Science in medicine
The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 6 June 2012
Clinical and epidemiological features
Squamous cell carcinoma of the head and neck (HNSCC) is the
sixth most common cancer worldwide, affecting 600,000 new
patients each year. In the United States, 50,000 new cases are diag-
nosed, and nearly 10,000 deaths are attributable to this disease
annually. Despite their common origin in the squamous mucosa
of the upper aerodigestive tract, there are several sources for the het-
erogeneity of HNSCC that complicate their consideration as a single
disease entity. Anatomically, the head and neck region consists of
several distinct structures (e.g., lip, tongue, nasopharynx, orophar-
ynx, larynx, hypopharynx) with distinct microscopic features and
lymphatic and venous drainage. As a result, treatment approaches
and outcomes vary significantly among the different subsites. In
addition, etiologic risk factors vary among the different subsites,
and HNSCC can occur in young patients without any known risk
factors. Biologic heterogeneity independent of subsite has been sug-
gested by molecular analyses that have uncovered distinct classes of
HNSCC with unique mRNA expression profiles or patterns of DNA
copy number alterations that correlate with clinical behavior (1–4).
Although the most important risk factors are tobacco use and alco-
hol consumption, infection with high-risk types of human papilloma
viruses (HPVs) has also been recognized as an increasingly important
risk factor, particularly for oropharyngeal squamous cell carcino-
ma (OPSCC). Importantly, survival for patients with HPV-positive
OPSCC is significantly better than for HPV-negative cancers, irre-
spective of treatment modality (5–8). Possible explanations include
both host-intrinsic factors (healthier patients with fewer comorbidi-
ties) and tumor-intrinsic factors (distinct genetic pathogenesis yield-
ing enhanced treatment sensitivity). The relatively good prognosis
of HPV-related cancers highlights an unfortunate paradox — despite
improvements in outcome for patients with oropharynx cancers, little
or no improvement has been observed for patients with HPV-negative
tumors over the past 30 years (9). This fact is attributable at least in
part to our limited understanding of molecular pathways that both
promote HSNCC pathogenesis and can be targeted therapeutically.
Linking pathways to genetics
Recent advances in our understanding of the molecular pathogenesis
of HNSCC were provided by whole-exome sequencing (i.e., sequenc-
ing exons of all known protein-coding genes) conducted on a total of
approximately 100 HNSCC specimens independently by two groups
(10, 11). While the two studies analyzed etiologically similar tumors
with related sequencing platforms, there was a five-fold difference in
the average number of mutations reported per tumor. This differ-
ence likely reflects distinct bioinformatic and validation approaches
used in the studies, and therefore a subset of identified changes may
represent “passenger” mutations (as a result of increased mutation
rates in cancer cells, or even mutation “miscalls”) rather than true
“driver” mutations with an etiologic role in HNSCC. Nevertheless,
several key findings were shared by these studies. This work, together
with a large body of previous genomic and functional analyses of
HNSCC, highlights the relatively small number of oncogenes tar-
geted by activating mutations and supports the fundamental roles
of tumor suppressor pathways including p53, Rb/INK4/ARF, and
Notch in disease pathogenesis. These and other bona fide HNSCC
cancer genes play major roles in at least four key functional path-
ways: cellular proliferation, squamous epithelial differentiation, cell
survival, and invasion/metastasis, with many of the genes impacting
more than a single pathway (Figure 1). These pathways are critical
to the pathogenesis of HNSCC and, not surprisingly, reflect normal
developmental programs within the stratified squamous epithelium.
Given the paucity of driver oncogenes in HNSCC, targeting these
pathways therapeutically represents a substantial and critical chal-
lenge for improving outcomes of this disease.
Cellular proliferation and p53/Rb/CDKN2A/CCND1
Mutation of the TP53 tumor suppressor gene is the most common
and among the earliest identified genetic alterations in HNSCC,
occurring in more than half of all cases (2). As in other human can-
cers, missense mutations primarily within the DNA binding domain
account for 75% of all mutations in the TP53 gene and confer both
dominant negative and poorly understood gain-of-function proper-
ties (12–15). In many of the remaining HNSCC tumors in which p53
is wild-type, p53 function may be inactivated by other mechanisms.
The molecular pathogenesis of head and neck
squamous cell carcinoma
S. Michael Rothenberg and Leif W. Ellisen
Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA.
Squamous cell carcinoma of the head and neck (HNSCC) is a relatively common human cancer
characterized by high morbidity, high mortality, and few therapeutic options outside of surgery,
standard cytotoxic chemotherapy, and radiation. Although the most important risk factors are
tobacco use and alcohol consumption, the disease is also linked to infection with high-risk types
of human papilloma viruses (HPVs). Recent genetic analyses have yielded new insights into the
molecular pathogenesis of this disease. Overall, while somatic activating mutations within classi-
cal oncogenes including PIK3CA and RAS occur in HNSCC, they are relatively uncommon. Instead
genetic data point to a contribution of multiple tumor suppressor pathways, including p53,
Rb/INK4/ARF, and Notch, in tumor initiation, progression, and maintenance. The increasingly refined knowledge
of HNSCC genetics, combined with ever-more-sophisticated animal models and newer drug targeting strategies,
should promote novel therapeutic approaches and improved disease outcomes.
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J Clin Invest. 2012;122(6):1951–1957. doi:10.1172/JCI59889.
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