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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Solid Tumour Section
Review
Squamous cell cancer
Daniel L Van Dyke
Department of Medical Genetics, Henry Ford Health System, 2799 West Grand Boulevard, Clara Ford
Pavillion, Detroit, MI 48202, USA (DLV)
Published in Atlas Database: September 2001
Online updated version : http://AtlasGeneticsOncology.org/Tumors/SquamousCellID5130.html
DOI: 10.4267/2042/37819
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
with SCC appear to have a heritable sensitivity to
chromosome breakage by certain clastogens.
Of mendelian diseases, xeroderma pigmentosum and
Bloom syndrome carry a significant risk of skin SCC.
Nasopharyngeal carcinomas are 25 times more frequent
in Kwang Tung Province, China than in whites with
certain HLA haplotypes and familial clustering being
identified. Chinese who emigrated from Kwang Tung
retain a significantly higher risk of developing
nasopharyngeal carcinoma.
Clinics and pathology
Disease
Squamous cell carcinoma (SCC) accounts for the
majority of non-small cell lung cancer, other bronchial
tree cancers, and cancers arising throughout the upper
aerodigestive tract including the oral cavity, paranasal
sinuses, pharynx, larynx, trachea, and esophagus. SCC
is the second most common skin cancer. SCC arises at
many other sites such as salivary gland, esophagus,
bladder, penis, and the female genital tract.
Pathology
Histologic grading (tumor, node, metastasis, TNM) and
evaluation of tumor thickness have been used to predict
survival and to develop algorithms for further
treatment.
The tissues surrounding an SCC often exhibit genetic
damage and premalignant lesions, perhaps secondary to
the same carcinogens, and this entire "cancerization
field" appears to be at risk for second primary cancers.
DNA content and ploidy are correlated with tumor
aggressiveness and responsiveness to some treatments.
Abnormal DNA content has been thought to reflect
altered proliferation capacity of tumor cells and has
been associated with adverse biologic and clinical
behavior. Although most studies suggest worse
prognosis and more aggressive behavior in aneuploid
tumors, these findings are not universal. At some
anatomic sites, aneuploid tumors have a better
prognosis, and improved response with advanced
differentiation.
Etiology
Environmental exposures such as tobacco, alcohol,
chronic mucosal irritation, certain human papilloma
viruses, actinic or low dose radiation, and some
occupational chemical exposures increase the risk of
developing SCC. The DNA of HPV 16,18, and 31 have
been found in human genital cancers and HPV 16 and
18 have been recognized in verrucous carcinomas of
the larynx and SCC of the tongue and tonsil. Epstein
Barr virus (EBV) is a risk factor for nasopharyngeal
SCC in southern China and the Aleutians. Sunlight
exposure is the major causal factor in SCC of the skin.
In the East and Far East, oral cavity and oropharyngeal
cancers account for almost one-half of all cancers. In
Bombay, 50% of all cancers are in the buccal mucosa,
and is associated with chewing pan.
Specific TP53 mutations are associated with tobacco
exposure. Deletions and allelic losses of 9p are more
common in smoking-associated SCC.
Treatment
Epidemiology
Treatments have resulted in modest improvements in
survival in recent years. For head and neck SCC,
standardized with traditional therapies relying on
surgery, radiation therapy, or combined surgeryradiation therapy treatments. Recent efforts in new
There is strong evidence that SCC has a genetic basis.
For families with smoking-related malignancies,
genetic segregation analysis showed strong evidence
favoring an autosomal dominant pattern of inheritance
for predisposition to malignancy. Some individuals
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(1)
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Squamous cell cancer
Van Dyke DL
with the recurrent gains and losses of chromosome
segments. Unbalanced translocations involving bands
1p11-p12, 5q13, 10p11.2, 18q11.2, 11q13, and 7q11.2
were typically associated with deletions. Likewise,
isochromosomes 3q, 5p, 7p, 8q, and 9p are typically
associated with duplication of the arm involved in the
isochromosome, and deletion of the other arm 81.
Deletions involving 3p suggest at least three distinct
targets of loss.
