BAP1 germline...
Transcript of BAP1 germline...
![Page 1: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/1.jpg)
BAP1 germline mutations A new Cutaneous Nevus Melanoma Syndrome
Thomas Wiesner
![Page 2: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/2.jpg)
Disclosure
US patent application US 61/463,389 BAP1 mutational analysis in determining susceptibility to melanocytic neoplasia and in the diagnosis, prognosis, and treatment of melanocytic neoplasia
Listed as co-inventor
![Page 3: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/3.jpg)
Familial atypical mole - malignant melanoma syndrome
![Page 4: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/4.jpg)
• Characterized by hundreds of flat and brown nevi
• Patients should be monitored closely
• Patient’s melanoma-risk: up to 20%
• Some patients have germline mutations in CDKN2A
Familial atypical mole - malignant melanoma syndrome
![Page 5: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/5.jpg)
A new Cancer Predisposition Syndrome caused by BAP1 Mutations
Multiple epithelioid, melanocytic tumors
Cutaneous melanoma
Uveal melanoma
Melanocytic tumor of uncertain malignant potential
Mesothelioma
Family 1 Family 3 Family 2
BAP1 germline mutation
BAP1 wildtype
3 families with germline mutations in the BAP1 gene:
![Page 6: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/6.jpg)
Very subtle, clinical phenotype in patients with BAP1 germline mutations
Family 1
![Page 7: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/7.jpg)
Skin-lesions: Inconspicuous, skin-colored, dome-shaped papules
Family 2
![Page 8: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/8.jpg)
3 Families with germline mutations in the BAP1 gene
Family 2
![Page 9: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/9.jpg)
Family 3
Number of skin lesions varies from only a few to > 50
![Page 10: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/10.jpg)
1mm 1mm 1mm
Resemble histologically ‘Atypical Spitz tumors’ (large, epithelioid cells)
![Page 11: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/11.jpg)
Histological appearance of a representative lesion
![Page 12: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/12.jpg)
![Page 13: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/13.jpg)
BAP1 IHC
![Page 14: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/14.jpg)
Epithelioid phenotype is associated with loss of BAP1 expression
BAP1
The epithelioid morphology and BAP1 immunohistochemistry enables the accurate identification of these tumors
![Page 15: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/15.jpg)
Epithelioid, melanocytic tumors may progress to melanoma
pHH3 ser10
Cutaneous melanoma Epithelioid tumor
Combined, melanocytic tumor
Despite the benign clinical appearance, epithelioid skin
tumors should be observed and — if changing — excised
![Page 16: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/16.jpg)
Tumor Spectrum in Patients with BAP1 germline mutations
Other investigators suggested also a predisposition to • Lung adenocarcinoma (Abdel-Rahman et al. 2011) • Meningioma (Abdel-Rahman et al. 2011) • Clear cell renal cell carcinoma (Pena-Llopis et al. 2012) • Paraganglioma (Wadt et al. 2013)
Tumor type % Number of patients
Epithelioid, melanocytic tumors 84.3 16/19
MELTUMPs 21.1 5/19
Cutaneous melanoma 26.3 4/19
Pleural mesothelioma 15.8 3/19
Peritoneal mesothelioma 15.8 3/19
Uveal melanoma 10.5 2/19
19 germline mutation carriers in 3 families
![Page 17: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/17.jpg)
When should we test patients for BAP1 germline mutations?
1. Individual being tested has a personal or family history suggestive of genetic cancer susceptibility. • Melanocytic tumors: epitheloid nevi (ASTs), melanocytic skin tumor of uncertain
malignant potential, cutaneous melanoma, uveal melanoma • Mesothelioma • Other cancers: lung adenocarcinoma, meningioma, clear cell renal cell carcinoma,
paraganglioma, bladder cancer, breast cancer…
2. The genetic test can be adequately interpreted
1. Test results aid in diagnosis or influence the medical or surgical management of the patient or family members.
Robson et al. J Clin Oncol (2010)
ASCO recommends genetic testing only under 3 conditions:
Carbone et al. Nat Rev Cancer (2013)
![Page 18: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/18.jpg)
Influence of BAP1 germline mutation on the medical or surgical management
Cutaneous, melanocytic tumors:
• Regular dermatologic examination
• Establish the presence/absence of epithelioid, melanocytic tumors
• If present, monitor for any changes
• Removal of changing lesions (they may progress to cutaneous melanomas)
• Exposure to UV-radiation may increase risk: extensive sun-protection
Eyes:
• Regular examinations by an ophthalmologist
Mesotheliomas:
• Regular examinations and monitoring with biomarkers e.g. Fibulin-3?
