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Genetic Testing Challenges in Oncology: VHL Variant in Atypical Patient Raises Management Questions

genetic testing

Precision Oncology News and My Gene Counsel have partnered to produce the "Genetic Testing Challenges in Oncology" series to highlight real-world issues that genetics experts and medical professionals are encountering as genetic tests are increasingly used in cancer care. Experts submit anonymized case reports to My Gene Counsel, and based on the details in these reports, Precision Oncology News writes a feature that describes the case history, challenges encountered by professionals in dealing with the case, and strategies they used in response to challenges or errors. The features also include a discussion with My Gene Counsel genetic counseling experts on better approaches that could be considered if similar cases are encountered in the future. In publishing this series, our aim is to educate experts in the field and foster discussion. If you would like to submit a case report, please email [email protected].

What happened?

A young woman went to see her gynecologist and shared during the visit that her paternal grandmother, who is still alive, had early-onset breast cancer. Upon hearing this family history, the gynecologist ordered a multi-gene panel for this 30-year-old woman to gauge her inherited risk for cancer. The test results came back positive for a pathogenic variant in the VHL gene. This finding was not consistent with her personal or family history.

How was this case solved?

Von Hippel-Lindau syndrome (VHL) is a hereditary condition affecting 1 in 30,000 individuals. Hemangioblastomas, which are tumors in the blood vessels of the brain, spinal cord, and retina, occur in up to 72 percent, 50 percent, and 60 percent of VHL patients, respectively. Patients can also develop malignant tumors in their kidneys, pancreas, and adrenal glands, as well as cysts in these and other organs.

Nearly all patients diagnosed with this condition will have a pathogenic variant in the eponymous VHL gene. Most patients inherit the variant from one of their parents, though around 10 percent of patients don't have a family history of VHL-associated tumors and are diagnosed with the condition due to a de novo pathogenic variant. In the case of this patient, it was unclear if she had an inherited or de novo pathogenic VHL variant.

The VHL Alliance recommends frequently screening of patients who have a VHL diagnosis but aren't yet displaying symptoms. Upon diagnosis, the VHLA recommends patients undergo various physical and eye exams every six to 12 months and MRI scans to look for hemangioblastomas every two years.

After seeing the test results in the 30-year-old woman, the gynecologist referred her to a geneticist familiar with VHL. At the geneticist's recommendation, the patient is receiving intensive imaging and biochemical testing to screen for VHL-associated tumors and symptoms.

Why is this case concerning?

"We thought we knew what VHL looked like until we started testing random people out of context," said Ellen Matloff, a certified genetic counselor and president and CEO of the digital health firm My Gene Counsel. "This case shows the complexity of doing population screening using widely available gene panels, where you're not even testing the right person in the family."

In a typical case when testing is ordered based on personal or family history of cancer and a pathogenic VHL variant is found, the chance of that patient having a tumor is "remarkably high," even though the patient may not have any symptoms yet, Matloff said. "VHL is a very tough syndrome as we know it," she added.

She recalled one of her first patients as a genetic counselor was also a 30-year-old woman with a pathogenic VHL variant. But unlike the woman in this case, Matloff's patient had a family history of VHL, and based on this, Matloff recommended a battery of screening tests and told the patient there was a high likelihood that the workup would find at least one tumor. "I wanted to prepare her," Matloff said. "She was diagnosed with three tumors, and she was totally asymptomatic."

This current case is concerning because a woman was tested for abnormalities in a large number of cancer-risk genes without personal or family history to support such testing. If the patient was concerned about her cancer risk because her grandmother had breast cancer at a young age, then that living relative would have been the most appropriate person to test first for an inherited cancer risk variant.

But when tests are offered to patients whose personal or family history doesn't match the typical profile of a someone with an inherited cancer syndrome and that test comes back positive for a pathogenic variant, it challenges the present understanding of the condition and creates uncertainty about how to manage the patient. "Testing that affected relative first would have been most scientifically and medically effective and could have potentially changed the trajectory of this now-challenging case," Matloff said.

Key takeaways_VHL unmatched family history

What could have been done differently?

In the absence of a personal or family history of VHL-associated tumors, it's unclear if this patient would necessarily benefit from frequent screening, which will be invasive, costly, and stressful. The patient in this case is on a path to being managed as if she's at risk for VHL-related tumors and undergoing frequent screening, as suggested by current guidelines. But additional screening brings with it a host of downstream considerations. For example, if one of those multi-thousand-dollar whole-body imaging scans finds a nodule in her lung, should doctors biopsy that and evaluate it for cancer? Should they subject an otherwise healthy person to an invasive biopsy, given the risks of infection and other complications associated with it? Would her health insurance company pay for the imaging and additional follow-on procedures?

"This patient is going to also have to take time off work for this screening. She might need to get childcare or eldercare, pay for parking and travel, not to mention she may experience scan-xiety about getting all these additional tests," Matloff said. "It becomes this diagnostic odyssey that she's going to have to repeat yearly, if we treat her like a typical VHL patient."

Even though this 30-year-old woman has already been tested and knows she has a pathogenic VHL variant, Matloff would gather a bit more information about the variant before putting her on an aggressive screening schedule. "If this were my patient, I would offer to test the grandmother, and if she were negative, I would suggest testing both parents, just to get a sense of the penetrance of the VHL variant in this family."

Not all pathogenic variants confer the same level of cancer risk and knowing whether a variant is inherited or de novo is important to understanding its association with disease. "A de novo variant could have explained why there was an absence of a VHL-like family history," Matloff explained. "But if this mutation had been found in her paternal grandmother, then her father, and then the father's siblings … and no one had a VHL-related tumor, it would give some sense of the penetrance of this variant in this family as opposed to in a traditional VHL family."   

Ultimately, in this case, a very detailed family history could have helped to determine the best course of surveillance for this patient. "On both sides of the family, knowing if relatives had any cancers or other findings associated with VHL, and at what age, can be helpful," Matloff said. "But 'helpful' is the key word here. It would be helpful, not conclusive."