The molecular biology of head and neck cancer
TL;DR: The recent literature on tumour heterogeneity, field cancerization, molecular pathogenesis and the underlying causative cancer genes that can be exploited for novel and personalized treatments of patients with HNSCC are discussed.
Abstract: Head and neck squamous cell carcinomas (HNSCCs) are caused by tobacco and alcohol consumption and by infection with high-risk types of human papillomavirus (HPV). Tumours often develop within preneoplastic fields of genetically altered cells. The persistence of these fields after treatment presents a major challenge, because it might lead to local recurrences and second primary tumours that are responsible for a large proportion of deaths. Aberrant signalling pathways have been identified in HNSCCs and inhibition of epidermal growth factor receptor (EGFR) has proved a successful therapeutic strategy. In this Review, we discuss the recent literature on tumour heterogeneity, field cancerization, molecular pathogenesis and the underlying causative cancer genes that can be exploited for novel and personalized treatments of patients with HNSCC.
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TL;DR: In this article, the authors analyzed whole-exome sequencing data from 74 tumor-normal pairs and found that at least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis.
Abstract: Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.
2,245 citations
TL;DR: To explore the genetic origins of head and neck squamous cell carcinoma, whole-exome sequencing and gene copy number analyses were used to study 32 primary tumors and identified mutations in FBXW7 and NotCH1, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
Abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
1,613 citations
TL;DR: It became apparent that HNSCC is a disease characterized by frequent mutations that create neoantigens, indicating that immunotherapies might be effective and that immunotherapy trials with immune checkpoint inhibitors were published, and these may be considered as a paradigm shift in head and neck oncology.
Abstract: Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are unexpectedly heterogeneous in nature. Classical risk factors are smoking and excessive alcohol consumption, and in recent years, the role of human papillomavirus (HPV) has emerged, particularly in oropharyngeal tumours. HPV-induced oropharyngeal tumours are considered a separate disease entity, which recently has manifested in an adapted prognostic staging system while the results of de-intensified treatment trials are awaited. Carcinogenesis caused by HPV in the mucosal linings of the upper aerodigestive tract remains an enigma, but with some recent observations, a model can be proposed. In 2015, The Cancer Genome Atlas (TCGA) consortium published a comprehensive molecular catalogue on HNSCC. Frequent mutations of novel druggable oncogenes were not demonstrated, but the existence of a subgroup of genetically distinct HPV-negative head and neck tumours with favourable prognoses was confirmed. Tumours can be further subclassified based on genomic profiling. However, the amount of molecular data is currently overwhelming and requires detailed biological interpretation. It also became apparent that HNSCC is a disease characterized by frequent mutations that create neoantigens, indicating that immunotherapies might be effective. In 2016, the first results of immunotherapy trials with immune checkpoint inhibitors were published, and these may be considered as a paradigm shift in head and neck oncology.
802 citations
01 Mar 2016
TL;DR: The changing epidemiology, advances in diagnosis, and treatment options for squamous cell cancers of the head and neck, along with data on risk stratification specific to oropharyngeal cancer are focused on, and the direction of current trials is highlighted.
Abstract: Squamous cell carcinoma arises from multiple anatomic subsites in the head and neck region. The risk factors for development of cancers of the oral cavity, oropharynx, hypopharynx, and larynx include tobacco exposure and alcohol dependence, and infection with oncogenic viruses is associated with cancers developing in the nasopharynx, palatine, and lingual tonsils of the oropharynx. The incidence of human papillomavirus-associated oropharyngeal cancer is increasing in developed countries, and by 2020, the annual incidence could surpass that of cervical cancer. The treatment for early-stage squamous cell cancers of the head and neck is generally single modality, either surgery or radiotherapy. The treatment for locally advanced head and neck cancers is multimodal, with either surgery followed by adjuvant radiation or chemoradiation as indicated by pathologic features or definitive chemoradiation. For recurrent disease that is not amenable to a salvage local or regional approach and for metastatic disease, chemotherapy with or without a biological agent is indicated. To date, molecular testing has not influenced treatment selection in head and neck cancer. This review will focus on the changing epidemiology, advances in diagnosis, and treatment options for squamous cell cancers of the head and neck, along with data on risk stratification specific to oropharyngeal cancer, and will highlight the direction of current trials.
758 citations
Cites background from "The molecular biology of head and n..."
