SGO Clinical Practice Statement: Next Generation Cancer Gene Panels Versus Gene by Gene Testing (SGO, March 2014)

The advent of next generation sequencing has led to an era of inexpensive, high throughput DNA sequencing, which is having a major impact on both cancer research and clinical care. Cancer gene panels use next generation sequencing technology to assess inherited mutations in multiple genes simultaneously and are currently commercially available. The unanimous decision by the U.S. Supreme Court in June, 2013 to invalidate human gene patents led to a rapid increase in vendors and expansion of clinical options for genetic testing. Current cancer gene panels vary in size from just two genes (i.e., BRCA1 and BRCA2) to larger panels that include more than 50 genes.

Until recently, most testing for cancer genetic risk involved traditional exon-by-exon Sanger sequencing of each candidate gene. In contrast, next generation sequencing allows parallel sequencing of millions of short pieces of DNA simultaneously. Prior to next generation sequencing, genetic testing usually started with the most commonly involved genes and proceeded to less likely genes only when clinical suspicion was very high. However, cancer panels allow testing of all genes in parallel without substantially increasing the cost, leading to a different clinical algorithm in which all known contributing genes can be assayed at first evaluation.

Approximately 15% of all ovarian cancers are attributable to a BRCA1 or BRCA2 mutation. An additional 5-6% of ovarian cancers have gene mutations in other genes including the Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2), and BRIP1, RAD51D, RAD51C, PALB2, BARD1, and TP53 [1-8]. Cancer gene panels that include some or all of these genes are commercially available. However, health care providers need to consider the limitations as well as the advantages of the cancer gene panels.

Advantages of cancer gene panels include decreased cost and improved efficiency of cancer genetic testing by decreasing the time involved, number of patient visits, and number of tests sent. A negative genetic test is more reassuring at eliminating the likelihood of inherited risk when all known genes for that phenotype have been assayed.

The major drawback of cancer gene panels is the increased complexity of results. For many genes, clear risk reduction strategies for mutation carriers are not established. A major concern is the increased likelihood of identifying results of uncertain clinical significance. Uncertain results occur when a rare variant is identified whose impact on protein function is unknown. Uncertainty can also arise from the identification of a clearly deleterious mutation in a gene of uncertain clinical significance. The more genes that are tested, the greater the chances are of such uncertain results. Clinical management should not be dictated by these uncertain variants; rather, family history should guide recommendations in these cases. However, clinicians may misinterpret uncertain results, treating patients as if a deleterious mutation is present, leading to unnecessary interventions. Given the increased variety of testing options and potential complexity of genetic results with cancer gene panels, genetic counselors or knowledgeable medical professionals should carefully discuss the pros and cons with patients.

References

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[2]        Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum J, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 2011;43(9):879-82.

[3]        Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 2010;42(5):410-4.

[4]        Pennington KP, Swisher EM. Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol 2012;124(2):347-53.

[5]        Rafnar T, Gudbjartsson DF, Sulem P, Jonasdottir A, Sigurdsson, Jonasdottir A, et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet 2011.

[6]        Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci USA 2011;108:18032-18037.

[7]        Casadei S, Norquist BM, Walsh T, Stray S, Mandell JB, Lee MK, et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res 2011;71(6):2222-2229.

[8]        Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 1995;378(6559):789-792.