Renal cell carcinomas (RCCs) are the most common type of primary renal malignancy, with the clear cell (ccRCC) subtype representing the majority of cases.1,2 Unfortunately, by the time patients are diagnosed with ccRCC, they are at an advanced stage with limited treatment options and increased risk of metastases.3 RCC can be challenging to treat, as there are limited chemotherapy options and there is typically low response to radiation therapy. Radical or partial nephrectomy are surgical options, however, the decision to proceed with surgery is complex and must take the patient’s overall prognosis into account. In addition, determination of a patient’s prognosis can be challenging, as there are multiple factors to consider including the presence of hypercalcemia.

Hypercalcemia represents a common paraneoplastic syndrome encountered in RCC; up to 20% of patients are found to have hypercalcemia on evaluation.4 Patients with hypercalcemia can present with a multitude of symptoms within multiple organ systems: gastrointestinal (nausea, vomiting, abdominal pain, constipation, anorexia), neurological (headache, anxiety, depression, memory issues), cardiac (arrhythmias), and generalized bone and muscle pain. Hypercalcemia can be caused via several mechanisms in RCC, including increased levels of parathyroid hormone-related peptide (PTHrP) and osteolytic bone metastases.4 The development of hypercalcemia is an important finding to note when evaluating a patient with ccRCC, as it has been shown to lead to a worse prognosis.5 Therefore, there is great interest in further evaluating the link between hypercalcemia and prognosis in ccRCC by researching the genes that influence calcium levels and their utility as prognostic biomarkers.

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Recently, Ha and colleagues published their analysis of the potential role of several calcium-sensing genes — including DYSF, GPRC6a, and CaSR — as prognostic biomarkers. The authors primarily focused on DYSF expression within the paper, as the GPRC6a and CaSR genes were not found to have any association with survival. The GPRC6a and CaSR data were not included in the manuscript.

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The DYSF gene encodes the dysferlin protein, which is typically found in skeletal muscles. Dysferlin increases membrane repair within muscle cells by promoting the secretion of injury-triggered acid sphingomyelinase.6 Most of the research involving dysferlin is in musculoskeletal disorders, as its exact role within the kidney has not yet been fully elucidated. There is some research to support that decreased dysferlin expression can lead to increased glomerular permeability and eventual proteinuria and potential development of other nephropathies.7 In addition to its primary role within the cell membrane, dysferlin has also been implicated in the innate immune system by promoting phagocytosis and activation of neutrophils and monocytes.4