Pan-Cancer Genetic Testing Provides Important Information for Identifying and Treating At-Risk Populations

Henry T. Lynch, MD

Henry T. Lynch, MD

BRCA1/BRCA2

The National Comprehensive Cancer Network (NCCN) guidelines support genetic testing in individuals who are genetically predisposed to cancer. These include patients with a family history of hereditary breast and ovarian cancer (HBOC), most frequently characterized bymutations, and patients with Lynch syndrome (LS), which is characterized by mutations in the DNA mismatch repair (MMR) genes.^1,2Although such testing may help identify patients with a clear genetic predisposition for cancer, it does not always address the potential for overlap among different hereditary cancer syndromes.

BRCA1/BRCA2

Pan-cancer multigene panels include genes that are expressed across a variety of cancer types, and offer the possibility of identifying potentially deleterious genes in patients who might not otherwise be tested.^3,4For example, an individual with a family history of breast cancer (who would qualify for genetic testing formutation) might also have a mutation in one or more of the LS genes, which would generally not be evaluated.

FIGURE. Examples of LS-mutation—positive patients who do not meet NCCN LS testing criteria.³

BRCA2indicates breast cancer gene 2; LS, Lynch syndrome, NCCN, National Comprehensive Cancer Network.

PMS2

,

MSH6

PMS2, MSH6

MLH1, MSH2

Recent presentations illustrate a potential benefit of pan-cancer testing in individuals who are already at risk for one type of hereditary cancer. In one study presented at the 2014 Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC) Conference, in 28 patients with no family history of LS-associated cancers (ie, colon or endometrial cancer), 36% (n = 10 patients) had a mutation in the LS geneand another 36% had a mutation in.³Notably, four patients had a mutation in two different genes (Patient A,Figure). The findings illustrate examples of LS-mutation—positive patients who would not otherwise meet the NCCN testing criteria for LS (Figure).³This may be particularly true for individuals with mutations in the less-penetrant LS genes (eg,), whose associated cancer risks are lower than those of other LS genes (eg,).³

ATM, BARD1, NBN, PALB2

BRCA1/BRCA2

⁴

Another work, presented at the 2014 National Society of Genetic Counselors’ (NSGC) 33rd Annual Education Conference, compared mutation detection using cancer-specific testing with a pan-cancer approach. In the study, 93 mutations were detected among patients who met the criteria for LS testing alone.⁴While most of these mutations (77.4%) were found in genes known to be associated with colon, endometrial, ovarian, or gastric cancers, a minority (16.1%) were found in genes with no such association (eg,), and another 6.5% were found in thegenes.⁴Notably, another 36 mutations were found in patients who did not meet NCCN testing criteria for either LS or HBOC. Collectively, the findings illustrate the potential to identify unexpected mutations with pan-cancer testing, whereas a portion of clinically actionable mutations may in fact be missed using a disease-specific approach.

Regarding these data, Elena M. Stoffel, MD, MPH, assistant professor, department of internal medicine, University of Michigan, stated, “What we are seeing here is the potential for overlap in the clinical spectra of different hereditary cancer syndromes. I think the two examples (seeFigure), which were individuals with breast cancer histories who had mutations in LS genes, were really important, because that tells us that the genetic mechanisms by which cancers develop can be shared among different cancer types. Just because one syndrome is usually associated with colon cancer and endometrial cancer does not mean that it might not be associated with an increased risk of breast cancer in a different family.” She explained that while the individuals in the example would have been encouraged to do genetic testing, they would only have been encouraged to do so for HBOC, and as such, the LS gene mutations would have been missed.

BRCA1

BRCA2

Stoffel pointed out that some insurers have argued against the use of multigene panel testing on the premise that it is appropriate to test only for those genes that would be most suspect, such that, in a family in which there was only breast cancer you should only order genetic testing forand.

