How Far Do We Go With Genetic Evaluation? Gene, Panel, and Tumor Testing

Abstract

OVERVIEW The traditional model by which an individual was identified as harboring a hereditary susceptibility to cancer was to test for a mutation in a single gene or a finite number of genes associated with a particular syndrome (e.g., BRCA1 and BRCA2 for hereditary breast and ovarian cancer or mismatch repair genes for Lynch syndrome). The decision regarding which gene or genes to test for was based on a review of the patient’s personal medical history and their family history. With advances in next-generation DNA sequencing technology, offering simultaneous testing for multiple genes associated with a hereditary susceptibility to cancer is now possible. These panels typically include high-penetrance genes, but they also often include moderate- and low-penetrance genes. A number of the genes included in these panels have not been fully characterized either in terms of their cancer risks or their management options. Another way some patients are unexpectedly identified as carrying a germline mutation in a cancer susceptibility gene is at the time they undergo molecular profiling of their tumor, which typically has been carried out to guide treatment choices for their cancer. This article first focuses on the issues that need to be considered when deciding between recommending more targeted testing of a single or a small number of genes associated with a particular syndrome (single/limited gene testing) versus performing a multigene panel. This article also reviews the issues regarding germline risk that occur within the setting of ordering molecular profiling of tumors.

Implications of CRISPR-Based Germline Engineering for Cancer Survivors

“…38 This demonstration must meet the requirements of the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) drawn up by the US Centers for Disease Control and Prevention and used by many health care systems, as well as the American Society of Clinical Oncology (ASCO). 39 EGAPP establishes four evaluation criteria that could apply to CRISPR: analytic validity, clinical validity, clinical utility, and ethical, legal, and social issues. To some extent, the clinical utility of CRISPR-based germline engineering could be compared with artificial reproductive technologies currently used to prevent the transmission of cancer predispositions in families at risk.…”

Patients with pathogenic variants for breast cancer other than BRCA1 and BRCA2: qualitative interviews about health care experiences

“…In addition, the advent of direct-to-consumer genetic testing options has increased the likelihood that patients may undergo genetic testing without direct involvement of their physicians. The exact cancer risks of many newly discovered genes are not always known, and some genes appear to convey a moderately increased risk of breast cancer compared with the high risk associated with BRCA1/2 [4, 10, 11]. Although the association of these other genetic variants with a characteristic of increased breast cancer risk may be apparent (even if that level of risk has not been quantified), often it is unclear which other organs may have an increased risk of malignancy [4, 12].…”

Advantages and Some Remaining Challenges in Hereditary Gastrointestinal Cancer Panel Testing

“…Yet, in this process, many families with striking cancer histories did not have a mutation in the gene interrogated. 4 …”

“…Both the New England Journal of Medicine (NEJM) and the American Society of Clinical Oncology (ASCO) released statements agreeing that multiple factors should be used to guide what type of genetic test to order. 3 , 4 Patient specific factors to consider include but are not limited to the clarity of the patient’s personal or familial characteristics or lack thereof, the patient’s preference and tolerance regarding the possibility of ambiguous or incidental findings, the time in which results may be needed to guide surgical decisions and lastly consideration of insurance coverage. 4 , 6 , 7 Panel testing can be beneficial for patients as long as providers and patients are aware of its limitations.…”