Comprehensive Management of Von Hippel-Lindau Disease: Genetic and Oncological Perspectives

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Von Hippel-Lindau disease (VHL) is an inherited disorder that predisposes individuals to specific types of benign tumors, malignant tumors, and cysts in multiple organs, requiring the involvement of genetic counselors and clinicians across the interprofessional team for optimal management.

1. Comprehensive Management of Von Hippel-Lindau Disease: Genetic and Oncological Perspectives Eric Jonasch, MD Professor, Department of Genitourinary Medical Oncology The University of Texas MD Anderson Cancer Center

2. Disclosures C onsultant: Aveo, Eisai, Exelixis, GlaxoSmithKline, Ipsen, Merck, NiKang, Novartis, Takeda, Telix G rants/research support: AbbVie, Aveo, Bristol Myers Squibb, Corvus, Merck, NiKang, Telix i3 Health has mitigated all relevant financial relationships

3. Learning Objectives Recognize the diverse clinical presentations of VHL disease–associated tumors across different organ systems Discuss the capabilities and limitations of current genetic testing techniques for VHL disease Evaluate the latest evidence on novel and emerging therapies for VHL disease–associated tumors Apply expert strategies to clearly communicate complex genetic information to patients and family members during counseling sessions VHL = von Hippel-Lindau disease.

4. Topics Covered I. Genetic underpinnings of VHL disease a. Overview of VHL gene mutations, pathophysiology, and inheritance patterns b. The relationship between genetic mutations and clinical phenotype II. Clinical p resentation and s urveillance s trategies a. Identifying and managing VHL disease–associated tumors b. Recommended screening protocols and early detection strategies III. Advances in genetic t esting for VHL disease a. Current state of genetic testing, including next-generation sequencing b. Case studies illustrating the impact of genetic testing on patient management IV. Treatment of VHL disease–associated t umors: current s tandards and new d ata a. Guideline-recommended treatment options b. Novel and emerging therapies V. Role of genetic c ounseling in the management of VHL disease a. Risk assessment, family testing, and psychosocial support b. Communicating complex genetic information to patients and families CNS = central nervous system.

5. Genetic Underpinnings of VHL Disease Stebbins et al, 1999; Kaelin , 2018. Overview: VHL Gene Mutations, Pathophysiology, and Inheritance Patterns Elongin C (15kDa) a Located on 3p25 213 amino acid protein 30 kDa size Binds to elongin C/B Forms “ VBC complex ”

6. Genetic Underpinnings of VHL Disease (cont.) a Each type of mutation was tested by Fisher’s exact test (2-tailed) for association with VHL types 1 or 2. Microdeletions/insertions ( P =0.019), nonsense mutations, ( P =0.044), and deletion mutations ( P =0.012) were predictive of VHL type 1. Missense mutations were significantly more common in VHL type 2 ( P≤ 0.001). Fifty-three VHL families without information sufficient to classify into VHL1/VHL2 were excluded from this analysis. Zbar et al, 1996. Types of Mutation Found in VHL Disease Without (Type 1) and With (Type 2) Pheochromocytoma a Number of mutations found VHL type Number of families Missense Nonsense Micro- deletion (1-9 bp) Insertion (1-8 bp) Deletion (4-380/kb) Splice site 1 336 72 29 31 13 53 10 2 78 61 1 2 2 Total 414 133 30 31 15 55 10 Overview: VHL Gene Mutations, Pathophysiology, and Inheritance Patterns

7. Genetic Underpinnings of VHL Disease (cont.) RCC = renal cell carcinoma. Chen et al, 1995; Nielsen et al, 2021. Type I: risk of pheochromocytoma is low, but can develop all other VHL disease–associated tumor types Type II: pheochromocytoma in association with other tumors IIa : low risk of RCC IIb: high risk of RCC IIc : pheochromocytoma only with no other neoplasms Relationship Between Genetic Mutations and Clinical Phenotype

8. Clinical Presentation and Surveillance Strategies ccRCC = clear cell renal carcinoma; MRI = magnetic resonance imaging. Ho & Jonasch, 2014. Identifying and Managing VHL Disease–Associated Tumors CNS hemangioblastomas Retinal hemangioblastomas Endolymphatic sac tumors of temporal bone Pheochromocytomas Pancreatic cysts, neuroendocrine tumors Renal cysts, ccRCC Uterine broad ligament cystadenomas Epididymal cystadenomas Ophthalmoscopy Plasma metanephrines MRI imaging Audiology

