- With the advent of panel testing, a more complete genetic evaluation can be performed at once, often at a similar cost to testing for a single syndrome.
- Next-generation sequencing, also referred to as massively parallel sequencing, involves thousands to millions of simultaneous polymerase chain reactions sequencing numerous small fragments from multiple genes. This is followed by an alignment of all short DNA segments to establish the full sequence through a digital readout.
- Multigene panel testing is likely to change clinical management for substantially more patients.
- As technology and science continue to advance, we can expect more opportunities to personalize care for patients and families in a cost-effective, time-efficient manner.
The past few years have seen tremendous growth in the use of multigene panel tests to evaluate patients at risk for hereditary cancer syndromes. This paradigm shift in clinical practice occurred for a number of reasons. Studies demonstrating improved outcomes (Domchek et al., 2010; Jarvinen et al., 2009; Moyer, 2014) confirm the importance of identifying individuals at an increased risk for cancer and offering risk reduction and intensive surveillance options. Increased knowledge about the genetic causes of cancer and the elucidation of concepts such as DNA repair pathways resulted in a greater understanding of the multiple genes that contribute to cancer risk. Technological advances enable laboratories to test multiple genes simultaneously with more efficiency than single-gene testing. Practically speaking, when a number of syndromes and potential genetic causes are on the list of differential diagnoses, it is time and cost prohibitive to test them individually. With the advent of panel testing, a more complete evaluation can be performed at a similar cost as genetic testing for a single hereditary syndrome. Because multiple genes contribute to cancer risk and there is significant overlap in the presentation of several hereditary cancer syndromes, a patient’s personal and family history often is compatible with several possible syndromes. Moreover, patients may not report a history that indicates a particular syndrome because of factors such as small family size, incomplete and age-related penetrance, and lack of family cohesiveness. Panel testing is particularly helpful in cancer genetics because it ensures a more complete assessment for syndromes associated with an overlapping pattern of cancers.
Saam et al. (2015) demonstrated a substantial phenotypic overlap between the two most common hereditary cancer syndromes, hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS or hereditary nonpolyposis colorectal cancer syndrome). They found that 7% of patients tested for HBOC also met testing criteria for LS, and almost 30% of patients tested for LS also met testing criteria for HBOC (Saam et al., 2015). As new data are published, professional societies such as the National Comprehensive Cancer Network (NCCN) provide updated management guidelines for additional gene mutations. For example, recent NCCN Guidelines® added recommendations for breast magnetic resonance imaging screening for carriers of PALB2, CHEK2, ATM, or CDH1 mutations and risk-reducing salpingo-oophorectomy for carriers of BRIP1, RAD51C, or RAD51D mutations based on current evidence of associated cancer risks (NCCN, 2016).
Historically, the gold standard for genetic testing was gene sequencing using the Sanger method, which involves sequencing all exons in a single gene with separate polymerase chain reactions (PCRs). Next-generation sequencing (NGS), also referred to as massively parallel sequencing, involves thousands to millions of simultaneous PCRs sequencing numerous small fragments of multiple genes. This is followed by an alignment of all short DNA segments, establishing the full sequence through a digital readout. This improved efficiency translates into a less expensive method of sequencing. However, clinically significant variants (mutations) must be found within massive amounts of data, and assays must be optimized to ensure that each and every relevant base pair is read accurately. The term “depth of coverage” refers to the number of times any particular base pair is read.
To demonstrate the equivalent accuracy of an NGS test compared to Sanger sequencing, a head-to-head validation study as performed by Judkins et al. (2015) is necessary. Although the cost of sequencing base pairs is cheaper with NGS, more genes sequenced lead to more genetic variants detected, and additional laboratory investments must be made for accurate variant interpretation. Recent literature highlights inconsistencies in variant classifications among testing labs (Thompson et al., 2014; Vail et al., 2015). This is a concern for providers because recommended medical management is frequently determined by genetic test results. To address laboratory inconsistencies and the potential for patient harm, the U.S. Food and Drug Administration stated its intention to regulate laboratory developed tests (U.S. Department of Health and Human Services, 2014).When a panel approach is used for hereditary cancer testing, more high-risk patients are identified compared to testing for a single syndrome.
When a panel approach is used for hereditary cancer testing, more high-risk patients are identified compared to testing for a single syndrome. In a study of patients with breast cancer referred for BRCA1 and BRCA2 mutation testing, Tung et al. (2015) found a 9% positive mutation detection rate in BRCA1 and BRCA2, but a 14% positive mutation detection rate when patients were tested with a 25-gene panel (Tung et al., 2015). In a study of patients with suspected LS, Yurgelun et al. (2015) identified 9% with LS mutations, but 15% tested positive for gene mutations using an expanded 25-gene panel.
When positive results are found in genes with established medical management guidelines, there is potential to improve clinical management. Desmond et al. (2015) reported that multigene panel testing yielded findings likely to change the clinical management for substantially more patients than BRCA1 and BRCA2 testing alone. An interim analysis of 332 patients tested with a multigene panel suggested no increase in distress with 81% of patients wanting all of their genetic test results and 87% expressing no regrets when learning their results (Kurian et al., 2015).
Since 2014, the NCCN Guideline for Hereditary Breast and Ovarian Cancer testing algorithm includes the option of first-line testing using a multigene panel as an alternative to testing for BRCA1 and BRCA2 mutations alone (NCCN, 2016). With the widespread provider use of panel testing for hereditary cancer and the inclusion of panel testing in the NCCN Guidelines, multigene panel tests are being evaluated for inclusion in coverage policies (Balliet, 2015).
It is an exciting time in cancer genetics and oncology nursing. Tremendous advancements have been made in technology and the detection and interpretation of genetic variants, improving the identification of at-risk patients and tailoring treatment options for those already affected. As technology and science continue to advance, we can expect more opportunities to personalize care for patients and their families in a cost-effective, time-efficient manner.
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Desmond, A., Kurian, A.W., Gabree, M., Mills, M.A., Anderson, M.J., Kobayashi, Y., . . . Ellisen, L.W. (2015). Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncology, 1, 943-951. Retrieved from http://oncology.jamanetwork.com/article.aspx?articleid=2425836
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