Germline VHL Mutation Discovered in Association with EGFR-Positive Lung Cancer and Metachronous Hepatocellular Carcinoma: A Case Report.

VHL is a tumor suppressor gene located on chromosome 3 that is classically associated with tumors of the eye and CNS, renal cell carcinoma, and pheochromocytoma. We describe what appears to be the first report of an association between a germline VHL mutation and non-small cell lung cancer and metachronous hepatocellular carcinoma (HCC). Our case involves a 63-year-old nonsmoking male who was initially diagnosed with EGFR mutation-positive metastatic nonsquamous, non-small cell lung adenocarcinoma, who subsequently developed HCC and squamous cell carcinoma of the femur despite first-line treatment with EGFR-blocking osimertinib. Caris molecular profiling unexpectedly identified a shared underlying VHL mutation in all 3 lesions. Genetic mapping through a machine learning-based tool called Genomic Prevalence Score (GPSai) helped determine that the femur tumor was a metastatic lesion as opposed to a separate primary and that the HCC was a distinct primary malignancy. We not only highlight the association between these tumors and a VHL mutation but also emphasize the value of next-generation sequencing and a molecular disease classifier in a patient with multiple primaries, how it helps guide therapy, and its value in guiding future studies.