The most universal class of cytogenetic change is
deletion, also observed as loss of heterozygosity (LOH)
in molecular genetic studies. Loss of segments of 3p,
5q, 8p, 9p, 10p, and 18q are among the most common.
The most frequent loss involved 3p.
SCC exhibit recurrent gain of segments within 3q, 5p,
7p, 8q, distal 1q, and 11q13-q23. Duplication 11q13q23 and an apparent homogeneously staining region
(hsr) at 11q13 or 11q21 is relatively common. An hsr
with amplification of PRAD1/CCND1 can be located
in 11q or elsewhere.
treatment strategies have revolved around adjuvant or
concomitant chemotherapy. For most skin SCC,
surgical excision is standard practice.
Prognosis
Largely depends on pathological stage at diagnosis,
which in turn depends to a great extent on the anatomic
site. For example, skin SCC and larynx SCC have a
relatively favorable prognosis because they are
frequently identified at an early stage. SCC of the
nasopharyngeal area is less often detected early, and
the rich blood supply and lymphatic anatomy of the
nasopaharynx encourages early metastatic disease and a
generally less favorable prognosis.
Cytogenetics
Note
The karyotype is typically very complex, but common
features in SCC at one anatomic site are often very
similar to SCC at other anatomic sites, irrespective of
the initiating events (tobacco and alcohol, pan, human
papilloma virus, etc.). These common changes strongly
suggest that initiation, development, and progression of
squamous epithelial neoplasia are controlled by some
of the same genetic pathways, irrespective of anatomic
site.
Cytogenetics Molecular
FISH analysis of SCC in vivo (from histologic
sections) has helped show that the karyotypes observed
in established cell lines accurate reflects that of the
tumor. FISH has also shown that many apparently
independent primary tumors are monoclonal.
Comparative genomic hybridization (CGH) studies
have generally paralleled classical cytogenetics,
although several important differences in findings
between the two techniques remain an area of interest.
Cytogenetics Morphological
Most early cytogenetic studies of SCCHN relied on
analysis of later stage tumors and established cell lines.
More recent studies included short term cell cultures,
and by-and-large the results have been similar.
A common sequence of SCC karyotype evolution
appears to be initial loss of chromosomes or segments,
followed by tetraploidization, and ultimately loss of
previously uninvolved chromosomes from the
tetraploid population. The hypotetraploid cell
population can have a near triploid or even lower DNA
index and number of chromosomes. Many tumors
exhibit both diploid and tetraploid cell subclones. As
with high DNA content, polyploidy is associated with a
more aggressive growth pattern in vitro, high
histopathologic grade, and poor survival.
Earlier stage tumors tend to have more simple
karyotypes. However, within every pathological stage
some tumors have more complex karyotypes. It has
been difficult to assemble a "typical" cascade of genetic
evolution that has broad applicability in SCC, because
most of the recurrent abnormalities have been observed
at every histopathologic stage. Nevertheless, some
recurrent cytogenetic changes tend to arise earlier in
tumor development, and others tend to confer greater
prognostic importance. Common early changes in head
and neck SCC include 9p and 3p deletion, and 17p
mutation, with 5q, 8p, 18q, 21q loss and 11q gain
arising later and involved in disease progression.
Few specific rearrangements or breakpoints have been
documented, and most of those are typically associated
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(1)
Genes involved and proteins
Note
Studies at the molecular level have helped to clarify
some of the cytogenetic observations of recurrent gain
and loss of specific segments. Allelotype studies, and
similar cytogenetic studies, have described a poorer
prognosis as genetic losses accumulate. As with
cytogenetic studies, allelotype results are fairly similar
across anatomic sites, and are even similar to those of
adenocarcinomas of the lung. Some genetic
abnormalities have been recognized by microsatellite
studies that were not common changes in classical
cytogenetic studies (e.g., 4q and 15q deletions and 3q
amplification).
Mismatch repair gene mutations play a negligible role
in the etiology and evolution of SCC. Microsatellite
instability has been reported, but does not appear to be
a major factor in most SCC.
