Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein

Von Hippel-Lindau disease (VHL) is an autosomal dominant rare disease that causes the formation of angiogenic tumors. When functional, pVHL acts as an E3 ubiquitin ligase that negatively regulates hypoxia inducible factor (HIF). Genetic mutations that perturb the structure of pVHL result in dysregulation of HIF, causing a wide array of tumor pathologies including retinal angioma, pheochromocytoma, central nervous system hemangioblastoma, and clear cell renal carcinoma. These VHL-related cancers occur throughout the lifetime of the patient, requiring frequent intervention procedures, such as surgery, to remove the tumors. Although VHL is classified as a rare disease (1 in 39,000 to 1 in 91,000 affected) there is a large heterogeneity in genetic mutations listed for observed pathologies. Understanding how these specific mutations correlate with the myriad of observed pathologies for VHL could provide clinicians insight into the potential severity and onset of disease. Using a select set of 285 ClinVar mutations in VHL, we developed a multiparametric scoring algorithm to evaluate the overall clinical severity of missense mutations in pVHL. The mutations were assessed according to eight weighted parameters as a comprehensive evaluation of protein misfolding and malfunction. Higher mutation scores were strongly associated with pathogenicity. Our approach establishes a novel in silico method by which VHL-specific mutations can be assessed for their severity and effect on the biophysical functions of the VHL protein.

SURG-31. SURGICAL OUTCOME ANALYSES ON 244 CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA

BACKGROUND Surgical resection of the central nervous system hemangioblastoma is often challenging, with vascular-rich nature and surrounding critical structures. von Hippel-Lindau (VHL) disease cases make the management more difficult with repeated surgeries required for multiple lesions. Here we investigated the surgical outcome of CNS HGBs on a large cohort to clarify the clinical and radiological parameters pertaining to the surgical success. METHODS Retrospective analysis of consecutive, neurosurgically managed CNS HGB at Mayo Clinic, 1988-2018. RESULTS Total 244 surgeries were performed for 172 patients. Gross total resection (GTR) was achieved in 90.0%, which was lower in cases brainstem lesions (78.3%) and was associated with the tumor, especially solid-portion volume (p=0.017). Intraoperative blood loss correlated with the size of solid portions, and the transfusion was performed in 7.5%. Postoperative complication was observed in 52.2%, including new/worsening neurological deficit in 45.4%, wound complication in 9.1% and systemic complication in 4.0%. Postoperative rehabilitation was introduced in 61.7% of the patients, which was statistically associated with age, non-GTR and tumor location (brainstem and spine) on multivariate analysis (p=0.0031, 0.027 and 0.0066, respectively). Treatment-free survival was longer in VHL (vs sporadic) cases and GTR (vs non-GTR) cases, and multivariate analysis showed GTR was the only factor associated with treatment-free survival (p=0.0015). CONCLUSIONS Surgery for CNS HGBs was shown to be challenging, with abundant intraoperative bleeding and high risk of postoperative complications necessitating rehabilitation. GTR of the lesion is of utmost importance, which increases the chance of long treatment-free survival as well as favorable direct postoperative clinical course.

Algorithmic Assessment of Missense Mutation Severity in the Von-Hippel Lindau Protein

Von Hippel-Lindau disease (VHL) is an autosomal dominant rare disease that causes the formation of angiogenic tumors. When functional, pVHL acts as an E3 ubiquitin ligase that negatively regulates hypoxia inducible factor (HIF). Genetic mutations that perturb the structure of pVHL result in dysregulation of HIF, causing a wide array of tumor pathologies including retinal angioma, pheochromocytoma, central nervous system hemangioblastoma, and clear cell renal carcinoma. These VHL-related cancers occur throughout the lifetime of the patient, requiring frequent intervention procedures, such as surgery, to remove the tumors. Although VHL is classified as a rare disease (1 in 39,000 to 1 in 91,000 affected) there is a large heterogeneity in genetic mutations listed for observed pathologies. Understanding how these specific mutations correlate with the myriad of observed pathologies for VHL could provide clinicians insight into the potential severity and onset of disease. Using a set of 285 ClinVar mutations in VHL, we developed a multiparametric scoring algorithm to evaluate the overall clinical severity of missense mutations in pVHL. The mutations were assessed according to eight weighted parameters as a comprehensive evaluation of protein misfolding and malfunction. Higher mutation scores were strongly associated with pathogenicity. Our approach establishes a novel in silico method by which VHL-specific mutations can be assessed for their severity and effect on the biophysical functions of the VHL protein.