9. Renal Cell Carcinoma Patterns in Hereditary RCC HLRCC = leiomyomatosis renal cell carcinoma; HPRC = hereditary papillary renal carcinoma; BHD = Birt-Hogg-Dubé. Linehan et al, 2003. Also seen in HLRCC Typical pattern in VHL disease HPRC BHD

10. VHL Disease–Associated Hemangioblastomas NCI, 2024; Larcher et al, 2022. Images adapted from Servier Medical Art by Servier , licensed under CC BY 3.0. Decreased feeling in the arms, legs, and body Walking difficulties Swallowing difficulties Headaches Poor coordination Brainstem Cumulative risk: 10%-25% Mean age: 32 years Age range: 12-46 years Difficulty walking/muscle coordination Dizziness Headaches Double vision Vomiting Cerebellum Cumulative risk: 44%-72% Mean age: 33 years Age range: 9-78 years Vision loss Retinal detachment Retina Cumulative risk: 25%-60% Mean age: 25 years Age range: 1-67 years Decreased feeling in the arms, legs, and body Weakness Difficulty walking Difficulties with bowel and bladder function Spinal Cord Cumulative risk: 13%-50% Mean age: 33 years Age range: 12-66 years Location Risk/Age Symptoms

11. Other VHL Disease–Associated Tumors NCI, 2024; Larcher et al, 2022; Mayo Clinic, 2024a; Mayo Clinic, 2024b; Cancer.org , 2018; MD Anderson, 2024. Images adapted from Servier Medical Art by Servier , licensed under CC BY 3.0. Hearing loss Tinnitus Improper balance Endolymphatic Sac Tumor Cumulative risk: 10% Mean age: 22 years Age range: 12-50 years Renal Cell Carcinoma Cumulative risk: 24%-45% Mean age: 37 years Age range: 16-67 years Hematuria Lump/mass on the side or lower back Pyrexia with unknown etiology Unintentional weight loss Lingering dull ache or pain in the side, abdomen, or lower back Fatigue Gravity-dependent edema Pheochromocytoma Cumulative risk: 10%-20% Mean age: 30 years Age range: 5-58 years High blood pressure Sweating Headaches Rapid or irregular heartbeats Feelings of anxiety/panic Pale skin Dizziness, lightheadedness Tremors Weight loss Pancreatic Neuroendocrine Tumor/Cysts Cumulative risk: 35%-70% Mean age: 36 years Age range: 5-70 years Jaundice or icterus Dark urine or light-colored stools Pain in the abdomen or middle of the back Bloating Nausea, vomiting, or indigestion Fatigue Lack of appetite Unexplained weight loss Sudden-onset diabetes Manifestation Risk/Age Symptoms

12. Clinical Presentation and Surveillance Strategies Images courtesy of Eric Jonasch, MD. Identifying and Managing VHL Disease–Associated Tumors

13. Clinical Presentation and Surveillance Strategies (cont.) Image courtesy of Eric Jonasch, MD. Identifying and Managing VHL Disease–Associated Tumors

14. Clinical Presentation and Surveillance Strategies (cont.) Images courtesy of Eric Jonasch, MD. Identifying and Managing VHL Disease–Associated Tumors

15. When to Suspect VHL Disease Binderup et al, 2022; NCI, 2024. Images adapted from Servier Medical Art by Servier , licensed under CC BY 3.0. Most Common Presenting Characteristics Raising Suspicion Multifocal and/or bilateral renal cysts or clear cell renal cell carcinoma CNS hemangioblastoma Retinal hemangioblastoma First manifestation in nearly 80% of those affected, as early as 1 year old Solitary pheochromocytoma/paraganglioma ≥1 retinal or CNS hemangioblastoma Early onset (≤40 years) or multiple RCCs Pancreatic neuroendocrine tumors ≥2 different abdominal manifestations Endolymphatic sac tumor Epididymal cystadenoma First-degree relative fulfills diagnostic criteria for VHL Family history or ≥2 first-degree relatives with ≥1 VHL manifestations ( ie , renal cancer in multiple family members) Patient fulfills diagnostic criteria for VHL VHL variant incidentally found First-degree relative with clinically actionable VHL variant Predictive genetic testing Genetic counseling and workup Medical history Detailed family history/pedigree Genetic testing Clinical examinations Findings Next Steps