Location: Chromosome arm 3p
Somatic mutations: The most frequent autosomal
abnormality is loss of 3p (50-75% of tumors). It
appears very early, e.g. in bronchial and esophageal
epithelial dysplasias. Isochromosome 3q usually
associated with loss of 3p. Other deletions reveal three
independent regions of loss at 3p14 (FHIT/FRA3B),
41
Squamous cell cancer
Van Dyke DL
3p21, and 3p24-p45. Specific targets at 3p21 remain
elusive but DCL1 is a candidate. The VHL (von Hipple
Lindau) locus may be the target of 3p24-p25 deletion.
Location: Chromosome arm 3q
Somatic mutations: Duplication 3q is often associated
with isochromosome formation and there is almost
always 3p loss in the same tumor. CGH studies suggest
one or more regions of amplification within 3q, and
p63, a p53 homolog, is a possible target of gain at
3q27-3q29.
Location: Chromosome arm 5q
Somatic mutations: 5q12-q31 deletion is very common,
and appears associated with an unfavorable prognosis.
Target candidate genes include MCC and APC at 5q21,
and the a-catenin locus at 5q31. In esophageal cancer,
reduced expression of ·-catenin and E-cadherin have
been associated with tumor dedifferentiation,
infiltration, and lymph node metastasis.
Location: Chromosome arm 7p
Somatic mutations: Frequent gains of 7p may permit
increased activity of EGFR, which is amplified in some
SCC. Amplification is associated with lymph node
involvement in esophageal SCC.
Location: Chromosome arm 8p
Somatic mutations: Distal 8p loss is a recurrent
abnormality, and may target different genes in 8p21,
8p22-p23, and 8p23. FEZ1, a transcription factor
residing at 8p22, may be one genetic target for deletion.
In lung SCC, 8p deletion is an intermediate event,
following after 3p and 9p deletion.
Location: Chromosome arm 9p
Somatic mutations: Loss of 9p is a common and
usually early event. The tumor suppressor gene
p16/CDKN2/MTS1 at 9p22 is the most likely primary
target of deletions. Homozygous deletions and
promoter methylation have been identified. In cervical
SCC, 9p deletion is associated with lymph node
metastasis.
Location: Chromosome arm 16q
Somatic mutations: 16q deletion is a less common but
recurrent finding in SCC at several anatomic sites. Ecadherin is one candidate target.
Location: Chromosome arm 17p
Somatic mutations: TP53 gene mutations are initiating
or very early events in SCC regardless of anatomic site,
already evident in premalignant lesions and are not
usually correlated with tumor aggressiveness or
survival. Deletion of 17p is very common and may
frequently serve to inactivate the remaining normal
homolog in a tumor with a TP53 mutation. In cervical
SCC, 17p loss appears to be a late event correlated
tumor invasion. The specific mutations are directed by
the mutagen involved, e.g, smoking and alcohol in
larynx, betel nut in buccal mucosa, and human
papilloma virus in vulvar SCC.
Location: Chromosome arm 18q
Somatic mutations: Loss of 18q, specifically 18q21q22, is a very poor prognostic indicator in SCC at many
sites, including the head and neck and the female
genital tract. The primary target of loss in SCC is
unknown, but probably exclude Smad2, Smad4, and
DCC.
Location: Chromosome arm 21q
Somatic mutations: Monosomy 21 is common.
Uncommon 21q deletions point to a ubiquitin-specific
protease gene as the possible target.
LocationX and Y chromosomes
Somatic mutations: Y loss is observed in about 50% of
SCC of males, and loss of the short arm of the
inactivated X is common in SCC of females.
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Somatic mutations: Loss of 10p has been observed in
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Location: Chromosome arm 11q
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This article should be referenced as such:
Van Dyke DL. Squamous cell cancer. Atlas Genet Cytogenet
Oncol Haematol. 2002; 6(1):40-43.
Worsham MJ, Wolman SR, Carey TE, Zarbo RJ, Benninger
MS, Van Dyke DL. Common clonal origin of synchronous
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