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

(3 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…Total RNA was previously submitted to the University of Michigan DNA sequencing core for library preparation and sequencing using the Illumina TruSeq Stranded Total RNA library prep kit. This data were previously summarized [19]. Here, to study viral content in greater detail, we leveraged the HPViewer pipeline using default settings to characterize HPV read counts in the cohort [20].…”

Section: Clinical Specimens and Annotation Of Viral Genomesmentioning

confidence: 99%

Analysis of Human Papilloma Virus Content and Integration in Mucoepidermoid Carcinoma

Bhangale

Neal

et al. 2022

Viruses

View full text Add to dashboard Cite

Mucoepidermoid Carcinomas (MEC) represent the most common malignancies of salivary glands. Approximately 50% of all MEC cases are known to harbor CRTC1/3-MAML2 gene fusions, but the additional molecular drivers remain largely uncharacterized. Here, we sought to resolve controversy around the role of human papillomavirus (HPV) as a potential driver of mucoepidermoid carcinoma. Bioinformatics analysis was performed on 48 MEC transcriptomes. Subsequent targeted capture DNA sequencing was used to annotate HPV content and integration status in the host genome. HPV of any type was only identified in 1/48 (2%) of the MEC transcriptomes analyzed. Importantly, the one HPV16+ tumor expressed high levels of p16, had high expression of HPV16 oncogenes E6 and E7, and displayed a complex integration pattern that included breakpoints into 13 host genes including PIK3AP1, HIPI, OLFM4,SIRT1, ARAP2, TMEM161B-AS1, and EPS15L1 as well as 9 non-genic regions. In this cohort, HPV is a rare driver of MEC but may have a substantial etiologic role in cases that harbor the virus. Genetic mechanisms of host genome integration are similar to those observed in other head and neck cancers.

show abstract

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

Analysis of Human Papilloma Virus Content and Integration in Mucoepidermoid Carcinoma

Contact Info

Product

Resources

About