The Landscape of Somatic Copy Number Alterations in Head and Neck Squamous Cell Carcinoma

Yang, Jian; Chen, Yi; Luo, Hong; Cai, Haoyang

doi:10.3389/fonc.2020.00321

Cited by 22 publications

(23 citation statements)

References 75 publications

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“…Likewise, in HNSCC, 11q loss is associated with cell line resistance to radiation and is linked to poor outcome in oral cavity cancer 30,41 . Several studies have highlighted the higher prevalence of 11q loss in HPV+ HNSCC as opposed to HPV− tumors, 37,42 and distal 11q loss is robustly associated with HPV‐driven carcinomas of the uterine cervix 43 . To our knowledge, no prior studies have demonstrated an association between distal 11q loss and VAF heterogeneity or CNV burden, as we herein report in HPV+ OPSCC.…”

Section: Discussionmentioning

confidence: 99%

Genomic heterogeneity and copy number variant burden are associated with poor recurrence‐free survival and 11q loss in human papillomavirus‐positive squamous cell carcinoma of the oropharynx

Schrank

Lenze

Landess

et al. 2021

Cancer

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Background Human papillomavirus–positive (HPV+) squamous cell carcinoma of the oropharynx (OPSCC) is the most prevalent HPV‐associated malignancy in the United States. Favorable treatment outcomes have led to increased interest in treatment de‐escalation to reduce treatment morbidity as well as the development of prognostic markers to identify appropriately low‐risk patients. Intratumoral genomic heterogeneity and copy number alteration burden have been demonstrated to be predictive of poor outcomes in many other cancers; therefore, we sought to determine whether intratumor heterogeneity and genomic instability are associated with poor outcomes in HPV+ OPSCC. Methods Tumor heterogeneity estimates were made based on targeted exome sequencing of 45 patients with HPV+ OPSCC tumors. Analysis of an additional cohort of HPV+ OPSCC tumors lacking matched normal sequencing allowed copy number analysis of 99 patient tumors. Results High intratumorally genomic heterogeneity and high numbers of copy number alterations were strongly associated with worse recurrence‐free survival. Tumors with higher heterogeneity and frequent copy number alterations were associated with loss of distal 11q, which encodes key genes related to double‐strand break repair, including ATM and MRE11A. Conclusions Both intratumor genomic heterogeneity and high‐burden copy number alterations are strongly associated with poor recurrence‐free survival in patients with HPV+ OPSCC. The drivers of genomic instability and heterogeneity in these tumors remains to be elucidated. However, 11q loss and defective DNA double‐strand break repair have been associated with genomic instability in other solid tumors. Copy number alteration burden and intratumoral heterogeneity represent promising avenues for risk stratification of patients with HPV+OPSCC.

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Section: Discussionmentioning

confidence: 99%

Genomic heterogeneity and copy number variant burden are associated with poor recurrence‐free survival and 11q loss in human papillomavirus‐positive squamous cell carcinoma of the oropharynx

Schrank

Lenze

Landess

et al. 2021

Cancer

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“…Furthermore, mesenchymal cells such as fibroblastic reticulum cells (CK-positive interstitial reticulum cells, CIRCs) can also express KRT18 in reactive LNs [30] and occur in large numbers in tumor-draining LNs that are subcapsular in the paracortical regions [31,32]. However, 11 of the 14 LN-DTCs displayed typical HNSCC copy number alterations similar to BM-DTCs [33]. In addition, we saw in the five patients with available material from both compartments that the LN-DTCs sometimes cluster very closely with the BM-DTCs of the same patient.…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of single disseminated tumor cells in the lymph nodes and bone marrow of patients with head and neck squamous cell carcinoma

et al. 2021

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Considering the limited information on the biology and molecular characteristics of disseminated tumor cells (DTCs) in head and neck squamous cell carcinoma (HNSCC), we examined the genomic alterations in DTCs from HNSCCs and their potential clinical relevance. To analyze both the lymphatic and hematogenous routes of tumor cell dissemination, we investigated samples from lymph nodes (LNs) and bone marrow (BM) of 49 patients using immunofluorescence double staining for epithelial cells expressing cytokeratin 18 (KRT18) and/or epithelial cell adhesion molecules (EpCAM, CD326). The identified marker-positive cells were isolated by micromanipulation followed by single-cell whole-genome amplification and metaphase-based comparative genomic hybridization (mCGH) to determine genome-wide copy number alterations. The findings were correlated with clinical parameters and follow-up data. We detected chromosomal aberrations in KRT18-and EpCAM-positive cells from both compartments; BM-derived cells showed a significantly higher percentage of aberrant genome (PAG) per cell than cells detected in LNs. No significant association was found between DTC data and clinical follow-up. Genomic profiling of BM-DTCs revealed genomic alterations typical for HNSCC, suggesting hematogenous dissemination of subclones around the time of surgery. In contrast, DTC data in LNs revealed that several marker-positive cells were not of malignant origin, indicating the presence of epithelial glandular inclusions in parts of the processed neck LN

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“…The Genomic Identification of Significant Targets in Cancer (GISTIC2.0) algorithm was utilized to classify the copy number variant genes with remarkable gains and losses ( Mermel et al, 2011 ). The confidence level was set to 0.95, and other parameters were left at default settings ( Luo et al, 2020 ; Yang et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Identification of Immune-Related Subtypes and Characterization of Tumor Microenvironment Infiltration in Bladder Cancer

Huang

Liu

Zhu

et al. 2021

Front. Cell Dev. Biol.

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Tumors are closely related to the tumor microenvironment (TME). The complex interaction between tumor cells and the TME plays an indisputable role in tumor development. Tumor cells can affect the TME, promote tumor angiogenesis and induce immune tolerance by releasing cell signaling molecules. Immune cell infiltration (ICI) in the TME can affect the prognosis of patients with bladder cancer. However, the pattern of ICI of the TME in bladder cancer has not yet been elucidated. Herein, we identified three distinct ICI subtypes based on the TME immune infiltration pattern of 584 bladder cancer patients using the ESTIMATE and CIBERSORT algorithms. Then, we identified three gene clusters based on the differentially expressed genes (DEGs) between the three ICI subtypes. In addition, the ICI score was determined using single sample gene set enrichment analysis (ssGSEA). The results suggested that patients in the high ICI score subgroup had a favorable prognosis and higher expression of checkpoint-related and immune activity-related genes. The high ICI score subgroup was also linked to increased tumor mutation burden (TMB) and neoantigen burden. A cohort treated with anti-PD-L1 immunotherapy confirmed the therapeutic advantage and clinical benefit of patients with higher ICI scores. In the end, our study also shows that the ICI score represents an effective prognostic predictor for evaluating the response to immunotherapy. In conclusion, our study deepened the understanding of the TME, and it provides new ideas for improving patients’ response to immunotherapy and promoting individualized tumor immunotherapy in the future.

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The Landscape of Somatic Copy Number Alterations in Head and Neck Squamous Cell Carcinoma

Cited by 22 publications

References 75 publications

Genomic heterogeneity and copy number variant burden are associated with poor recurrence‐free survival and 11q loss in human papillomavirus‐positive squamous cell carcinoma of the oropharynx

Genomic heterogeneity and copy number variant burden are associated with poor recurrence‐free survival and 11q loss in human papillomavirus‐positive squamous cell carcinoma of the oropharynx

Genetic analysis of single disseminated tumor cells in the lymph nodes and bone marrow of patients with head and neck squamous cell carcinoma

Identification of Immune-Related Subtypes and Characterization of Tumor Microenvironment Infiltration in Bladder Cancer

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