Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors

Lechner, Matthias; Frampton, Garrett M.; Fenton, Tim R.; Feber, Andrew; Palmer, Gary A.; Jay, Amrita; Pillay, Nischalan; Förster, Martin; Cronin, Maureen; Lipson, Doron; Miller, Vincent A.; Brennan, Timothy A; Henderson, Stephen; Vaz, Francis; O’Flynn, Paul; Kalavrezos, Nicholas; Yelensky, Roman; Beck, Stephan; Stephens, Philip J.; Boshoff, Chris

doi:10.1186/gm453

Cited by 190 publications

(226 citation statements)

References 41 publications

Supporting

Mentioning

198

Contrasting

Unclassified

Order By: Relevance

“…The consistent observation in early work of a mutually exclusive relationship between amplification of the 11q13.3 chromosomal band (found in high frequency across HNSCC, and other cancers) and the presence of HPV in tumours remains one of the most striking differences observed within HNSCCs (Smeets et al, 2006;Ragin et al, 2006;Klussmann et al, 2009;Lechner et al, 2013;Seiwert et al, 2015). This separation may be attributable to the divergent mechanisms by which chemical carcinogens (via genetic amplification and consequent over-expression of Cyclin D1 gene CCND1 within the 11q13.3 amplicon -often in combination with genetic or functional loss of restriction point Cyclin Kinase Inhibitor p16INK4A) and HPV (via HPV oncoproteins E6 and E7) achieve dysregulation of the cell cycle.…”

Section: Introductionmentioning

confidence: 88%

“…A mutually exclusive association between 11q13.3 amplification, smoking history and HPV/p16 has been widely reported across many populations (Smeets et al, 2006;Ragin et al, 2006;Klussmann et al, 2009;Lechner et al, 2013;Seiwert et al, 2015). Our findings are consistent with this model, observing again an inverse relationship between HPV/p16 status and the presence of CCND1 and ANO1 copy number gains.…”

Section: Genes Chromosomes and Cancermentioning

confidence: 99%

“…example, mutation, amplification and over-expression of elements of the PI3 kinase pathway (in particular the p110 catalytic subunit gene PIK3CA at 3q26.3) have been consistently observed across both aetiological groups (Smeets et al, 2006;Wilting et al, 2009;Lechner et al, 2013;Cancer Genome Atlas Network, 2015;Keck et al, 2015;Seiwert et al, 2015).…”

Section: Page 3 Of 33 John Wiley and Sons Genes Chromosomes And Cancermentioning

confidence: 99%

“…( Lechner et al, 2013;Walter et al, 2013;Cancer Genome Atlas Network, 2015;Keck et al, 2015;Seiwert et al, 2015). In the present study, we targeted one aspect of genetic change that can underlie malignant progression -copy number gain -at specific sites in four genes strongly associated with head and neck cancer -PIK3CA, TP63, CCND1 and ANO1.…”

Section: John Wiley and Sons Genes Chromosomes And Cancermentioning

confidence: 99%

See 3 more Smart Citations

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma

Pattle¹,

Utjesanovic²,

Togo

et al. 2016

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Squamous cell carcinomas of the hypopharynx (HPSCC) and oropharynx (OPSCC) have markedly different patient outcomes. Differences in HPV prevalence between these two patient groups may account for some of this difference, but other molecular markers of prognosis or pathological phenotype have not been established. Copy number gain of oncogenes is a well-established molecular change contributing to HNSCC development. Quantitative PCR was used to explore copy number gains of specific genes (3q -PIK3CA, TP63; 11q13.3 -CCND1, ANO1) in tumour DNA recovered from HPSCC (n=48) and OPSCC (n=52) patients. Associations between copy number gain, patient demographics, HPV/p16INK4a status and pathological stage were examined.HPV/p16 prevalence in HPSCC and OPSCC groups was 2.1% and 46.0% respectively. HPSCCs had frequent gains of CCND1 (56.3%) and ANO1 (56.3%) but few gains of PIK3CA (6.3%). By contrast, OPSCCs had significantly fewer CCND1 (23.1%) and ANO1 (17.3%) gains, and significantly more PIK3CA (26.9%) gains. A mutually exclusive relationship between HPV/p16 and 11q13.3 gains was observed in OPSCCs, while PIK3CA and TP63 gains were similar across HPVassociated and smoking/alcohol-associated patients. ANO1 gain was significantly linked to tumour pathology in HPSCC, associating with nodal metastasis and smaller and less invasive tumours at presentation (p=0.010). Our results provide a convincing link between a specific molecular change and disease phenotype that appears unique to our HPSCC population, supporting a model of 11q13.3 in promoting metastatic disease progression in HNSCC, and suggest a role for ANO1 as a molecular marker of metastatic disease. words

show abstract

Section: Introductionmentioning

confidence: 88%

Section: Genes Chromosomes and Cancermentioning

confidence: 99%

Section: Page 3 Of 33 John Wiley and Sons Genes Chromosomes And Cancermentioning

confidence: 99%

Section: John Wiley and Sons Genes Chromosomes And Cancermentioning

confidence: 99%

See 2 more Smart Citations

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma

Pattle¹,

Utjesanovic²,

Togo

et al. 2016

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

show abstract

“…HPV positive ( C ) HNSC is associated with better prognosis, 49 while TP53 mutation and CDKN2A deletion are associated with HPV-negative ( ¡ ) HNSC. 50 Unsupervised clustering on 211 AA gene expression levels grouped HPV C patients with patients showing the most favorable survival and HPV ¡ patients with TP53 and CDKN2A mutant patients (Fig. 5); therefore, it seems that distinct HNSC phenotypes are detectable as perturbed AA transcript abundance.…”