...Human papillomavirus is a small-DNA virus with predilection to cutaneous or mucosal squamous epithelium located in the cervix, anogenital region, and a subset of HNSCCs arising from the oropharynx.(13,14) The oncogenic types HPV-16, HPV-18, HPV-31, and HPV-33 are sexually transmitted and considered as high-risk factors for malignant transformation of infected cells....
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TL;DR: The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes, includingtargetable genomic alterations in FGFR1, DDR2, EGFR, FGFR2/3, EPHA2, and PIK3CA.
Abstract: Purpose: The genetic differences between human papilloma virus (HPV)–positive and –negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown To identify differential biology and novel therapeutic targets for both entities, we determined mutations and copy-number aberrations in a large cohort of locoregionally advanced HNSCC Experimental Design: We performed massively parallel sequencing of 617 cancer-associated genes in 120 matched tumor/normal samples (425% HPV-positive) Mutations and copy-number aberrations were determined and results validated with a secondary method Results: The overall mutational burden in HPV-negative and HPV-positive HNSCC was similar with an average of 152 versus 144 somatic exonic mutations in the targeted cancer-associated genes HPV-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53 , CDKN2A , MLL2 , CUL3 , NSD1 , PIK3CA , and NOTCH genes HPV-positive tumors showed unique mutations in DDX3X , FGFR2 / 3 and aberrations in PIK3CA , KRAS , MLL2 / 3 , and NOTCH1 were enriched in HPV-positive tumors Currently targetable genomic alterations were identified in FGFR1 , DDR2 , EGFR , FGFR2/3 , EPHA2 , and PIK3CA EGFR , CCND1 , and FGFR1 amplifications occurred in HPV-negative tumors, whereas 176% of HPV-positive tumors harbored mutations in fibroblast growth factor receptor genes ( FGFR2 / 3 ), including six recurrent FGFR3 S249C mutations HPV-positive tumors showed a 58% incidence of KRAS mutations, and DNA-repair gene aberrations, including 78% BRCA1/2 mutations, were identified Conclusions: The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes HNSCC harbors multiple therapeutically important genetic aberrations, including frequent aberrations in the FGFR and PI3K pathway genes Clin Cancer Res; 21(3); 632–41 ©2014 AACR See related commentary by Krigsfeld and Chung, p 495
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TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
28,811 citations
"The molecular biology of head and n..." refers background in this paper
...The process of multi-step carcinogenesis and the role of field cancerization is addressed, and signalling pathways that are altered during carcinogenesis are highlighted in line with the cancer-associated phenotypes as defined by Hanahan and Weinber...
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TL;DR: The four articles in this special section onMeta-analysis illustrate some of the complexities entailed in meta-analysis methods and contributes both to advancing this methodology and to the increasing complexities that can befuddle researchers.
Abstract: During the past 30 years, meta-analysis has been an indispensable tool for revealing the hidden meaning of our research literatures. The four articles in this special section on meta-analysis illus...
20,272 citations
TL;DR: The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer, and the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening.
Abstract: A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The formerly HPV-negative cases from this study have therefore been reanalyzed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV-negative and a sample of 48 of the 866 cases which were HPV-positive in the original study. Moreover, 55 of the 66 formerly HPV-negative biopsies were also reanalyzed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR-negative and -positive. Type-specific E7 PCR for 14 high-risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV-negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA-positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV-negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0.001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99.7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening.
8,407 citations
TL;DR: Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.
Abstract: Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.
6,362 citations
TL;DR: In addition to HPV types 16 and 18, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82Should be considered carcinogenic, or high-risk, types, and types 26, 53, and 66 should be considered probably carcinogenic.
Abstract: Background Infection with human papilloma virus (HPV) is the main cause of cervical cancer, but the risk associated with the various HPV types has not been adequately assessed. Methods We pooled data from 11 case–control studies from nine countries involving 1918 women with histologically confirmed squamous-cell cervical cancer and 1928 control women. A common protocol and questionnaire were used. Information on risk factors was obtained by personal interviews, and cervical cells were collected for detection of HPV DNA and typing in a central laboratory by polymerase-chain-reaction–based assays (with MY09/MY11 and GP5+/6+ primers). Results HPV DNA was detected in 1739 of the 1918 patients with cervical cancer (90.7 percent) and in 259 of the 1928 control women (13.4 percent). With the GP5+/6+ primer, HPV DNA was detected in 96.6 percent of the patients and 15.6 percent of the controls. The most common HPV types in patients, in descending order of frequency, were types 16, 18, 45, 31, 33, 52, 58, and 35. A...
5,979 citations