16. Diagnosing VHL Disease NCI, 2024. Family History Yes Genetic Testing Test DNA for same VHL pathogenic variant as biological relative Scenario for Clinical Diagnosis Pathogenic VHL variant unknown Clinical Diagnosis Requirements ≥1 required: Epididymal or broad ligament cystadenoma CNS hemangioblastoma Multifocal clear cell renal cell carcinoma Pheochromocytoma Retinal hemangioblastoma Pancreatic neuroendocrine tumor Pancreatic cysts and/or cystadenoma Endolymphatic sac tumor No Genetic tests may be negative (VHL mosaicism) Pathogenic VHL variant unknown or germline-negative, clinical signs present ≥1 required: Hemangioblastoma Retinal CNS If only 1 of the above , then also 1: Renal cell carcinoma Pheochromocytoma Pancreatic cysts or cystadenomas Endolymphatic sac tumor Epididymal or broad ligament cystadenomas

17. Clinical Presentation and Surveillance Strategies Q = every. Daniels et al, 2023. Surveillance modality (tumors being screened) <5 years old Beginning at age 5 Beginning at age 11 Beginning at age 15 Beginning at age 30 Beginning at age 65 Pregnancy History and physical examination Yearly from age 1 Yearly Yearly Yearly Yearly Yearly Prior Blood pressure and pulse (pheochromocytoma/paraganglioma) Yearly from age 2 Yearly Yearly Yearly Yearly Yearly Prior Dilated eye examination (retinal hemangioblastomas) Q6-12 months, beginning before age 1 Q6-12 months Q6-12 months Q6-12 months Yearly Yearly Prior, then Q6-12 months Metanephrines (pheochromocytoma/paraganglioma) Yearly Yearly Yearly Yearly Stop routine Prior MRI brain and spine with/without contrast (CNS hemangioblastomas) Q2 years Q2 years Q2 years Stop routine Prior Audiogram (endolymphatic sac tumors) Q2 years Q2 years Q2 years Stop routine Prior MRI abdomen with/without contrast (renal cell carcinoma, pheochromocytoma/paraganglioma, pancreatic neuroendocrine tumor/cyst) Q2 years Q2 years Stop routine Prior MRI internal auditory canal (endolymphatic sac tumors) Once No specific changes

18. Slide courtesy of Donika Saporito, MS. Current State of Genetic Testing, Including Next-Generation Sequencing Majority of testing Comprehensive sequencing Looks to identify large missing or extra pieces of genetic material Rearrangement analysis (deletion/duplication) Tests for a single mutation that has already been identified in a family Can also be used when a certain mutation is likely in a certain ethnic group (ie , Ashkenazi Jewish founder mutations) Single site analysis or known familial mutation analysis Advances in Genetic Testing for VHL Disease (cont.)

19. Types of Genetic Testing Results Slide courtesy of Donika Saporito, MS. Pathogenic : positive result, leads to abnormal gene function Likely pathogenic : likely leads to abnormal gene function, treated as a positive result but has slightly more uncertainty Variant of unknown/uncertain significance : there is not enough data on this change to know if it is benign and tolerated or associated with an abnormal gene function Likely benign/polymorphism : unlikely to cause any change in gene function, treated as a negative result Benign/polymorphism: this is a normal change in the gene leading to normal gene function, these changes are common and what make us each a little different ?

