Genetic Testing: When should it be ordered? Julie Schloemer, MD Dermatology
Outline Germline testing CDKN2A BRCA2 BAP1 Somatic testing Gene expression profiling (GEP) BRAF
Germline vs Somatic testing Genetic testing Germline Somatic CDKN2A mutation Diagnosis Treatment Prognosis BRCA2 mutation FISH, CGH, GEP BRAF mutation GEP BAP1
CDKN2A Encodes 2 cell cycle regulatory proteins, both function as tumor suppressors p16 p14 Mutations in p16 pancreatic tumors Mutations in p14 neural tumors familial melanoma, familial melanoma,
CDKN2A who should be tested? Patients diagnosed with 3 invasive melanomas at any given time Patients with 1 invasive melanoma AND family history of 2 other diagnoses of invasive melanoma or diagnosis of pancreatic cancer in first- or seconddegree relative(s) on the same side of family Leachman et al. Selection criteria for genetic assessment of patients with familial melanoma. J Am Acad Dermatol 2009; 61:677.e1-677.e14
BAP1 BRCA1-associated protein-1 encodes a tumor suppressor protein Mutations in BAP1 uveal and cutaneous melanoma, mesothelioma, clear cell renal cell carcinoma, BAPoma, basal cell carcinoma BAPoma indolent, atypical, Spitzoid melanocytic lesion characterized by loss of BAP1 expression Detected via immunostaining of biopsy specimen
BAP1
BAP1 who should be tested? Patients with 2 confirmed BAP1 tumors Patients with a BAP1 tumor AND first- or second-degree relative with a confirmed BAP1 tumor www.genetests.org
Germline vs Somatic testing Genetic testing Germline Somatic CDKN2A mutation Diagnosis Treatment Prognosis BRCA2 mutation FISH, CGH, GEP BRAF mutation GEP BAP1
BRAF 50-60% of melanomas harbor BRAF mutation at 600 codon V600E mutation (90%) Mutation results in constitutively activated MAP kinase pathway proliferation tumor V600E/K mutation treat with BRAF inhibitors and/or MEK inhibitors
BRAF who should be tested? Patients with Stage III and IV disease Patients with local, satellite, in-transit, nodal and/or distant recurrence When chemotherapy is being considered PCR testing is performed on histopathology slides created from biopsy specimen or excision (fixed in formalin and embedded in paraffin) NCCN Guidelines Version 3.2018 - Melanoma
Gene expression profiling - diagnosis Used to evaluate pigmented lesions using a signature gene expression profile Myriad - mypath (23 biomarker genes) Reports likelihood of malignancy vs benignity Sensitivity: 91.5% Specificity: 92.5% Cost: $1,950 Clarke et al. An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi. Cancer. 2017;617-628.
Gene expression profiling - diagnosis
Gene expression profiling - diagnosis Who should be tested? Original biopsy specimen with uncertain diagnosis, can be used as alternative to or in conjunction with consultation NOT validated on metastatic lesions, nonmelanocytic lesions, re-excision specimens or biopsies from patients on immunosuppressants or receiving radiation
Gene expression profiling - prognosis Castle Biosciences DecisionDX - Melanoma Evaluates expression of 31 gene markers Divides lesions into 2 classes: Class 1: low metastatic risk Class 2: high metastatic risk Cost: $8,000
Gene expression profiling - prognosis Who should be tested? 5% of patients with Breslow thickness <0.75mm have +SLN Patients with stage IA disease account for ~25% of deaths due to melanoma Consider in patients with thin melanomas and/or negative SLN to determine if closer follow-up or adjuvant therapy is warranted Han et al. Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. Journal of Clinical Oncology. 2013;31:4387-4393. Criscione et al. Melanoma thickness trends in the United States, 1988-2006. J Invest Dermatol. 2010;130:793-797.
Gene expression profiling - prognosis Who should be tested? While there is interest in newer prognostic molecular techniques such as gene expression profiling to differentiate melanomas at low versus high risk for metastasis, routine (baseline) prognostic genetic testing of primary cutaneous melanomas (before or following SLNB) is not recommended outside of clinical study (trial). NCCN Guidelines Version 3.2018 - Melanoma
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