Amendments (CLIA) of 1988, but that CLIA does not required such tests to prove clinical validity or utility.

The researchers who published the NEJM article suggested that the U.S. Food & Drug Administration (FDA) should regulate LDTs in a similar manner to drugs.

“However, the fact that the technology is available does not necessarily mean that such [gene panel] tests are appropriate or desirable,” stressed the researchers. “A genomic test should not be offered until its clinical validity has been established,” they contended, citing criteria for evaluating genetic tests from the Centers for Disease Control and Prevention (CDC) genomic test ACCE model, which stands for:

• Analytic validity,
• Clinical validity;
• Clinical utility, and,
• Ethical, legal, and social implications.

Are All the Genes in these Clinical Laboratory Tests Necessary?

What is in dispute is whether the lesser-known genes included in the multi-gene panel tests are actually necessary to generate useful information for determining a patient’s level of risk for breast cancer. Some genetic experts argue that these genes are critical to the results.

The authors of the NEJM study further pointed out that, in recent years, there has been an explosion of research and information about molecular and genetic processes. Yet, much of these new insights come without a full comprehension of how all the moving parts work together.

An example is “junk DNA” (all the non-gene DNA in a genome). Until recently, scientists believed that junk DNA did not play much of a role compared to genes. But new insights into how it functions are changing that assumption.

Similar to non-coding DNA, which scientists only recently discovered is “not” junk DNA, geneticists suspect these lesser-understood genes may be important to cancer risk. However, they don’t yet know what or how much of a role that the non-coding DNA plays in cancer. “It’s been pretty widely assumed that all of these genes on all of these panels have clear clinical validity, meaning the genes are clearly associated with cancer,” stated breast cancer expert Susan Domchek, M.D., Professor of Oncology at the University of Pennsylvania Medical School and coauthor of the study, in an interview with Reuters. “The point of [the NEJM] article was to say, we’re not finished with that step yet.”

Reliable Estimates of Risk Needed for Effective Patient Guidance

As critical as these test have become in diagnosing genetic risk factors for cancer, the potential exists that patients and doctors could be confused by the test results. “The reality is that we don’t have good risk estimates for mutations that occur in many of the genes on the panels, said Fergus Couch, Ph.D., in the Reuters report. Couch is a Professor of Laboratory Medicine & Pathology at Mayo Clinic. He specializes in breast and pancreatic cancer research.

The NEJM article authors concluded that, “As the costs of sequencing decline, it is inevitable that the use of gene-panel testing, and indeed whole-exome and whole-genome sequencing, will become widespread. Therefore, there is an urgent need for much larger, well-designed population—and family—based studies in diverse populations that will provide reliable estimates of risk for the purpose of counseling.”

The researchers agree that gene-panel tests can benefit prediction of a woman’s risk for breast cancer, but clinicians should be aware of the limitations of these panels and differences in high-risk and moderate risk variants.

Fergus Couch, Ph.D., a Professor of Laboratory Medicine & Pathology at Mayo Clinic, coauthored the study published in the New England Journal of Medicine (NEJM), that analyzed the level of risk posed by various gene variants included in commercially produced gene-panel tests for breast cancer. The 17 researchers involved in this study called for stiffer regulation of these tests. (Photo copyright Mayo Clinic.)

Fergus Couch, Ph.D., a Professor of Laboratory Medicine & Pathology at Mayo Clinic, coauthored the study published in the New England Journal of Medicine (NEJM), that analyzed the level of risk posed by various gene variants included in commercially produced gene-panel tests for breast cancer. The 17 researchers involved in this study called for stiffer regulation of these tests. (Photo copyright Mayo Clinic.)

Research Scientists Call for Greater Transparency in the Generation of Clinical Information

Another issue related to this issue is the quality, thoroughness, and accuracy of scientific studies that deal with specific genes and their role in diseases such as cancer. Scientists in various research areas have voiced concerns about publication bias and have called for validating findings with additional studies that reproduce the findings. They also recommend establishing guidelines and/or test standards to help ensure research and diagnostic accuracy.

It was during a webinar, presented by The Scientist, that C. Glenn Begley, Ph.D., Chief Scientific Officer and Senior Vice President of Research & Development at TetraLogic Pharmaceuticals, cited findings of a reproducibility study he led in 2012. He and his team examined 53 published research studies, only six of which had reproducible scientific findings. (See Dark Daily “Medical Scientists Call for Standard Method for Validating Antibodies Used in Research and Clinical Laboratory Diagnostics,” September 23, 2015.)

This call by research scientists for more validation of gene panel tests for inherited cancers and how they are used for clinical purposes is consistent with the increased calls for more transparency in healthcare. Not just outcomes transparency, not just price transparency, but transparency in the clinical information that supports the use of a medical laboratory test or a therapeutic drug (derived from the clinical studies/clinical trials conducted by the companies who developed the lab test or drug).

—Patricia Kirk

Related Information:

Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk

Researchers Oppose Unvalidated Gene Panel Tests for Cancer Links

An Urgent Need for Validating and Characterizing Antibodies

Genetic Technologies Supports Research Findings: Clinical Validation Needed for Gene-Panel Sequencing Associated with Hereditary Breast Cancer Risk

Breast Cancer: Predicting Individual Risk

Medical Scientists Call for Standard Method for Validating Antibodies Used in Research and Clinical Laboratory Diagnostics