20. Case Study 24-year-old woman with no prior family history develops sudden- onset vision loss in her left eye Ophthalmoscopy is performed, revealing several retinal hemangioblastomas in each eye Lesions are treated with laser photocoagulation Illustrating the Impact of Genetic Testing on Patient Management

21. Question 1 Please choose the correct statement: Unilateral hemangioblastomas are almost never associated with a hereditary syndrome Absence of family history provides concrete evidence that this patient does not have a hereditary syndrome Referral for genetic counseling should occur for all patients with retinal hemangioblastomas Eventual enucleation is required for the majority of patients with retinal hemangioblastoma due to risk for malignant transformation

22. Question 1: Answer Please choose the correct statement:  Unilateral hemangioblastomas are almost never associated with a hereditary syndrome Absence of family history provides concrete evidence that this patient does not have a hereditary syndrome Referral for genetic counseling should occur for all patients with retinal hemangioblastomas Eventual enucleation is required for the majority of patients with retinal hemangioblastoma due to risk for malignant transformation 

23. Case Study (cont.) Ophthalmologist suspects VHL disease Patient is referred to nearest VHL disease Clinical Care Center Genetic counselor reviews case and recommends germline genetic testing Testing is performed, revealing a R167Q mutation in the VHL gene Family history is negative; parents are tested as well; both are negative, showing patient is first-in-family Illustrating the Impact of Genetic Testing on Patient Management

24. Question 2 Choose the correct statement about VHL disease: VHL disease is an autosomal recessive, germline genetic disease Most patients with VHL disease only have 1 organ site involved Penetrance for VHL disease is approximately 20% Patients with VHL disease need to undergo regular surveillance, including retinal, auditory, CNS, and abdominal evaluations

25. Question 2: Answer Choose the correct statement about VHL disease:  VHL disease is an autosomal recessive, germline genetic disease Most patients with VHL disease only have 1 organ site involved Penetrance for VHL disease is approximately 20% Patients with VHL disease need to undergo regular surveillance, including retinal, auditory, CNS, and abdominal evaluations

26. Case Study (cont.) CCC = clinical care center.  CCC navigator (medical oncologist) orders MRI brain, spine, abdomen, plasma metanephrines/normetanephrines, audiology evaluation Multiple small (<5 mm) cerebellar hemangioblastomas and bilateral renal cell carcinomas (<2 cm) are found, as well as multiple pancreatic cysts. Plasma nor/metanephrines are normal. Audiology exam is normal Navigator coordinates with neurosurgery and urology teams to continue annual monitoring of identified lesions and continues screening studies for remaining areas of potential involvement Illustrating the Impact of Genetic Testing on Patient Management

27. Treatment of VHL Disease–Associated Tumors

28. Managing VHL Disease–Associated Renal Manifestations Gläsker et al, 2020; Larcher et al, 2022. Images adapted from Servier Medical Art by Servier, licensed under CC BY 3.0. Renal cell carcinoma and associated complications are the primary drivers of mortality in patients with VHL disease Therapeutic goals: Maintain renal function Prevent metastasis Challenges: Multifocal disease Bilateral disease Dozens of tumors at times Need for multidisciplinary care Balancing act between pros and cons of monitoring for progression and intervening Active monitoring is appropriate <3 cm Common cutoff for metastatic concern Surgery Nephron-sparing techniques: standard of care Radical nephrectomy: reserved for unsalvageable renal function Adverse effects: Repeat surgery  more scarring, removal of more tissue Ablation Successful for tumors <3 cm Less robust data for efficacy compared to surgery Attractive option for patients at high morbidity risk following surgery Surrounding tissue damage Thermal damage: bowel, ureter, renal tissue Adverse effects:

29. Managing VHL Disease–Associated Ocular Manifestations Ruppert et al, 2019; Khan et al, 2021; Karimi et al, 2020. Images adapted from Servier Medical Art by Servier , licensed under CC BY 3.0. Slow-growing, often stable for long periods of time Monitor for development of retinal edema and hard exudates Observation <1.5 mm Larger tumors are associated with engorged, tortuous feeder vessels Most common treatment for small peripheral retinal hemangioblastomas >90% control rate May require multiple treatments Results in scarring Laser Photocoagulation <1.5 mm Option for larger tumors Combination of laser photocoagulation and cryotherapy may be needed 1.5-4.5 mm Cryotherapy Retinal fluid accumulation Potential complications : Exudative retinal detachment Fibrotic contraction Pars Plana Vitrectomy ≥4.5 mm Can be performed in conjunction with adjunct laser photocoagulation or cryotherapy Can improve vision in cases of large hemangioblastoma High recurrence rate Vitreoretinopathy following surgery a concern Adjunctive treatment in patients ineligible for conventional treatments Anti–vascular endothelial growth factor (VEGF) therapies: Bevacizumab Ranibizumab Propranolol Intravitreal Injections Control exudation in tumors located close to macula and optic nerve Inconsistent efficacy data

