JOURNAL OF THE ROYAL SOCIETY OF MEDICINE
The role of oncogenes and tumour-suppressor genes in the
aetiology of oral, head and neck squamous cell carcinoma
J K Field MA PhD BDS
J R Soc Med 1995;88:35P-39P
Keywords: oncogenes; tumour suppressor genes; head and neck; oral cancer
INTRODUCTION
Squamous cell carcinoma of the head and neck accounts for
the sixth most common solid tumour worldwidel. Even
though there is a very high incidence of the disease in India
and South East Asia it still accounts for approximately 2% of
all neoplasms in the Western World and the prognosis for
treatment of this disease is generally accompanied by severe
dysfunction and disfigurement with a poor prognosis2,3. The
importance of identifying the molecular mechanisms in oral
and head and neck cancer has begun to receive a great deal of
attention in the last 8 years and it is now possible to suggest
certain molecular events in the progression of this disease.
This information may in time lead to the development of
strategies to target therapy at the gene products causing
malignant transformation and progression of these tumours.
In the future, it may also be possible to identify individuals
who have a genetic susceptibility to oral, head and neck
cancers.
Cancer is a multi-step process which is initiated by
carcinogenic induced genetic damage in certain cells and, if
undetected by the cells' DNA repair mechanism, develop a
selective growth advantage and form a tumour. It is now
recognized that there are two classes of cancer genes,
oncogenes and tumour suppressor genes. The oncogene class
of genes are probably involved in both initiation and
progression of the disease, whereas the tumour suppressor
genes produce tumours following mutational damage or
inactivation. The reader is referred to a number of good
reviews for further background information on these two
classes of cancer genes".
Normal cells or proto-oncogenes may become activated
oncogenes by a carcinogen, irradiation or possibly a virus.
Activation of the oncogene may be in the form of
chromosomal translocations, gene amplification, point
mutations or deletionss. The action of oncogenes has been
demonstrated at the level of growth factors and their
receptors, signal transduction systems and also nuclear
proteins. In contrast to proto-oncogenes, the tumour
suppressor genes are normal genes, when activated by a
mutation, deletion or by a virus, causes deregulation of
critical pathways controlling growth and differentiation6.
Department of Clinical Dental Sciences, Univerty of Lverpool, P 0 Box 147,
Uverpool L69 3BX, UK
Volume 88 January 1995
PAPER READ TO RSM SYMPOSUM, 6 OCTOBER 1992
A search for molecular changes in the progression of
head and neck cancer have been undertaken at all levels of
molecular oncology, which includes; cytogenetic analyses for
chromosomal rearrangements, deletions, inversions,
translocations; DNA level for mutations, amplification,
translocations and deletions, as well as expression at both
the RNA and protein level.
Cytogenetic and loss of heterozygosity studies
Cytogenetic analysis has demonstrated that oral, head and
neck carcinomas are of a polyclonal origin, as a range of
different clonal lines have been isolated from many single
tumours analysed. Even though all of the chromosomal
complement in various studies has been shown to have a
cytogenetic abnormality, there is mounting evidence to
indicate that specific breakpoints are important in the
development of the disease (Table 1)7-10. In a study on 16
head and neck squamous cell carcinoma cell lines,
chromosomal deletions and duplications were examined in
detail9. The regions with the most frequent duplications
were found to be: 7 cen-plS (87.5%) and 3 cen-qter and 8
cen-q21.2 less frequently; whereas other regions were more
frequently deleted (7q, 8p, 10p, 18, 19p, 21q, 22q and the
short arms of the acrocentric chromosomes).
Cytogenetic and loss of heterozygosity studies in fresh
tumour specimens, point to two specific chromosomal areas
that are clearly important in the development of head and
neck cancers, namely the 1 lqI 3 region7 and a deletion in the
3p region. The 1 1q13 region has already received a great
deal of attention in a number of neoplasiasll-12. The 1lql3
region contains two separate amplifiable regions, one
fibroblast growth factor proto-oncogene, and the putative
tumour suppressor gene MEN 1. Amplification of the int-2
(FGF3), bcl-1 and hst-1 genes have been specifically reported
in head and neck cancers13. However, the Prad- 1 gene is the
only one of this group which has been shown to be
overexpressed in any neoplasm11.