BT-06 CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA; DIFFERENCES IN CLINICAL PICTURE OF SPORADIC CASES AND VON-HIPPEL LINDAU DISEASE IN 184 CASES

INTRODUCTION Central nervous system hemangioblastoma (CNS HGB) is a rare neoplasm, which predominantly arise in the posterior fossa and spinal cord. The etiology is divided into sporadic and von-Hippel Lindau (VHL) disease. The difference in clinical picture of these 2 types of HGB and differentiation of treatment have not been extensively unraveled yet. METHODS Retrospective analysis of consecutive, neurosurgically managed CNS HGB at Mayo Clinic, 1988–2018. RESULTS 117 sporadic and 67 VHL HGBs were treated by Mayo Clinic. No significant difference in sex was observed. Compared with sporadic cases, VHL cases were younger (51.8 vs 36.0 years old, p<0.0001), had more frequent family history (0.0 vs 41.5 %, p<0.0001), and higher frequency of germline alteration (0.0 vs 84.2 %, p<0.0001). Regarding imaging findings, VHL cases had multiple lesions at presentation more frequently (3.4 vs 82.1 %, p<0.0001), it was more common for sporadic lesions to contain cysts (72.2 vs 51.0 %, p=0.0004), the solid portion rate in the entire lesion was larger in VHL lesions (60.2 vs 69.5 %, p=0.02), and the volume was larger in sporadic cases (15.1 vs 6.6 cc, p<0.0001). Regarding treatment, 131 and 123 surgeries were performed for sporadic and VHL cases, respectively, among which the indication of surgery was preventative in 8.4 and 47.3 %, respectively (p<0.0001). VHL cases had higher number of treatments per case in the follow-up (1.3 vs 2.1, p<0.0001). Recurrence-free survival of sporadic cases was significantly longer than that of VHL cases (p=0.007) and overall survival was longer in sporadic cases than VHL, but not significant (p=0.07). CONCLUSION Clinical presentation and tumor appearance on imaging are highly dependent on the etiology. Differences in clinical manifestations require further study, but may reflect contrasting tumor biology that are tied to genetic differences.

RARE-24. GROWTH PATTERN ANALYSES OF HEMANGIOBLASTOMA IN SPORADIC AND VHL CASES

Central nervous system hemangioblastoma (CNS HGB) is a rare neoplasm. Sporadic and von-Hippel Lindau (VHL)-associated forms exist. Predicting tumor growth is difficult, making the indication for intervention challenging. A retrospective analysis of consecutive, neurosurgically managed CNS HGB at Mayo Clinic spanning 1988–2018 was performed to clarify their characteristics. 117 sporadic and 67 VHL HGBs were reviewed. 9 sporadic lesions (8 cases) and 80 VHL lesions (35 cases) had tumor size data at ≥4 follow-up time-points beyond 1 year. The median follow-up was 8.0 years. No statistical difference existed between sporadic and VHL lesions regarding growth speed or growth latency (period of time without growth). Symptomatic lesions showed faster growth than asymptomatic lesions (2.79 vs 0.59 cm3/month, p=0.005). Solid and cystic portions often showed different growth patterns in cases harboring both (66.7%). Cyst growth was faster than solid portions (1.22 vs 1.05cm3/month, p=0.009) and growth latency was longer in the latter (15.2 vs 18.5%, p=0.25). Lesions’ growth were classified as linear (7), exponential (49), cubic (regressed to cubic function curve, 7), saltatory (19) and no-growth (7) patterns. Growth latency often existed in growing lesions (27-out-of-64 linear/exponential/cubic lesions, 57.8%), being average 8.3% of follow-up time. Contrarily, although saltatory lesions grew slower than exponential lesions (p=0.03), their overall growth speed was comparable to linear/cubic lesions (0.67cm3/month), and 9-out-of-19 showed growth surges at their ends. Growth speed at each follow-up roughly depended on the tumor size in cubic regression (R2=0.52). However, whereas total 18/821 time-point lesions showed rapid growth (≥1cm3/m, 2.2%), relatively small lesions (≤2cm3) also occasionally showed rapid growth (5/687, 0.73%). Not all large (>5cm3) lesions grew rapidly (8/62, 12.9%). These results revealed while symptomatic/large/cystic lesions tend to grow more rapidly, HGB behavior is difficult to predict, which stresses the importance of careful follow-up.