As a genetic counselor at Cone Cancer Center for the last twelve years, Karen Powell, CGC, enjoys helping patients understand their cancer risks. Hereditary cancer testing may provide important and possibly life-saving information for not only the patient but their family members as well.
Many patients present with a family history of cancer, and genetic testing confirms the suspected hereditary cause. For example, a pathogenic variant or mutation in the BRCA1, BRCA2, ATM, or CHEK2 genes may be the explanation for a family with several instances of breast and prostate cancer, or Lynch syndrome may explain a family's history of colorectal and gynecologic cancers, etc.
However, some patients have a compelling personal or family history, but genetic testing just does not provide the expected answer. In these cases, genetic counselors look at the resources available to them and dig deeper. This was one of those cases for Karen.
Karen saw a young man in her clinic who had been referred because of his striking medical history. He had a diagnosis of polyposis, meaning many colon polyps. His father had been clinically diagnosed with familial adenomatous polyposis (FAP), which means he was diagnosed based on having the corresponding symptoms for this condition, and he had undergone colectomy, meaning removal of the colon.1 Mutations in the APC gene cause FAP; however, the patient's father's APC testing was negative. Because Karen’s patient had a history of around 50 polyps himself, he was also likely affected by FAP, but Karen reports she had “a gut feeling” that he would likely have negative genetic testing, same as his father.
Interestingly, the patient’s paternal uncle had previously been seen at Cone Cancer Clinic and testing identified a single MUTYH mutation, but he did not have an APC mutation. This single MUTYH mutation, a relatively common finding, was an unlikely explanation for his history.2
Karen explained that the patient would be managed as having FAP based on his clinical presentation, but at the same time, they were going to offer genetic testing to determine if they could identify an APC genetic variant that was causing the polyposis.
Genetic testing for this patient was ordered shortly after Ambry began offering +RNAinsight®, which is concurrent DNA and RNA analysis. Karen says, “This was the very first patient we sent for RNA testing, and the feeling was that we would try it out and hope it provided answers.” RNA testing identified a deep intronic APC mutation, which is consistent with a diagnosis of FAP. The patient’s father probably also had this deep intronic mutation, but it had been missed with DNA analysis alone.
Having this additional information allowed the patient’s family to be tested for this mutation so that those with FAP could begin colonoscopy earlier, and when necessary, colectomy, before cancer developed. It could also identify family members who did not need to begin colonoscopies at an early age because they tested negative for the familial APC mutation.
Karen was able to follow up with the patient’s paternal aunt, her daughter, and his grandmother, and referred his two young children to a pediatric cancer program for further analysis. In these discussions with the family, they explained that technology had improved to the point where this particular variant could be identified and that when their family members underwent testing, they had to make sure that the lab that they were choosing utilized this additional RNA technology, because if they did not, they were not going to be able to identify this mutation.
Without paired DNA and RNA testing, a positive result would be missed in approximately 1 in 25 hereditary cancer testing cases.4 Ambry has published on using this technology to uncover missing genetic causes of polyposis in particular.3 But at the time of this case, RNA testing was a new option. Karen remembers, “This was our very first RNA case. RNA provided the information to solve the mystery for people in this family who had developed colon polyps and gave us better insight into recommendations for their preventive care and management.”
As a result of this experience, Cone started ordering RNA testing for more patients, especially those who were returning for repeat testing or for family members who had tested negative to ensure nothing was missed. Karen shared, “We feel RNA is an important tool to provide answers to more patients.”
1. Yen T, Stanich PP, Axell L, et al. APC-Associated Polyposis Conditions. 1998 Dec 18 [Updated 2022 May 12]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1345/
2. Nielsen M, Infante E, Brand R. MUTYH Polyposis. 2012 Oct 4 [Updated 2021 May 27]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK107219/
3. Colin C. Young et al., Solving Missing Heritability in Patients With Familial Adenomatous Polyposis With DNA-RNA Paired Testing. JCO Precis Oncol 8, e2300404(2024). DOI:10.1200/PO.23.00404
4. Horton C et al. Expanding the reach of paired DNA and RNA sequencing: Results from 450,000 consecutive individuals from a hereditary cancer cohort; (Oral Presentation Session 84 - Strategies to Interpret Germline Variants in Cancer Predispostion Genes). Presented at the Annual Meeting of The American Society of Human Genetics, November 68, 2024, in Denver, CO.