“So what these studies show us is that if you test for only two genes, you could be missing mutations in other genes that are also associated with very high cancer risk, but that are typically associated with a different clinical spectrum. I think the premise is that there can be overlap in the clinical spectra of different hereditary cancer syndromes, so that they are not quite as distinct from each other as we have historically believed,” Stoffel said.

“Data such as these are helpful because they prove to insurers that there is value in testing for multiple genes, especially when the differential diagnosis is broad,” she said.

BRCA

Stoffel also alluded to the ongoing debate among insurers and clinicians about the clinical utility of testing for mutations in genes that have less clearly defined cancer risks. “An argument could be made that, for the genes associated with very well-defined cancer risks, and well-defined hereditary cancer syndromes, like the LS genes, thegenes—for those genes, even if you find an alteration in someone in whom you did not expect, that’s still very helpful, because there are clear guidelines for how those patients should be managed.” By comparison, she noted, “There are other genes included on these multigene panels that have less well-defined cancer risks, if you found an alteration in one of those genes, it’s not clear how that should impact medical management.”

“The more genes you test for, the more likely you are to find a variant of uncertain significance, which then could lead to unnecessary testing,” Stoffel cautioned. Initiatives such as PROMPT, a study cosponsored by Dana Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and the University of Pennsylvania, are attempting to collect information on the frequency of incidental findings and variants of uncertain clinical significance, to glean information about associated cancer risks.

Henry T. Lynch, MD, pioneered work on the hereditary basis of LS and HBOC cancers in the 1960s and 1970s and is chairman of preventive medicine and public health, professor of medicine, and director of Creighton University’s Hereditary Cancer Center in Omaha, Nebraska. He and genetic counselor Carrie Snyder, MSN, RN, at his institution recognize the emerging use of multigene hereditary cancer panels to improve the detection of deleterious mutations over single-syndrome testing practices during the past several years. “There is increasing significance in detecting mutations in some of the lower-penetrant MMR genes, inclusive

MSH6

PMS2,

MLH1, MSH2

EPCAM

ofandin those individuals who lack a history of colon or endometrial cancers,” Lynch said. “The rationale for this emanates from the direction in which genomics has been emerging at an incredibly rapid pace. Low-penetrant genes, for example, may be very important as cancer drivers, in concert with more highly penetrant genes, such as those in the LS, namely, mismatch repair germline mutations in, and.”

Lynch and Snyder also recognize a benefit of obtaining additional genomic information from at-risk populations. “We know from experience that so-called high-penetrant genes fail to explain all of the hereditary variants that go on to [form] cancer. The panel will be important in that it will attempt to provide additional genomic information, which could aid again in diagnosis and management,” they said.

Lynch and Snyder emphasized the importance of careful interpretation of findings from pan-cancer testing. “This is a fast-moving area, and it does have problems with the very interpretation of the findings, [which] will require highly skilled knowledge of the physician and/or genetic counselor. Multigene hereditary cancer panels will improve our ability to identify patients with LS and families who would otherwise have been missed because they did not meet the standard criteria for testing. Panel testing may very well lead to new criteria for testing and identifying LS families,” Lynch concluded.

References

World J Gastroenterol.

1. Esteban-Jurado C, Garre P, Vila M, et al. New genes emerging for colorectal cancer predisposition.2014; 20(8):1961-1971.

Ann Oncol.

1. Lynch HT, Snyder C, Casey MJ. Hereditary ovarian and breast cancer: what have we learned?2013;24(suppl 8):viii83-viii95.
2. Kaushik P, Evans B, Moyes K, Landon M, Saam J, Wenstrup R. Clinical presentations of MMR mutation positive patients with no personal or family history of colon or endometrial cancer. Presented at CGA, September 15, 2014.
3. Kaushik P, Moyes K, Evans B, Landon M, Wenstrup R. Comparison of mutation detection in cancer-specific versus pan-cancer approaches to an at-risk population. Presented at NSGC 33rd Annual Education Conference. September 17-20, 2014.