April 2013 VOL 4, NO 2

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In the News

2013 NCCN Guidelines Mention Gene Panels

Cristi Radford, MS, CGC 

In March, the National Comprehensive Cancer Network (NCCN) guidelines for genetic/familial high-risk assessment for breast and ovarian cancers were updated.1 Among the updates is a section on “gene panels.”

Gene panels allow multiple genes to be analyzed simultaneously for mutations, at a cost that is often comparable to testing for a single inherited condition. In the case of cancer risk assessment, gene panels contain genes associated with an increased risk of developing cancer. For example, the panel may be targeted for a particular disease type, such as one containing a multitude of genes that are all associated with a high risk of colon cancer, or it may be targeted for several disease types, such as breast cancer, colon cancer, and ovarian cancer. Further, each laboratory selects which genes are included on their panels; thus, it cannot be assumed that a “colon panel” or a “breast panel” at various laboratories will include the same genes. Genes included on breast/ovarian panels include ATM, BARD1, BRIP, CDH1, CHEK1, CHEK2, MLH1, MSH2, MSH6, MUTYH, MRE11A, NPN, PALB2, PMS2, PTEN, RAD50, RAD51B, RAD51C, RAD51D, STK11, and TP53.1

One premise behind cancer panels is reflected in the statement “individually rare, collectively common.” This concept is best illustrated by a study conducted by Walsh and colleagues,2 in which 360 women with primary ovarian, peritoneal, or fallopian tube carcinoma were screened for mutations in 21 genes. Participants were not selected on the basis of age or family history. Approximately 1 in 4 women (82/360, 24%) were found to carry a germline, loss-of-function mutation. Mutations in BRCA1/2 accounted for 18% of the mutations, while mutations in 10 other genes accounted for the remaining 6%. Thus, although the non-BRCA mutations could be considered individually rare, ranging from 0.03% to 1.4%, the chance of carrying a mutation became more common when they were analyzed collectively.

Additionally, gene panels are also providing more insight into the phenotypes of hereditary cancer syndromes. Gene panels allow a clinician to cast a wider net and analyze genes that may have been low on their differentials list or not on it at all. This was also demonstrated in the Walsh study, where of the 3 individuals found to have a mutation in TP53, which is associated with Li-Fraumeni syndrome, none actually met the testing criteria for Li-Fraumeni syndrome. Additionally, whereas only 2 individuals were found to have germline mutations associated with Lynch syndrome and both mutations were in MSH6, neither of these individuals had a family history of Lynch syndrome. Furthermore, if genetic testing had relied on an age less than 60, 30 individuals (>35%) with germline mutations would have been missed.

To further understand the applications of gene panels, consider Marie’s family history. Marie reports being recently diagnosed with invasive lobular breast cancer at age 34. She has one brother, aged 38, who has a daughter, aged 12. Her mother, aged 67, has a large family with no reported cancers. Her father, aged 68, has no siblings. His father (Marie’s paternal grandfather) died at age 85 from complications of a stroke. His mother (Marie’s paternal grandmother) died from cancer at age 44; the type of cancer is unknown, but the family believes it was “stomach or abdominal.” Additionally, Marie has a history of a thyroid nodule and reports a history of skin biopsies that “weren’t melanoma.” Based on reported information, your differentials may include BRCA1/2, P53, and CDH1.1 Additionally, depending on the skin findings and/or your degree of suspicion, you may also be interested in testing for PTEN and moderate penetrance breast cancer genes. Prior to the development of next-generation sequencing technologies, testing all of these genes would most likely have been cost and time prohibitive. However, with the advent of gene panels, a clinician now has the option of testing for BRCA1/2 mutations and then proceeding with a gene panel for other breast cancer genes. Currently, due to restrictive patents, BRCA1/2 is not clinically available on a gene panel.

As a result of the new technology, researchers and clinicians are beginning to see a shift in how inherited cancer is investigated and diagnosed. Gene panels provide the following benefits: (1) simultaneously testing multiple genes can be more time and cost-effective; (2) when clinical criteria are uncertain or multiple differentials are present, gene panels can aid in clinical diagnosis; and (3) as many high-risk patients are negative for BRCA1/2 mutations, gene panels provide an expanded method of screening for less common mutations. However, as with any new technology, there are also limitations, including a higher chance of obtaining a variant of uncertain significance (VUS) result or finding a mutation in a gene with undefined cancer risks and/or medical management guidelines.

Listed below are a number of issues a provider should consider when developing a genetic testing strategy:

Laboratory and Gene Analysis Considerations

  • Does the panel of interest contain all of the genes in your differential diagnosis?
  • What is the turnaround time (TAT) for the test?
    • If you were to order an analysis of each gene individually rather than as part of a panel, would the TAT be longer or shorter?
  • What is the out-of-pocket cost for the patient?
    • If you were to order an analysis of each gene individually rather than as part of a panel, would the expense be more or less?
  • Can you find out the cost to your patient before the test is performed? Does the laboratory stand by its quote?
  • What findings are reported (eg, polymorphisms, mutations, and/or variants of uncertain significance)? Are all findings confirmed and how?
  • How often is the result “VUS” reported? What is the laboratory’s experience interpreting VUS results? How often do they reclassify VUS results? What is the notification process? Are their internal studies available to your patient to help reclassify a VUS? Does the laboratory provide you with resources to help you determine the functional significance of the VUS?
  • What regions of the genes are analyzed? Is rearrangement analysis performed?

Counseling Considerations

  • As multiple genes are analyzed at the same time, what is your pre- and posttest genetic counseling strategy?
  • How would the test result impact your patient’s medical management?
  • How crucial is TAT in medical management decision- making for the patient?
  • Do you know of available research studies/cancer registries to help further delineate the risks associated with various genes?
  • The level of risk conveyed with a particular gene may not be well defined and, therefore, guidelines on risk management may not be available. How would you counsel an individual who receives a positive, negative, or VUS result? How would you counsel his or her family members?
  • Does the mutation track with the cancers in the family?

Take-Home Messages

  • Gene panels allow a clinician to cast a wider net. This can be useful when syndromes have overlapping phenotypes, family history is uncertain, or there are multiple genes in your differential diagnosis.
  • Although gene panels appear promising, limitations include a higher chance of receiving a VUS result and the possibility of finding a mutation in a gene with cancer risks that aren’t well defined.

References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2013. http://www.nccn.org/professionals/physician_gls/recently_updated.asp. Accessed March 12, 2013.
2. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(44):18032-18037.

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