Melanocytic Nevi Arise From Outline Initiating Oncogenic Mutations - - PowerPoint PPT Presentation

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melanocytic nevi arise from outline initiating oncogenic
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Melanocytic Nevi Arise From Outline Initiating Oncogenic Mutations - - PowerPoint PPT Presentation

Oct 14, 2023 30 likes •282 views

5/24/2014 Thanks to: Molecular Aspects of Melanocytic Neoplasia Boris Bastian Timothy McCalmont Philip LeBoit Beth Ruben Iwei Yeh MD, PhD Jeff North University of California, Laura Pincus San Francisco Thaddeus Mully Swapna Vemula

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5/24/2014 1

Molecular Aspects of Melanocytic Neoplasia

Iwei Yeh MD, PhD University of California, San Francisco

Thanks to:

Boris Bastian Timothy McCalmont Philip LeBoit Beth Ruben Jeff North Laura Pincus Thaddeus Mully Swapna Vemula

Outline

  • Melanoma oncogenes and implications for

treatment

  • Assessment of copy number aberrations

for diagnostic purposes

Melanocytic Nevi Arise From Initiating Oncogenic Mutations

Normal melanocyte Nevus Melanoma

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SLIDE 2

5/24/2014 2

Initiating Oncogenes in Common Nevi

NRAS Unknown

Pollock et al. Nature Genetics 2003

Initiating Oncogenes in Blue Nevi and Uveal Melanoma

VanRaamsdonk et al. 2010 NEJM

Blue Nevi

Initiating Oncogenes in Spitz Tumors circa 2010

Unknown

Bastian et al. 2000 Am J Pathology

HRAS Spitz Nevus

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Initiating Oncogenes in Spitz Tumors circa 2012

Unknown

Wiesner et al. 2012 Am J Surg Path

Spitz Tumor with BAP1 loss

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BRAF/NRAS +BAP1

Initiating Oncogenes in Spitz Tumors

HRAS BRAF Fusions ROS1 Fusions NTRK1 Fusions ALK Fusions unknown RET Fusions

Wiesner et al. 2014 Nature Communications

ALK Fusion AST

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SLIDE 5

5/24/2014 5 Targeted Therapies

Oncogenic Event FDA approved in MM Clinical Trials in MM FDA approved in cancer BRAF mutation vemurafenib, dabrafenib, trametinib NRAS mutation MEK162 KIT mutation imatinib ALK fusion crizotinib ceritinib RET fusion cabozantinib vandetanib ROS1 fusion crizotinib BRAF fusion sorafenib trametinib NTRK1 fusion cabozantinib

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Outline

  • Melanoma oncogenes and implications for

treatment

  • Assessment of copy number aberrations for

diagnostic purposes

Detecting copy number abnormalities: FISH (fluorescence in situ hybridization) CGH (comparative genomic hybridization) NGS (next generation sequencing) Melanomas Frequently Demonstrate Copy Number Aberrations

Bastian et al. Cancer Research 1998 Copy number changes for 32 melanomas 94% demonstrated copy number aberrations

FISH: What gets analyzed?

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25

FISH: Potential effectiveness in melanoma diagnosis

  • 86.7% sensitivity
  • 95.4% specificity
  • (Mixed validation cohort of 301 tumors

with known behavior; often thick melanomas)

Gerami et al. American Journal of Surgical Pathology 2009

FISH: effectiveness in the context of Spitzoid melanoma

  • 70% sensitivity
  • Can be improved with assessment for

9p21 homozygous loss

Gammon et al. American Journal of Surgical Pathology 2012

What gets FISHed?

  • Spitz vs. spitzoid MM
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What gets FISHed?

  • Spitz vs. spitzoid MM
  • Combined nevus vs. MM ex nevus

What gets FISHed?

  • Spitz vs. spitzoid MM
  • Combined nevus vs. MM ex nevus
  • Acral nevus vs. acral MM

What gets FISHed?