Deletions in the long arm of chromosome 3 have also
been studied by loss of heterozygosity (LOH) analysis, and a
commonly deleted region on 3p distal to 3pl4 and proxinal
to 3p25 has been identified14. Furthermore, in a cytogenetic
analysis of 15 laryngeal tumours, a deletion in 3p was found
in 60% of the cases10. This is a particularly interesting region 35P
 IJOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 88 January 1 995

Table 1 Chromosome abboratons In head and neck squamous cell India19. All other investigations into ras mutations in the
carcinoma from data on breakpoint hotapots, chromosomal deletons/
dupllcaions, and loss of hoterozygosi studies. This table has been Western World have shown that incidence of these
compiled from the results of the following papers: Jin et aL, 1991 (Ref 7); mutations is 5% less2O-24; thus mutations in this gene
Owens et aL.; 1992 (Ref 8); Cowan, 1992 (Ref 9); Allegrm t al., 1992 (Ref most likely play a minor role in the development of head and
10); Latit et aL, 1992 (Ref 14); Sheng et al., 1989 (Ref 22); Hauser-Urfer neck cancer outside India and South East Asia.
and Stauffer, 1985 (Ref 68); Saranath et al., 1991 (Ref 70); Howell et aL,
1989 (Ref 71); Mtleman, 1992 (Ret 72)
Amplification of oncogenes in oral,
head and neck cancer
Chromosome Regions with aberrations
Amplification of oncogenes has been associated with the
1 1p13; 1p22; 1p36: 1q21: 1q32
development of a range of cancers; however, amplification of
2
a gene does not always result in overexpression of the gene
3 3p11; 3p13; 3p21; 3pter-p23; 3p14-25;
product and therefore its role in such neoplastic cells is
3cent-qter unclear25. Amplffication of a number of oncogenes has been
4 4q21; 4q1 -q21; 4q21-qter studied in head and neck cancer. These include the ras and c-
5 myc gene families and int-2 and erbB1 oncogenes.
6 The ras and myc gene families are not normally found to
7 7q22; 7cent-p15; 7cent be amplified in head and neck carcinomas in the Western
8 8p1 1.2; 8cent-q21.2; 8cent worldl3. In a recent study only 4% of a group of 141
9 9q32; 9cent squamous cell carcinomas of the head and neck were found
10 1Oq11.2; 1Qpter-q21.2 to have c-myc amplification (Field et al., unpublished) and the
11 llp; 11p15; 11q13; 11q23 ras gene family has not been found to be amplified by any
12 research group. The one exception to these findings comes
13 13p11-p13: p c.m from a study in India, where Saranath et al.26, found
14 14p11:parm amplification of H-ras (17%), N-ras (30%), N-myc (39%) and
15 p arm c-myc (17%), in Indian patients with oral cancer. These
16 atypical results may be explained by the specific smoking
17 habits and betel nut chewing in India.
18 18q22; 18q21; 18q21-qter Low numbers of tumours with amplification of the
19 19p13.1; 19pter-cen epidermal growth factor receptor gene (erbB-1) have been
20 20p1 3 reported in Western head and neck cancer patients27-28;
21 p arm however, the most important amplification region in head
22 p arm and neck cancers to date has been shown to be in
x chromosome 11 at llql3. The llql3 amplicon region
y contains int-2, hst-1 and bd-1 genes which have been found
to be amplified or co-amplified in the range of 25-52%13.
