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Evaluation of the clonal origin of multiple primary melanomas using molecular profiling.

ABSTRACT: Numerous investigations have been conducted using molecular profiling to evaluate the possible clonal origin of second malignancies in various cancer types. However, to date no study assessing clonality of multiple primaries has been conducted in melanoma. In this investigation using patients treated at a specialist melanoma treatment center, we compared the somatic mutational profiles of pairs of melanomas designated as independent on the basis of thorough assessment of their clinical and pathologic characteristics. We used a set of highly polymorphic genetic markers selected on the basis of their chromosomal positions and the frequencies of reported allelic losses at these genetic loci. Our statistical testing strategy showed no significant evidence of clonal origin of the two primaries in 17 of the 19 patients examined. The results suggest that most second melanomas designated as independent primary tumors on the basis of their clinicopathologic features are indeed independent occurrences of the disease, supporting the validity of the criteria used by experienced pathologists in distinguishing new primaries from metastases.

SUBMITTER: Orlow I

PROVIDER: S-EPMC2745834 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Evaluation of the clonal origin of multiple primary melanomas using molecular profiling.

Orlow Irene I Tommasi Diana V DV Bloom Bradley B Ostrovnaya Irina I Cotignola Javier J Mujumdar Urvi U Busam Klaus J KJ Jungbluth Achim A AA Scolyer Richard A RA Thompson John F JF Armstrong Bruce K BK Berwick Marianne M Thomas Nancy E NE Begg Colin B CB

The Journal of investigative dermatology 20090312 8

Numerous investigations have been conducted using molecular profiling to evaluate the possible clonal origin of second malignancies in various cancer types. However, to date no study assessing clonality of multiple primaries has been conducted in melanoma. In this investigation using patients treated at a specialist melanoma treatment center, we compared the somatic mutational profiles of pairs of melanomas designated as independent on the basis of thorough assessment of their clinical and patho ...[more]

PMID: 19282844

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Project description:BackgroundCarcinoma of unknown primary origin (CUP) accounts for 2%-5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm.Materials and methodsCentrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture-based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death-ligand 1 (PD-L1) positivity were determined.ResultsA total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ?16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD-L1 expression (tumor proportion score ?50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%.ConclusionsThirty-two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD-L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP-informed treatment. Clinical trial identification number. NCT03498521 IMPLICATIONS FOR PRACTICE: The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death-ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling-informed treatment.

Dataset Information

Evaluation of the clonal origin of multiple primary melanomas using molecular profiling.

Publications

Evaluation of the clonal origin of multiple primary melanomas using molecular profiling.

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