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  • Review Article
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The molecular biology of head and neck cancer

Nature Reviews Cancer volume 11, pages 9–22 (2011)Cite this article

Subjects

Key Points

  • Head and neck squamous cell carcinomas (HNSCCs) develop in the mucosal linings of the upper aerodigestive tract and are the sixth leading cause of cancer worldwide. Risk factors are exposure to carcinogens, most notably tobacco smoking and alcohol consumption, infection with high-risk types of human papillomavirus (HPV) and genetic predisposition.

  • HNSCC is a heterogeneous disease. At least two genetic subclasses can be distinguished: HPV-positive and HPV-negative tumours. Preliminary data suggest that further subclassification is likely to follow.

  • A key issue in HNSCC pathogenesis is that carcinomas develop within large preneoplastic fields of mucosal epithelium made up of genetically altered cells that are clonally related to the carcinoma and often extend into the surgical margins when tumours are excised, and can cause local recurrences and second primary tumours.

  • Limitless replicative potential of head and neck cancer cells is caused by abrogation of the p53 and retinoblastoma (RB) pathways that perturb cell cycle regulation, probably in the context of telomerase reverse transcriptase (TERT) expression.

  • A subgroup of HNSCCs becomes independent from growth factors owing to somatic changes in the epidermal growth factor receptor (EGFR) signalling pathway.

  • Some, if not all, HNSCCs escape from the growth inhibitory transforming growth factor-β (TGFβ) pathway by somatic mutation or chromosome loss of key genes. This pathway seems to be interconnected to the nuclear factor-κB (NF-κB) pathway.

  • Somatic mutations and genetic changes indicate that the PI3K–PTEN–AKT pathway is frequently activated in HNSCC.

  • Metastatic dissemination of HNSCC is initially to the lymph nodes in the neck. Expression profiles predict lymph node metastasis, but causative cancer genes have not yet been identified.

  • The unravelling of the biological characteristics of HNSCC will lead to novel and personalized therapies in the near future.

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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Figure 1: Cell cycle deregulation by human papilloma virus.
Figure 2: Schematic overview of the genetic classification of head and neck squamous cell carcinoma.
Figure 3: Field cancerization and local relapse.
Figure 4: Proposal of an integrated model of molecular carcinogenesis for head and neck squamous cell carcinoma.
Figure 5: Schematic overviews of two signalling pathways that have a role in head and neck squamous cell carcinoma.

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Acknowledgements

The authors' research summarized here is supported by the Cancer Center Amsterdam/VU Research Institute on Cancer and Immunology, the Dutch Cancer Society, the European Commission (6th framework program), The Netherlands Organization for Scientific Research (NWO), The Fanconi Anaemia Research Fund, The German Fanconi Support Group, the Dutch Children Cancer-free Foundation, and the Center for Translational Molecular Medicine (AIRFORCE project). The authors would like to apologize to those authors whose work could not be cited directly owing to space constraints.

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  1. Department of Otolaryngology–Head and Neck Surgery, VU University Medical Center, PO BOX 7,057, 1007 MB, Amsterdam, The Netherlands

    C. René Leemans, Boudewijn J. M. Braakhuis & Ruud H. Brakenhoff

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Correspondence to C. René Leemans.

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Glossary

Chemoradiation

Combined treatment with chemotherapy (usually cisplatin) and radiation.

Ploidy

The number of chromosomes in a cell. Normal human cells are diploid, having a DNA index of 2c, a state also referred to as euploid. Cancer cells are often tetraploid, with a DNA index of 4c, or aneuploid, with a DNA index somewhere between 2c and 4c. The DNA index reflects the number of numerical genetic changes: the losses and gains of chromosomes or parts of chromosomes.

Comparative genomic hybridization

(CGH). A method to visualize the presence or absence of chromosomes or parts of chromosomes in a tumour sample by fluorescence microscopy. Array CGH is comparable to CGH, except that the labelled DNAs are not hybridized to metaphase spreads but to DNA molecules on a glass slide, which increases the resolution.

Oral leukoplakia

The most common premalignant lesion of HNSCC, defined as a white plaque in the mucosal linings that indicates questionable risk after the exclusion of other known diseases or disorders that carry no increased risk of cancer.

Squamous epithelium

Multilayered epithelium covering the linings of the upper aerodigestive tract.

Loss of heterozygosity

(LOH). A genetic change that describes the loss of one allele of a gene for which the other allele is already inactivated.

Telomere

The linear end of a chromosome. The telomere is shortened with each round of DNA replication.

MicroRNA

(miRNA). Small RNA (of 22–24 oligonucleotides) generated from larger transcripts that bind target sequences in messenger RNAs in a large complex called the RNA-induced silencing complex (RISC). Binding of miRNAs to their (usually multiple) target transcripts causes transcript degradation or inhibition of protein translation.

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Leemans, C., Braakhuis, B. & Brakenhoff, R. The molecular biology of head and neck cancer. Nat Rev Cancer 11, 9–22 (2011). https://doi.org/10.1038/nrc2982

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