mentioning

confidence: 99%

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

et al. 2015

View full text Add to dashboard Cite

Aberrant activation or disruption of autophagy promotes tumorigenesis in various preclinical models of cancer, but whether the autophagy pathway is a target for recurrent molecular alteration in human cancer patient samples is unknown. To address this outstanding question, we surveyed 211 human autophagy-associated genes for tumorrelated alterations to DNA sequence and RNA expression levels and examined their association with patient survival outcomes in multiple cancer types with sequence data from The Cancer Genome Atlas consortium. We found 3 (RB1CC1/FIP200, ULK4, WDR45/WIPI4) and one (ATG7) core autophagy genes to be under positive selection for somatic mutations in endometrial carcinoma and clear cell renal carcinoma, respectively, while 29 autophagy regulators and pathway interactors, including previously identified KEAP1, NFE2L2, and MTOR, were significantly mutated in 6 of the 11 cancer types examined. Gene expression analyses revealed that GABARAPL1 and MAP1LC3C/LC3C transcripts were less abundant in breast cancer and non-small cell lung cancers than in matched normal tissue controls; ATG4D transcripts were increased in lung squamous cell carcinoma, as were ATG16L2 transcripts in kidney cancer. Unsupervised clustering of autophagy-associated mRNA levels in tumors stratified patient overall survival in 3 of 9 cancer types (acute myeloid leukemia, clear cell renal carcinoma, and head and neck cancer). These analyses provide the first comprehensive resource of recurrently altered autophagy-associated genes in human tumors, and highlight cancer types and subtypes where perturbed autophagy may be relevant to patient overall survival.

show abstract

Prevalence of High-Risk Nonvaccine Human Papillomavirus Types in Advanced Squamous Cell Carcinoma Among Individuals of African vs Non-African Ancestry

Williams

Newberg²,

Williams

et al. 2021

JAMA Netw Open

View full text Add to dashboard Cite

High-risk human papillomavirus (hrHPV) causes squamous cell carcinoma (SCC) at a variety of sites, including cervix, head and neck, anus, vulva, vagina, and penis. The 9-valent HPV vaccine is highly effective at preventing carcinomas at these sites related to the specific HPV types it covers. Among women with hrHPV detected in routine cervical swabs, however, the distribution of hrHPV types is known to differ by racial/ethnic group, with East and West Africans 1 and North Americans of African ancestry 2,3 showing overrepresentation of hrHPV types that are not covered by the current 9-valent HPV vaccine. Corresponding studies of HPV type distribution by ethnicity in advanced-stage hrHPV-related cancers are limited. In this investigation, we performed a retrospective analysis of a large multiethnic study of advanced-stage carcinoma samples to test the hypothesis that patients of African vs non-African ancestry may show dissimilar distributions of nonvaccine hrHPV types. MethodsOur archive of 290 311 tumor samples, each from a different patient, underwent comprehensive genomic profiling using a hybrid-capture-based DNA sequencing platform. 4 The samples were sent from medical care facilities across North America from January 2014 to June 2020 for detection of targetable genetic alterations during routine clinical care. Western Institutional Review Board approved this study, including issuing an informed consent waiver and a HIPAA waiver of authorization. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies. We detected hrHPV genomic sequences in 3793 cervical, anogenital, and head and neck SCCs by de novo assembly of nonhuman reads, followed by alignment to the RefSeq database, which distinguishes hrHPV types. 5 Patient ancestry was determined by classifying specific single-nucleotide variations by genomic profiling based on their known variation among populations in the 1000 Genomes Project. 6 The comparator groups were individuals of African vs non-African ancestry. Categorical data were analyzed by Fisher exact test using Prism version 8.3.1 (GraphPad Software). Data were analyzed in July 2020. A 2-tailed P value of <.05 was considered statistically significant; the Bonferroni correction was applied for multiple simultaneous comparisons. Statistical analysis was performed for hrHPV types with 10 or more cancer cases total in individuals of African ancestry. ResultsWe identified 5 hrHPV types each with 10 or more SCC cases in individuals of African ancestry: HPV-16 (193 cases), HPV-18 (56 cases), HPV-35 (17 cases), HPV-45 (27 cases), and HPV-59 (16 cases).Compared with non-African groups, individuals of African ancestry showed significant, several-fold enrichments for HPV types 35 (5.3% vs 1.6%; P < .001), 45 (8.4% vs 3.4%; P < .001), and 59 (5.0% vs 0.5%; P < .001) (Figure ), with significant enrichments in cervical (HPV-35, 5.2% vs 1.3%; P = .003; HPV-59, 9.0% vs 0.9%; P < .001) and anal (HPV-45, 7.0% vs 1.0%; P = .0...

show abstract

Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors

Cited by 190 publications

References 41 publications

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

Prevalence of High-Risk Nonvaccine Human Papillomavirus Types in Advanced Squamous Cell Carcinoma Among Individuals of African vs Non-African Ancestry

Contact Info

Product

Resources

About