30. Managing VHL Disease–Associated CNS Manifestations Larcher et al, 2022; Binderup et al, 2022. Images adapted from Servier Medical Art by Servier , licensed under CC BY 3.0. Surgical resection is standard practice with most lesions well-defined and easily resectable Recurrence of the removed lesion is not a major concern Drainage of an associated cyst is recommended prior to surgical approach >3 cm may require multiple surgical interventions However, new lesions commonly develop every 2 years in patients with VHL disease Radiotherapy and/or stereotactic radiosurgery are effective for sub-totally excised or unresectable lesions Stereotactic radiosurgery is an option for patients with multiple tumors that are difficult to treat and can result in excellent tumor control Solid tumor characteristics on imaging, small treatment volume are associated with longer tumor control Symptoms predominantly arise from cystic formation within the tumor, resulting in a local mass-effect on surrounding tissues Intervention modality and timing depends on: Signs Symptoms Number of lesions Localization Tumors commonly remain stable for long periods of time Saltatory growth is commonly observed – monitoring important Observation only common

31. Managing VHL Disease–Associated Pancreatic Manifestations Larcher et al, 2022; Laks et al, 2022. Images adapted from Servier Medical Art by Servier , licensed under CC BY 3.0. Low risk - <1.5 cm or stable in 2 consecutive images Often non-functional and can be monitored if localized and small Larger tumors (1.2-3 cm) with a VHL missense variant and rapidly growing tumors have been associated with greater metastatic potential Tumor enucleation is possible if the tumor is not near the pancreatic duct and is preferred given it spares the parenchyma Neuroendocrine Tumors ≤2 cm ≤3 cm Lesions of the body or tail: ≥3 cm Lesions of the head : 2 cm Resection considered: 18 F-2-deoxy-D-glucose ( 18 F-FDG) is not beneficial or characterizing VHL disease–associated pancreatic neuroendocrine tumors 68 Gallium-dodecanetetraacetic acid tyrosine-3-octreotate ( 68 Ga-DOTATE) PET/CT imaging is recommended prior to planned intervention or for lesions with radiological characteristics not consistent with pancreatic neuroendocrine tumors Identifying/Assessing Neuroendocrine Tumors Biliary or gastrointestinal obstruction due to mass-effect from cysts may corrected with endoscopic stent placement or surgical bypass Simple cysts may be addressed with image-guided drainage or marsupialization Cysts/Cystadenomas Pancreatic cysts – benign Cystadenomas – no malignant potential Monitor:

32. Managing VHL Disease–Associated Pheochromocytoma Gläsker et al, 2020; Sanford et al, 2021; Larcher et al, 2022. Images adapted from Servier Medical Art by Servier , licensed under CC BY 3.0. 68 Ga-DOTATE PET/CT and 18 F-FDG imaging can aid in assessment and staging ~39% Bilateral Close monitoring: potential for metastasis Monitor ≤2 cm Paragangliomas may develop in the sympathetic chain Often asymptomatic Undetectable catecholamines/metanephrines ≤1 cm Surgical Intervention Considerations for ANY surgery for patients with pheochromocytoma: Preoperative alpha blockade to prevent excessive catecholamine release Detailed endocrine evaluation Metastatic and recurrence rates are low Based on: Size Anatomic location Symptoms Cortical sparing partial adrenalectomy: Retain functional adrenal tissue Laparoscopy preferred Bilateral involvement Complications : Hypotension Concern for adrenal insufficiency if persistent Hypoglycemia Monitor closely following surgery Often transient

33. Novel and Emerging Therapies

34. Treatment of VHL Disease–Associated Tumors Novel and Emerging Therapies

35. Treatment of VHL Disease–Associated Tumors (cont.) HIF = hypoxia-inducible factor.  Novel and Emerging Therapies Tumor cells VHL HIF VEGF HIF inhibitors