The int-2 and hst-1 genes are members of the fibroblast
of the genome as it is already known that the 3pl4-p25 area growth factor gene family and function in angiogenesis as
contains a number of as yet unidentified tumour suppressor mitogenic growth factors. The clinical correlations of hst/
genes, in renal carcinomas, small cell and non small cell int-2/bd-l amplification are uncertain in these tumours but
carcinomas of the lung and carcinomas of the cervixls ,6 there may be an interaction that affects prognosis27'30.
Recent evidence points to Prad- 1 in the I 1ql 3 region having
Oncogene mutations In oral, a possible role in squamous cell carcinomas as it has
head and neck cancer
sequence homology with the cyclin family which may
The ras gene family has been implicated in the development control cell cycle progression31-33. Further research is
of a large number of human malignancies17. This gene family required to dissect out which of these genes in conjunction
consists of H-ras, K-ras and N-ras which encode for a protein with the putative tumour suppressor genes of this region
of 21 kD molecular weight, which possess guanosine (MEN-1, EmS1), are the main players in the progression of
triphosphate (GTP) activity18. Mutations in the ras genes head and neck cancer.
are usually found in codons 12, 13, and 61. An exceptionally
high incidence of ras mutations has been found in carcinoma Over expression of oncogenes In
of the pancreas (90%) and approximately 50% of carcinomas oral and head and neck cancer
of the colon and thyroid also have these mutations17. Over expression of erbB-1, ras gene family and the c-myc
However, the importance of ras mutations in oral, head and oncogene has been reported in head and neck squamous cell
36P neck carcinomas appears to be limited to oral cancer in carcinomasI3. Over expression of erbB-1 has been shown to
 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 88 January 1995

Table 2 Po3 Overepmosion In

Number Overexpressed Anotomical squamous eall carcinomas of the
of tumours (%) region Reference head and neck

73 67 Head and neck Field et a. 1992 (Ref 52)

47 34 Head and neck Gusterson et at. 1992 (Ref 54)
55 62 Head and neck Watling et at. 1992 (Ref 59)
33 64 Head and neck Pavelic et a. 1992 (Ref 60)
37 54 Oral Ogdon et a. 1992 (Ref 55)
15 80 Oral Langdon and Partridge 1992 (Ref 56)
20 20 Tongue Sauter et a/. 1992 (Ref 73)
58 60 Larynx Maestro et a/. 1992 (Ref 57)
30 81 Larynx Dolcetti et a/. 1992 (Ref 58)

correlate with the level of differentiation of the tumour34;
however, erbB-2 probably has no role in the development of
the disease35.
Over expression of ras p2l has been reported by a
number of groups in a high percentage of head and neck
cancers despite the fact that ras mutations are rare in this
disease. It is of note that Sheng et aL.22 found that the level of
Ha-ras expression in head and neck cancer was not determined
by genetic alterations of the Ha-ras gene, in the form of loss of
an allele, mutations or the presence of a rare allele. Therefore
as yet unexplained mechanisms are responsible for over
expression of ras in head and neck cancer. Over expression of
ras p2l was found to correlate with a favourable cinical
prognosis in a UK group of patients36 but two groups in
Japan37-38 found differing results which were at variance with
each other. It is of note that a Japanese group found a
correlation between ras p2l expression and a history of
smoldng37 but this was not found in the UK study39. In
contrast, an asssociation between over expression of ras p2l
and the p53 tumour suppressor gene correlated with a history
of heavy smoking in the UK study39.
Over expression of the c-myc gene has been found to
correlate with a poor prognosis in head and neck cancers40.