  • Spitz vs. spitzoid MM
  • Combined nevus vs. MM ex nevus
  • Acral nevus vs. acral MM
  • Dysplastic nevus vs. nevoid MM

What gets FISHed?

  • Spitz vs. spitzoid MM
  • Combined nevus vs. MM ex nevus
  • Acral nevus vs. acral MM
  • Dysplastic nevus vs. nevoid MM
  • Cellular blue nevus vs. blue-like MM
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What gets FISHed?

  • Spitz vs. spitzoid MM
  • Combined nevus vs. MM ex nevus
  • Acral nevus vs. acral MM
  • Dysplastic nevus vs. nevoid MM
  • Cellular blue nevus vs. blue-like MM
  • Nevus NOS vs. nevoid MM
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A FISH-negative tumor

  • Is it not melanoma?
  • Is it a melanoma that lacks aberrations

RREB1, MYB, or CCND1 (is it a tumor with no copy number abnormality within chromosomes 6 and 11)?

FISH advantages

  • Potentially applicable to single cells
  • Quick turnaround (within a week)
  • Easily adaptable to existing equipment,

including microscopes, hybridizers, etc.

FISH limitations

  • Operating in a darkfield environment,

tumor cells may be overlooked

  • 4-6 probes are commonly utilized
  • Only chromosomes 6 and 11 were

analyzed in the initial protocol

  • With many probes, technical costs can

become prohibitive

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CGH (Comparative Genomic Hybridization)

Test DNA Reference DNA

Chromosome CGH provides "cytogenetic" resolution ~ 10 Mb Kallioniemi et al Science 1992

Array CGH

Test DNA Reference DNA

Snijders et al., Nat. Genet. 1998

Our array CGH platform Agilent 4x180k human array

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Microdissect tumor sections Extract DNA Label DNA Hybridize to Microarray Image Analyze Normal DNA Tumor DNA

Comparative Genomic Hybridization

CGH CGH CGH gain

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CGH loss

CCND1

What gets analyzed by CGH?

  • Spitz vs. spitzoid MM
  • Combined nevus vs. MM ex nevus
  • Acral nevus vs. acral MM
  • Dysplastic nevus vs. nevoid MM
  • Cellular blue nevus vs. blue-like MM
  • Nevus NOS vs. nevoid MM
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36 year old woman Spitz vs. melanoma

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Advantages of aCGH

  • Entire genome is examined
  • Timely (2 week turnaround)
  • Expense similar to FISH

RREB1 CEP6 MYB CCND1

CGH vs. FISH

Limitations of aCGH

  • Inapplicable to single cell

analysis

  • Significance of small genomic

anomalies, such as small monoaberrations, remain undefined

  • Thickness threshold ~0.5 mm
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56 year old man Mole vs. melanoma

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60 year old male; back Indication: diagnostic uncertainty (probably triggered by spitzoid melanocytes in an

  • lder patient)
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BAP-1

  • BRCA1 associated protein-1
  • Deubiquitinating enzyme (ubiquitin

carboxy-terminal hydrolase)

  • Localizes to transcription start sites and

modulates transcriptional regulation

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5/24/2014 22

Spitz Nevi with BAP1 loss

  • Sporadic or familial (syndromic)
  • Germline BAP1 loss families with

increased incidence of uveal/cutaneous melanoma, renal cell carcinoma, mesothelioma.

  • Not clinically atypical (small, domed,

papular, often non-pigmented)

  • BAP1 loss often observed in the Spitzoid

portion of combined nevi

39 yo woman on the back Indication: diagnostic ambiguity

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Botton, Yeh et al. PCMR 2013 MAD1L1-BRAF fusion

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5/24/2014 24

23 year old woman with melanoma

  • f small

bowel No history

  • f

melanoma

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97

Skin 2008 Small bowel 2011

Thank you

iwei.yeh@ucsf.edu

Initiating Oncogenes in Blue Nevi and Uveal Melanoma

VanRaamsdonk et al. 2010 NEJM

GNAQ GNA11 Unknown

Blue Nevi Uveal Melanoma