36. Treatment of VHL Disease–Associated Tumors (cont.) bHLH = basic helix loop helix; PAS = Per-ARNT-Sim; ODDD = oxygen-dependent degradation (ODD) domain; TAD = transactivation domain; C-term = carboxy-terminal. Cho et al, 2016; Chen et al, 2016; Courtney et al, 2018; Wallace et al, 2016; Mohlin et al, 2013. Atlas of Genetics and Cytogenetics in Oncology and Hematology

37. Treatment of VHL Disease–Associated Tumors (cont.) ECOG = Eastern Cooperative Oncology Group; PS = performance status; RECIST = Response Evaluation Criteria in Solid Tumors; ORR = objective response rate; DOR = duration of response. Jonasch et al, 2021. MK-6482 120 mg orally once daily Key Inclusion Criteria (N=61) Diagnosis of VHL disease, based on germline mutation ≥1 measurable RCC tumor No p rior systemic anticancer therapy No metastatic disease ECOG PS 0 or 1 Primary End Points ORR in VHL disease–associated RCC tumors per RECIST v1.1 by independent central review Tumor Evaluation Performed at screening and every 12 weeks thereafter Primary Objective To evaluate efficacy in VHL disease–associated RCC Secondary End Points ORR in non-RCC lesions DOR in RCC and non-RCC lesions Safety

38. Treatment of VHL Disease–Associated Tumors (cont.) Jonasch et al, 2021. Best Objective Response in Renal Cell Carcinoma Associated With VHL Disease Variable Efficacy population (N=61) Objective response n (% [95% CI]) 30 (49% [36%-62%]) Best response n (%) Complete response Partial response 30 (49%) Stable disease 30 (49%) Disease progression Unable to be evaluated 1 (2%) Median time to response (range), months 8.2 (2.7-19.1) Median duration of response (range), months NR (2.8+ - 22.3+)

39. Treatment of VHL Disease–Associated Tumors (cont.) a Includes pancreatic neuroendocrine tumors and serous cystadenomas. Jonasch et al, 2021. Pancreatic Lesion a (n=61) Pancreatic Neuroendocrine Tumors (n=22) CNS Hemangioblastoma (n=50) ORR 77.0% (64.5%-86.8%) 90.9% (70.8%-98.9%) 30.0% (17.9%-44.6%) Best response, n (%) Complete response 6 (9.8%) 3 (13.6%) 3 (6.0%) Partial response 41 (67.2%) 17 (77.3%) 12 (24.0%) Stable disease 13 (21.3%) 2 (9.1%) 31 (62.0%) Progressive disease 2 (4.0%) Not evaluable 1 (1.6%) 2 (4.0%)

40. Treatment of VHL Disease–Associated Tumors (cont.) Jonasch et al, 2021. Adverse Events of Any Cause in the Full Safety Population Adverse Event Safety Population (N=61) Any grade Total 61 (100%) Treatment-related 61 (100%) Grade 3-5 20 (33%) Grade 3 treatment-related 9 (15%) Grade 4-5 treatment-related Treatment discontinuation Total 2 (3%) Due to a treatment-related adverse event 1 (2%) Death Total 1 (2%) Due to a treatment-related adverse event

41. Treatment of VHL Disease–Associated Tumors (cont.) Jonasch et al, 2021. Adverse Events in ≥10% of the Safety Population (N=61) Event Any Grade Grade 1 Grade 2 Grade 3 Anemia 55 (90%) 24 (39%) 26 (43%) 5 (8%) Fatigue 40 (66%) 29 (48%) 8 (13%) 3 (5%) Headache 25 (41%) 20 (33%) 5 (8%) Dizziness 24 (39%) 20 (33%) 4 (7%) Nausea 21 (34%) 15 (25%) 6 (10%) Dyspnea 14 (23%) 13 (21%) 1 (2%) Arthralgia 12 (20%) 10 (16%) 2 (3%) Constipation 12 (20%) 10 (16%) 2 (3%) Myalgia 12 (20%) 9 (15%) 2 (3%) 1 (2%) URTI 11(18%) 4 (7%) 7 (11%) ALT increase 10 (16%) 10 (16%) Hypertension 10 (16%) 3 (5%) 2 (3%) 5 (8%) Vision blurred 10 (16%) 6 (10%) 4 (7%)