We have also found a similar correlation in nasopharyngeal
carcinomas from Hong Kong41. C-myc genetic alterations
have also been shown to be associated with a poor prognosis
in cancer of the breast and cervix4243.
p53 Tumour suppressor gene in oral
and head and neck cancers
Over half of adult cancers, induding lung, breast, colon,
oesophagus and skin cancers contain p53 mutations44 and
aberrant expression is now considered to be one of the most
common genetic features in a wide range of human
cancers45. The p53 gene is located on chromosome 17 and
behaves as a negative regulator; however, it may be
converted into a dominant oncogene by a mutation in its
gene. Recently, it has been shown to have a biochemical role
as a specific transcription factor and to have a biological role
as a G1 check point control for DNA damage4"9. The
majority of p53 mutations in human tumours have been
reported to date in the highly conserved evolutionary domains
of exons 5-844. Furthermore, the p53 tumour suppressor
gene (TSG) is ideally suited to study mutational spectra in
association with certai mutagens6. Chibia et al.50 found that
56% of bronchial carcinoma had G-T tranversions in the p53
TSG and Suzuki et al. have reported similar findings51.
Initial investigations into p53 expression in head and neck
cancer indicated that about 60% of these cancers over-
expressed this geneS240 (Table 2), but no correlations have
been found between p53 overexpression and any of the
clinicopathological parametersS2. P53 mutations have been
shown in squamous cell carcinomas from the head and neck
region using site specific primers, single stranded
conformational polymorphism (SSCP) analysis and
sequencing techniquesS4S7'61-66. P53 mutations in head and
neck tumours appear to have a hot spot region at position
238-248 and these comprise 33% of the 47 head and neck
cancers so far sequenced. The nudeotide transversion
patterns of the p53 mutations in head and neck cancers
have shown that G-T transversions account for 63% of cases
in the USA64 whereas G-A transversions have been found in
50% of the Japanese patients analysed65. Further research in
the area of sequencing may point to a relationship between
specific mutagens and p53 mutations and thus advance our
knowledge of head and neck carcinogenesis.
In none of the studies into p53 expression in head and
neck cancers has a correlation been found with any of the
clinico-pathological data and we have found no correlation
with survival in 103 patients calculated from the date of
diagnosis66. However, we have recently demonstrated a
correlation between p53 over expression and a very poor
prognosis in 'end stage disease patients', indicating that p53
over expression has a very specific effect on tumour behaviour
in the late stages of the disease. A further correlation between
p53 expression and heavy smoking was initially shown by us52
and subsequently by other groupsS5-56. Furthermore, we
found that the majority of patients that have stopped smoking 37P
 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE
Chromosomal Break Points
I 1p22 IIqlS3 pdol
11q13 ampicon
Q(int4/beIi/hst-I/prad-1)
..............................
..
pS mutatlons and over-expresslon
.........
ra over-expression and mutationa
... , ....~~................
m o- overrexpreaon
Eb
E-cadherin down regulation
INITIATION PROGRESSION
POTENTIALY _ CARCINOMA a NODAL
MALIGNANT METASTASIS
LESION
Figure 1 Proposed molecular model for the genetic events In
squamous cell carcinoma of the head and neck
5-18 years prior to developing a head and neck cancer also
over expressed the p53 gene52. An interaction between the
alcohol and tobacco has been considered for some time as
having a synergistic role in the development of head and neck
cancer and thus the correlation we have recently
demonstrated between heavy smoking/drinling and over
expression of pS3 would support this hypothesis53.
Molecular models have been proposed to explain the
different genetic events that are involved in the development
of neoplasia. The most elaborate model to date is that
suggested by Fearon and Vogelstein67 for colonic neoplasia.
Research into head and neck cancer has progressed
considerably in latter years and a model has been
postulated for a number of genetic events in the
development of this disease13 (Figure 1). The elegant
mouse model system for squamous cell carcinomas
developed by Balmain and co-workers has shown many
similarities with the proposed model for head and neck
cancers and even though the sequence of these genetic events
is still very poorly understood, the model does provide a
hypothesis on which to develop this line of tiinldng.
Only with the development of large international data
bases of head and neck tumour material and the careful
clinical follow-up of these patients, together with the
rigorous investigation of multiple genetic markers, will we
be able to make the next major steps in our understanding of
this disease process. Then the clinical potential of molecular
markers will be realized in the fields of diagnosis, prognosis
and possibly, in future, in therapy.
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(Accepted 8 MCarch 1994) 39P