Activating mutations of the oncogene EZH2 in cutaneous melanoma revealed by next generation sequencing

Abstract

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that promotes tumorigenesis by epigenetic repression of tumor suppressor genes. Although EZH2 is overexpressed in many malignancies, activating EZH2 mutations have been described predominantly in follicular lymphoma and diffuse large B-cell lymphoma. EZH2 activating mutations in melanoma are not well described. Here, we report a case of cutaneous melanoma that displayed an EZH2 (Y641S) activating mutation detected by transcriptome sequencing as well as BRAF (V600K). The patient had concurrent follicular lymphoma that lacked both the EZH2 (Y641) and BRAF (V600K) mutations present in the patient's melanoma. Further, we screened publicly available sequence data and identified four additional melanoma cases harboring activating EZH2 mutation. Our findings provide additional evidence that activating recurrent EZH2 mutations occur in cutaneous melanoma, to our knowledge the first solid tumor shown to ⁎

The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD)

“…These modifications have clear implications for cancer biology, as EZH2 modifications promoting protein stability have been recently associated with lung cancer (42) and lymphoma (43). An example of a critical motif with clear human evidence of disease pathogenesis is Tyr-641; variable mutations in humans lead to lymphoma, reportedly through hyperactivation (Y641S) (44) or altered substrate specificity or affinity (45,46). It is tempting to speculate that cytokine signaling pathways common in the intestinal milieu of CD may lead to kinase activation regulating EZH2 function, as has been suggested for Akt-and Stat3-dependent pathways (47,48).…”

Next generation sequencing of Cytokeratin 20-negative Merkel cell carcinoma reveals ultraviolet-signature mutations and recurrent TP53 and RB1 inactivation

“…BAP1 tumor suppressor is a deubiquitinating enzyme that undergoes somatic mutation in many cancers and has been linked to a hereditary cancer syndrome associated with mesothelioma and uveal melanoma, among other tumors (36-38). EZH2 , a histone methyltransferase in the Polycomb Repressor Complex, undergoes oncogenic activating mutations affecting Y641 (also reported as Y646) in lymphoma and melanoma (21, 29, 39). Therapies targeting EZH2 in malignancy are under active investigation (40).…”

“…Selected single nucleotide variations affecting AKT1, PIK3CA, RB1, TP53, EZH2, PTCH1, TSC1, and BAP1 were validated by PCR amplification using new or previously reported primer pairs (Supplemental Table S3)(19-21), followed by Sanger sequencing at the University of Michigan Sequencing Core. Chromatograms were visualized using Sequence Scanner 2 software.…”

PRC2 is high maintenance

“…The EZH2-Y646 mutations, including tyrosine to serine, asparagine, phenylalanine, cysteine, or histidine (EZH2 Y646X ; X = S, N, F, C, or H), are gain-of-function "kinetic mutants" ( Fig. 13B; see "EZH2 Y646X Mutant Tumors") and are found in ∼20% of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and ∼1% of cutaneous melanoma (Morin et al 2010;Harms et al 2014). Intriguingly, recent reports indicate that the EZH1 Q571R mutation exhibits a gain-offunction activity in ∼27% of autonomous thyroid adenomas (ATA) (Calebiro et al 2016).…”