Introduction:

The use of genomic and molecular classification of renal cell carcinoma has led to an increasing

appreciation of tumor biology and as well as characterization of previously unclassified subset of tumors.

The importance of identifying specific drivers of tumorigenesis has wide-ranging implications for clinical

care including risk stratification and treatment decision in the localized and systemic setting.  We present

a series of previously unclassified renal cell carcinoma patients that are primarily driven by a

mutation in the NF2 gene.

Methods:

We queried the MSK Clinical Sequencing Cohort, a database containing 90,744 patients who were sequenced using MSK-IMPACT, a DNA sequencing platform that captures 468 whole exome cancer genes.  We found 48 patients with an NF2 mutation who had tumors designated as “unclassified” based on their pathology report.  We also identified patients in our prospectively maintained surgical registry if they had undergone extirpative kidney surgery.

Results:

Our cohort had a median age at presentation of 63.5 years with a healthy body habitus (BMI 25.2).  Mass size was small at 4.70cm, however 32 out of 48 patients (66.67%) had metastatic disease.  13 patients underwent surgical resection of primary tumor and 10 patients  (76.92%) had evidence of non-localized disease on pathology.  The median overall survival for our cohort of patients was 18.35 months compared to 45.83 months in the cohort of sequenced renal cell carcinoma patients, a high risk population.

            Genomic analysis of sequenced tumors demonstrated that the NF2 mutation was noted to be a primary driver of tumorigenesis (87.50%), with a high frequency noted to be a clonal event (72.92%), and that the mutation  was biallelic (81.25%), with a high ccf score (0.97), all suggestive that NF2 is the main driver of tumorgenesis in these patients.  Additionally, a high MSI score which may suggest responsiveness to immunotherapy.

Conclusion:

 We provide clinical and genomic characterization of a group of patients who were previously found to be unclassified renal cell carcinoma, however now found to have NF2 mutation as the putative driver of tumorigenesis. NF2 mutated renal cell carcinoma is an aggressive histology that undergoes early metastatic spread at small tumor size and is lethal. Greater awareness of this tumor histology can lead to early identification and can help guide treatment decisions, including surgical approach as well as tailored systemic therapy if warranted.

Funding: No Funding