Integrative sequencing discovers an ATF1-motif enriched molecular signature that differentiates hyalinizing clear cell carcinoma from mucoepidemoid carcinoma

Neal, Molly Heft; Gensterblum-Miller, Elizabeth; Bhangale, Apurva; Kulkarni, Aditi; Zhai, Jingyi; Smith, Joshua D.; Brummel, Collin; Foltin, Susan K.; Thomas, Deena; Jiang, Hui; McHugh, Jonathan B.; Brenner, J. Chad

doi:10.1016/j.oraloncology.2021.105270

Cited by 5 publications

(2 citation statements)

References 38 publications

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“…Some authors proposed that PPMS and AFH exist on a morphologic and molecular spectrum 43 , 49 . Finally, both HCCC 50 – 55 and CCOC 56 – 60 harbor only EWSR1-ATF1 , supporting the notion that HCCC and CCOC are likely related tumors. Nevertheless, it is evident from our meta-analysis of the published literature and from the current study that there is significant intertumoral overlap as well as intratumoral heterogeneity of fusion transcript variants and exon usage across the different CREB family translocation tumors.…”

Section: Discussionsupporting

confidence: 63%

Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates

et al. 2022

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To elucidate the mechanisms underlying the divergent clinicopathologic spectrum of EWSR1/FUS - CREB translocation-associated tumors, we performed a comprehensive genomic analysis of fusion transcript variants, recurrent genetic alterations (mutations, copy number alterations), gene expression, and methylation profiles across a large cohort of tumor types. The distribution of the EWSR1 / FUS fusion partners – ATF1 , CREB1 , and CREM – and exon involvement was significantly different across different tumor types. Our targeted sequencing showed that secondary genetic events are associated with tumor type rather than fusion type. Of the 39 cases that underwent targeted NGS testing, 18 (46%) had secondary OncoKB mutations or copy number alterations (29 secondary genetic events in total), of which 15 (52%) were recurrent. Secondary recurrent, but mutually exclusive, TERT promoter and CDKN2A mutations were identified only in clear cell sarcoma (CCS) and associated with worse overall survival. CDKN2A/B homozygous deletions were recurrent in angiomatoid fibrous histiocytoma (AFH) and restricted to metastatic cases. mRNA upregulation of MITF , CDH19 , PARVB , and PFKP was found in CCS, compared to AFH, and correlated with a hypomethylated profile. In contrast, S100A4 and XAF1 were differentially upregulated and hypomethylated in AFH but not CCS. A sarcoma methylation classifier was able to accurately match 100% of CCS cases to the correct methylation class; however, it was suboptimal when applied to other histologies. In conclusion, our comprehensive genomic profiling of EWSR1/FUS - CREB translocation-associated tumors uncovered mostly histotype, rather than fusion-type associated correlations in transcript variants, prognostically significant secondary genetic alterations, and gene expression and methylation patterns.

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Section: Discussionsupporting

confidence: 63%

Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates

et al. 2022

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“…A summary of sequencing quality statistics including total unique mapped reads for each sample is provided in Table S1, Supporting Information. FPKM and TPM were quantified from the data as previously described 18,19 …”

Section: Methodsmentioning

confidence: 99%

Tumor immune microenvironment alterations using induction cetuximab in a phase II trial of deintensified therapy for p16‐positive oropharynx cancer

et al. 2023

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Background We sought to characterize early changes in CD8+ tumor‐infiltrating lymphocytes and tumor transcriptomes after induction cetuximab in a cohort with p16‐positive oropharyngeal cancer on a phase II clinical de‐escalation trial. Methods Tumor biopsies were obtained before and 1 week after a single cetuximab loading dose in eight patients enrolled in a phase II trial of cetuximab and radiotherapy. Changes in CD8+ tumor‐infiltrating lymphocytes and transcriptomes were assessed. Results One week after cetuximab, five patients (62.5%) had an increase in CD8+ cell infiltration with a median (range) fold change of +5.8 (2.5–15.8). Three (37.5%) had unchanged CD8+ cells (median [range] fold change of −0.85 [0.8–1.1]). In two patients with evaluable RNA, cetuximab induced rapid tumor transcriptome changes in cellular type 1 interferon signaling and keratinization pathways. Conclusions Within 1 week, cetuximab induced measurable changes in pro‐cytotoxic T‐cell signaling and immune content.

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Molecular Pathology of Salivary Gland Tumors

Cheung,

Gupta

2023

Molecular Surgical Pathology

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Integrative sequencing discovers an ATF1-motif enriched molecular signature that differentiates hyalinizing clear cell carcinoma from mucoepidemoid carcinoma

Cited by 5 publications

References 38 publications

Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates

Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates

Tumor immune microenvironment alterations using induction cetuximab in a phase II trial of deintensified therapy for p16‐positive oropharynx cancer

Molecular Pathology of Salivary Gland Tumors

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