42. Treatment of VHL Disease–Associated Tumors (cont.) pNET = p ancreatic n euroendocrine t umors. Jonasch et al, 2021. Not Ideal Younger individual with solitary lesion of concern, where a local procedure will likely allow multiple years of treatment-free observation For example, 24-year-old with 2.9-cm RCC and no other significant disease manifestations Who Is a Good Belzutifan Candidate? Ideal Individual with multiple lesions in various organ sites, with prior local treatments to ≥1 lesion For example, 40-year-old with several RCC, hemangioblastomas, and pNETs, with prior history of surgery to cerebellum

43. Role of Genetic Counseling in the Management of VHL Disease

44. Slide courtesy of Donika Saporito, MS. Risk Assessment, Family Testing, and Psychosocial Support Genetic counseling “Genetic counseling is the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease”

45. Purpose of Cancer Genetic Counseling Slide courtesy of Donika Saporito, MS. Hear the client’s “cancer story” Obtain cancer- specific pedigree Provide cancer risk assessment Discuss hereditary cancer syndrome, management, and surveillance Explain genetic testing options and process, cost, etc Provide client with patient resource(s) Psychosocial support and referrals, when appropriate

46. Role of Genetic Counseling in the Management of VHL Disease Slide courtesy of Donika Saporito, MS. Communicating Complex Genetic Information to Patients and Families Assess patient understanding of genetics referral Obtain at least 3-generation, detailed family history Conduct risk assessment for hereditary syndromes Explain medical genetic information and testing Discuss insurance coverage and discrimination laws Follow-up Disclose genetic test results Implications of test results for patient and family members Psychosocial assessment and counseling Provide patient-friendly resources Discuss and coordinate appropriate referrals

47. Key Takeaways VHL disease is an autosomal dominant inherited disorder that affects multiple organs, including eye, brain, spine, adrenals, pancreas, kidney, and middle ear Recognition of disease manifestations, genetic testing, and appropriate follow-up are vital for patients with VHL disease Organ-specific management strategies have been developed, with preservation of function a major goal The biology of VHL loss has led to the development of highly-specific targeted therapy, which appears to decrease need for surgical intervention Genetic counseling is a vital part of the management of patients with VHL disease and their families

48. References Binderup MLM, Smerdel M, Borgwadt L, et al (2022). Von Hippel-Lindau disease: updated guideline for diagnosis and surveillance. Eur J Med Genet , 65(8):104538. DOI:10.1016/j.ejmg.2022.104538 Cancer.org (2018). Signs and symptoms of pancreatic neuroendocrine tumor. Available at: https:// www.cancer.org /cancer/types/pancreatic-neuroendocrine-tumor/detection-diagnosis-staging/signs-and- symptoms.html Chen F, Kishida T, Yao M, et al (1995). Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat , 5(1):66-75. DOI:10.1002/humu.1380050109 Chen W, Hill H, Christie A, et al (2016). Targeting renal cell carcinoma with a HIF-2 antagonist. Nature , 539:112-117. DOI:10.1038/nature19796 Cho H, Du X, Rizzi JP, et al (2016). On-target efficacy of a HIF-2⍺ antagonist in preclinical kidney cancer models. Nature , 539(7627):107-111. DOI:10.1038/nature19795 Courtney KD, Infante JR, Lam ET, et al (2018). Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2⍺ antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol, 36(9):867-874. DOI:10.1200/JCO.2017.74.2627 Daniels AB, Tirosh A, Huntoon K (2023). Guidelines for surveillance of patients with von Hippel-Lindau disease: consensus statement of the International VHL Surveillance Guidelines Consortium and VHL Alliance. Cancer , 129(19):2927-2940. DOI:10.1002/cncr.34896 Gläsker S, Vergauwen E, Koch CA, et al (2020). Von Hippel-Lindau disease: current challenges and future prospects. Onco Targets Ther , 16:5669-5690. DOI:10.2147/OTT.S190753 Ho TH & Jonasch E (2014). Genetic kidney cancer syndromes. J Natl Compr Canc Netw , 12(9):1347-1355. DOI:10.6004/jnccn.2014.0129 Jonasch E, Donskov F, Iliopoulos O, et al (2021). Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med , 385(22):2036-2046. DOI:10.1056/NEJMoa2103425 Kaelin WG (2018). The von Hippel-Lindau tumor suppressor protein. Annu Rev Cancer Biol , 2:91-109. DOI:10.1146/annurev-cancerbio030617-050527 Karimi S, Arabi A, Shahraki T & Safi S (2020). Von Hippel-Lindau disease and the eye. J Ophthalmic Vis Res , 15(1):78-94. DOI:10.18502/jovr.v15i1.5950 Khan HA, Shahzad MA, Iqbal F, et al (2021). Ophthalmological aspects of von-Hippel-Lindau syndrome. Semin Ophthalmol , 36(7):531-540. DOI:10.1080/08820538.2021.1897851 Laks S, van Leeuwaarde R, Patel D, et al (2022). Management recommendations for pancreatic manifestations of von Hippel-Lindau disease. Cancer , 128(3):435-446. DOI:10.1002/cncr.33978 Larcher A, Belladelli F, Fallara G, et al (2022). Multidisciplinary management of patients diagnosed with von Hippel-Lindau disease: a practical review of the literature for clinicians. Asian J Urol , 9(4):430-442. DOI:10.1016/j.ajur.2022.08.002

