الفهرس 
Histological Classification of Lung CancerOnly 14 pages are availabe for public view
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Abstract
Summary
Lung cancer is one of the deadliest cancers worldwide, with
the highest incidence and mortality amongst all cancers. While
the prognosis of lung cancer is generally grim, with 5-years
survival rates of only 15%, there is hope, and evidence, that
early detection of lung cancer can reduce mortality. Lung
cancer can be classified into two major groups: small cell lung
cancer (SCLC) and non-small cell lung cancer (NSCLC). The
latter group is further divided into subtypes of squamous cell
carcinoma, large cell carcinoma and adenocarcinoma. Among
these three, adenocarcinoma is the most common subtype and
has a high mortality rate. The methylation of tumor suppressor
genes has been investigated in all kinds of cancer.
Identification of tumor specific epigenetic alterations can be
used as a molecular marker of malignancy, which can lead to
better diagnosis, prognosis and therapy. Therefore, the aim of
this study was to evaluate the association between gene
hypermethylation and expression of fragile histidine triad
(FHIT), glutathione S-transferase P1 (GSTP1) and p16 tumor
suppressor genes and various clinicopathologic characteristics
in primary non-small cell lung carcinomas (NSCLC).
Summary
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This study was conducted on 28 primary untreated NSCLC
patients and 28 corresponding adjacent apparently normal
tissue specimens. The patients were comprised of 20 males
and 8 females who ranged in age from 32–68 years (median,
53 years) at the time of diagnosis. The morphological
classification of the carcinomas was conducted according to
the WHO specifications. Of the carcinomas, 16 were
adenocarcinomas, 9 were squamous carcinomas, and 3 were
large cell carcinomas. All patients were staged at the time of
their surgery according to the guidelines of the American Joint
Committee on Cancer. Five patients had Stage I, 11 patients
had Stage II, and 12 patients had Stage III. The methylation
status of the FHIT, GSTP1 and p16 promoters by MSP, and
the expression levels of these genes as mRNA using a realtime
PCR assay with SYBR -Green I were analyzed in all
tissue sections (NSCLC & Control).
The results presented in this study revealed that:
• The promoter methylation of the FHIT gene was 53.57%
(15/28) and 3.57% (1/28) in NSCLC and control groups;
respectively, while that for the GSTP1 gene was 25%
(7/28) and 0% (0/28) in NSCLC and control groups;
respectively, however, the frequency for p16 gene promoter
methylation was 0% (0/28) in both groups.
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• There were a significant statistical association between
promoter methylation of the FHIT and GSTP1 genes and
lung cancer risk as results of Relative Risk Ratio (RRR)
showed that the risk of FHIT hypermethylation increased
among patients with NSCLC by 2.88 while the risk of
GSTP1 hypermethylation increased among patients with
NSCLC by 2.33.
• FHIT methylation occurred in 13 out of 20 men (65%) and
2 out of 8 women (25%) while GSTP1 promoter
methylation in both males and females was 25% (5/20 and
2/8; respectively). Hypermethylation of the FHIT & GSTP1
gene promoters had no correlation with gender (p > 0.05).
• The percentage of smoking patients with FHIT promoter
methylation was 68.42% (13/19) and that for nonsmokers
was 22.22% (2/9), while the percentage of smoking patients
with GSTP1 methylation was 26.32% (5/19), similar to
nonsmoking patients (22.22%), i.e. percentages of
nonsmoking patients with FHIT & GSTP1 methylation
were the same. Hypermethylation of FHIT gene promoter
had a significant correlation with smoking habit (p <0.05)
but there was no correlation between GSTP1 promoter
hypermethylation and smoking habit (p > 0.05), table 5.
• FHIT methylation occurred more frequently in squamous
cell carcinomas (77.78%) than in adenocarcinomas
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(43.75%) and large cell carcinoma (33.33%) while GSTP1
methylation occurred more frequently in large cell
carcinoma (33.33%) than in adenocarcinomas (25%) and
squamous cell carcinomas (22.22%), however, these
differing results were not statistically significant (p > 0.05).
• FHIT promoter methylation in stage I was 0% (0/5), in
stage II was 27.27% (3/11), and in stage III was 100%
(12/12) while GSTP1 methylation in stage I was 20% (1/5),
in stage II was 36.36% (4/11) and in stage III was 16.67%
(2/12). Hypermethylation of FHIT gene had a highly
significant correlation with pathologic staging (p < 0.01)
but there was no correlation between GSTP1
hypermethylation and pathologic staging (p > 0.05).
• About 10.71% (3/28) of the NSCLC patients had
methylation of both gene promotors, while 57.14% (16/28)
of NSCLC patients had methylation of at least one of the
two gene promoters, and 32.14% (9/28) of NSCLC patients
had no methylation of any of the two gene promoters.
• Data obtained from qPCR analysis revealed that the
expression level of FHIT mRNA was downregulated in
53.57% (15/28) of NSCLC tissues and that of GSTP1
mRNA was downregulated in 21.43% (6/28) of NSCLC
tissues while that of p16 mRNA was upregulated in 75%
(21/28) of NSCLC tissues.
Summary
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In conclusion, the results of the current study suggest that
methylation of FHIT is a useful biomarker of biologically
aggressive disease in patients with NSCLC. FHIT methylation
may play a role in lung cancer’s later metastatic stage while
GSTP1 methylation may play a role in the early pathogenesis
of lung cancer rather than in its later metastatic stage.