• Check and avoid exposure to asbestos and erionite
Other Cancer:
• Regular check-ups to detect malignancies early?
![Page 19: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/19.jpg)
Uncertainties for genetic testing and counseling
Multiple epithelioid, melanocytic tumors Cutaneous melanoma
Uveal melanoma Melanocytic tumor of uncertain malignant potential
Mesothelioma
Family 1 Family 3 Family 2
Currently, we do not know:
• Relative risk of patients to develop cancer?
Is BAP1 a low-, intermediate-, and high penetrance gene for cancer?
• What is the full tumor spectrum of BAP1 germline mutation carriers?
• Frequency of BAP1 mutation in the general population?
![Page 20: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/20.jpg)
Progeny has increased risk
1st hit present in all cells
Inheritable
Germline mutations
• Mutations are present in all cells (including egg and sperm)
• Can be inherited Cause cancer predisposition syndromes
• Only one more hit is necessary in somatic cells
Normal cell
Cancer cell
Germline vs. somatically acquired BAP1 mutations
2nd hit – only 1 somatic hit necessary
Non-inheritable
Progeny has normal risk
Somatic mutations
• Mutations occur only in non-germline tissue (e.g. melanocytes, renal cells)
• Can cause cancer Cannot be inherited
• Two hits are necessary in somatic cells
Normal cell
Cancer cell 2 hits necessary –
low probability
2 normal alleles – no mutations
![Page 21: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/21.jpg)
Sporadic ‘Atypical Spitz Tumor’ with somatically acquired BAP1 loss
![Page 22: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/22.jpg)
BAP1 IHC
Large epithelioid and pleomorphic melanocytes; loss of BAP1 expression
![Page 23: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/23.jpg)
Loss of BAP1 marks the transition from a nevus to a melanoma
Sporadic melanoma arising in a nevus 60-year-old patient, back
![Page 24: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/24.jpg)
No loss 3p21 BRAFV600E No BAP1 mutation
Nevus part: small nevoid cells, BRAFV600E mutation, no BAP1 loss
![Page 25: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/25.jpg)
BRAFV600E BAP1 c.999-1050del Loss 3p21
Melanoma part: highly atypical cells, BRAFV600E mutation, BAP1 loss
![Page 26: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/26.jpg)
Proliferation stain (Ki-67): High cell mitotic index in the melanoma part
Melanoma
Nevus Ki-67 BAP1
![Page 27: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/27.jpg)
Somatic BAP1 mutations in Cancer
Primary tissue % Mutated Mutated samples Total samples
Uveal Melamoma 43.1 41 95
Mesothelioma 26.9 51 189
Clear Cell Renal Cell Carcinoma 13.0 58 446
Bladder Cancer 5.4 2 37
Cutanous Melanoma/AST 3.5 13 363
Endometrium Carcinoma 1.4 3 204
Lung Carcinoma 1.1 11 929
Prostate Cancer 1.0 4 376
Ovary Carcinoma 0.6 4 665
Breast Cancer 0.5 4 691
Colon Carcinoma 0.4 3 689
![Page 28: BAP1 germline mutationscb813cf9c30af085a008-d8e9550dbd84db85126fec246b3a4c0e.r6.cf1.rackcdn.com/...Disclosure . US patent application US 61/463,389 . BAP1. mutational analysis in determining](https://reader036.fdocuments.in/reader036/viewer/2022070722/5f01d3e07e708231d4013c5e/html5/thumbnails/28.jpg)
Summary - Loss of BAP1
Germline BAP1 mutations predispose to
• Epithelioid melanocytic tumors – Atypical Spitz tumors (“ASTs”)
• Uveal melanoma
• Cutaneous melanoma
• Mesothelioma
• (and possible other tumors like renal cell carcinoma, paraganglioma)
Sporadic BAP1 mutations are found in
• “AST” - characterized by BRAF mutation and loss of BAP1 (BAP1oma)
• Uveal melanoma (40%)
• Cutaneous melanoma (5%)
• Mesothelioma (25%)
• Clear cell renal cell cancer (10%)
Patients with a personal or family history of these tumors should be tested for BAP1 mutations