Genomics in Clinical Practice, Part 1: The Rise of Multiplex Gene Testing for Cancer

Kate M. O'Rourke


July 20, 2016

In This Article

Multiplex Panels in Practice

So, when multiplex gene panels are used in practice, what do they find? A number of recent studies shed light on this question.

In a study of 2079 patients who were clinically referred for multigene panel testing (breast, colon, ovarian, and general cancer panels), 93% had a personal history of cancer or had an adenoma, and between 7% and 10% were positive for at least one pathogenic mutation in the panel.[10] Between 15% and 25% of the individuals tested had a variant of uncertain significance (VUS).

In another study of 1781 consecutive patients with breast cancer who had BRCA1/BRCA2 testing with a 25-gene panel, 9.3% were positive for BRCA1/BRCA2, 4.2% were positive for another gene on the panel, and 42% had at least one VUS.[11] The majority of the other genes found were moderate-penetrance genes, such as CHEK2 (1.6%) and ATM (0.7%). Just less than 1% of patients were found to have the high-penetrance genes PALB2 and TP53. Three patients tested positive for mutations in the Lynch syndrome genes, MSH2 and MSH6.

Investigators at three cancer genetics clinics in California (Stanford University, University of Southern California, and Los Angeles County) are currently conducting the Cancer Genetics Hereditary Cancer Panel Testing study.[12,13] This prospective trial is evaluating the use of a 25-gene panel test (APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53). Individuals in this study had no prior genetic testing and at least a 2.5% probability of carrying one of the mutations on the panel. Patients were surveyed at study entry and then at 3, 6, and 12 months after receiving their results.

In an interim analysis of the first 1001 patients (81% of whom were female), 11.6% tested positive for a pathogenic mutation, 36.5% had a VUS only, and 51.9% tested negative.[12,13] Almost 40% had a personal history of breast cancer history, 16% had a personal history of colon cancer, and 10.3% had a personal history of gynecologic cancer. The population was diverse (40% Hispanic, 12% of Asian ancestry, 4% of African ancestry, 29% Spanish-speaking only, and 35% with high school education or less). Gregory Idos, MD, an assistant professor of clinical medicine in the Division of Gastroenterology and Hepatology at University of Southern California, Los Angeles, reported that the most frequently identified mutations were in BRCA1 (18%), BRCA2 (18%), MUTYH (17%), APC (6%), CHEK2 (6%), and ATM (4%). Roughly 20% of patients had at least one positive result in a mismatch repair gene (MLH1, 6 patients; MSH2, 5 patients; MSH6, 5 patients; and PMS2, 5 patients). The distribution of pathogenic variants found were overwhelmingly led by BRCA1/BRCA2, said Dr Idos, followed by other breast cancer genes, Lynch syndrome genes, mismatch repair genes, and monoallelic pathogenic variants.

When the researchers compared their results with the differential diagnosis done before testing, they found that among persons with a pathogenic variant, 26% of those variants were in an unsuspected gene.[13] The most frequently missed gene was MUTYH monoallelic (12 patients), followed by APCI1307k (4 patients), CHEK2 (4 patients), ATM (3 patients), and a smattering of other genes for which one or two patients were missed. "This [study] suggests a significant contribution of expanded multiplex testing for clinical cancer risk assessment," said Dr Idos.


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