DNA methylation in lung cancer

1. Introduction
 Lung carcinoma ,is 2nd most malignant tumor characterized by
uncontrolled cell growth in lung tissue.
 Untreated cancer spreads to nearby organs or organs distant from
the primary site by the process of metastasis.
 236,740 and 130,180 cases of newly diagnosed and deaths resp, in
2022 were reported.

2. Types of Lung cancer

3. Epigenetics
 Epigenetics involves reversible changes
that affect gene activity and expression
turning it ON or OFF.
 Epigenetics controls gene
expression in two ways without
changing DNA sequence.
1. DNA Methylation.
2. Histone Modification.

4. DNA Methylation
 DNA methylation involves covalent addition
of a methyl group to the carbon 5 position of
a cytosine base by DNA methyltransferases
(DNMTs).
 DNA methylation occurs at the genomic
regions enriched with CpG dinucleotide
contexts, called CpG Islands.

5. .

6. DNMTs Dysregulation in Lung cancer
Mechanism of DNMTs include.
 Dysregulation of Transcription Factors (P53/sp1).
 Downregulation of miRNA
 Impaired proteasomal degradation DNMTs.
DNMTs
DNMT1 DNMT2 DNMT3A DNMT3B DNMT3L
Upregulated in Cancers
Upregulated in lung cancers
DNMT3A might act as tumor suppressor.

7. Hypermethylation of tumor suppressor genes (TSGs) promoters by
DNA methyltransferase (DNMT)
Direct Inhibition Indirect Inhibition
Interaction blocked between methylated
DNA and methylation sensitive TFs.
Recruitment of HDAC to the MBD
complex

8. DNA Methylation and cancer

9. TETs Dysregulation
Ten- Eleven Translocation
TET1 TET2 TET3
Downregulation in normal cells,
exposed to carcinogens
 TET1 acts as an oncogene in LUAD, LUSC , with a P53 loss of function.

10. Inhibitors of DNMTs
 Commonly used as 5- Azacytidine
 They work by forming covalent bonds with
DNMTs, inactivating these enzymes
 Thus the previously silenced genes including TSG
are expressed.

11. Smoking and DNA methylation
 Tobacoo smoking_ higher risks for lung cancer.
Highly related to SCLC development.
 2.5% cases among non-smokers
 Associated with hypomethylation and
hypermethylation.
 Smoke Carcinogens are likely to increase DNMT1
expressions.
Effects of cigarette smoke on DNAm

12. Conclusion
 Changes in DNA methylation patterns are an important characteristic of human cancer including
lung cancer
 In particular, hypermethylation of CpG islands is a signature of malignant progression
 Methylated CpG islands are promising diagnostic markers for the early detection of cancer
 The dysregulation of DNMTs, TETs plays a major role in altering DNAm patterns in Lung cancer
 Determination of the methylation patterns of multiple genes to obtain complex DNA methylation
signatures promises to provide a highly sensitive and specific tool for lung cancer diagnosis