49. References (cont.) Linehan WM, Walther MM & Zbar B (2003). The genetic basis of cancer of the kidney. J Urol , 170(6 pt 1):2163-2172. DOI:10.1097/01.ju.0000096060.92397.ed Mayo Clinic (2024a). Pheochromocytoma. Available at: https:// www.mayoclinic.org /diseases-conditions/pheochromocytoma/symptoms-causes/syc-20355367 Mayo Clinic (2024b). Symptoms & causes of kidney cancer. Available at: https:// www.mayoclinic.org /diseases-conditions/kidney-cancer/symptoms-causes/syc-20352664 MD Anderson Cancer Center (2024). Von Hippel-Lindau disease symptoms. Available at:https :// www.mdanderson.org /cancer-types/von- hippel - lindau -disease/von- hippel - lindau -disease- symptoms.html Mohlin S, Hamidian A, Bexell D, et al (2013). EPAS1 (Endothelial PAS Domain Protein 1). Atlas Genet Cytogenet Oncol Haematol. Available at: https:// atlasgeneticsoncology.org /gene/44088/epas1-(endothelial-pas-domain-protein-1) National Cancer Institute (2024). Von Hippel-Lindau Disease (PDQ®)—health professional version. Available at: https:// www.cancer.gov /publications/pdq/information-summaries/genetics/ vhl -syndrome-hp-pdq Nielsen SM, Rubinstein WS, Thull DL, et al (2011). Genotype-phenotype correlations of pheochromocytoma in two large von Hippel-Lindau (VHL) type 2A kindreds with different missense mutations. Am J Med Genet A , 155A(1):168-173. DOI:10.1002/ajmg.a.33760 Ruppert MD, Gavin M, Mitchell KT & Peiris AN (2019). Ocular manifestations of von Hippel-Lindau disease. Cureus , 11(8):e5319. DOI:10.7759/cureus.5319. Sanford T, Gomella PT, Siddiqui R, et al (2021). Long term outcomes for patients with von Hippel-Lindau and pheochromocytoma: defining the role of active surveillance. Urologic Oncology: Seminars and Original Investigations , 39(2):134.e1-134.e8. DOI:10.1016/j.urolonc.2020.11.019 Stebbins CE, Kaelin WG & Pavletich NP (1999). Structure of the VHL- elonginC - elonginB complex: implications for VHL tumor suppressor function. Science, 284(5413):455-461. DOI:10.1126/science.284.5413.455 Wallace EM, Rizzi JP, Han G, et al (2016). A small-molecule antagonist of HIF2⍺ is efficacious in preclinical models of renal cell carcinoma. Cancer Res , 76(18):5491-5500. DOI:10.1158/0008-5472.CAN-16-0473. Zbar B, Kishida T, Chen F, et al (1996). Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe and Japan. Human Mutat , 8(4):348-357. DOI:10.1002/(SICI)1098-1004(1996)8:4<348::AID-HUMU8>3.0.CO;2-3