LUNG CANCER

Iman Azari| Prof. Omrani

Shahid BeheshtiUniversity of Medical Sciences

INTRODUCTION & HISTORY

Lung cancer, which was rare prior to 1900 with fewer than 400 cases described in the medical literature, is considered a disease of modern man.

By the mid-twentieth century, lung cancer had become epidemic and firmly established as the leading cause of cancer-related death in North America and Europe

Tobacco consumption is the primary cause of lung cancer, a reality firmly century and codified with the release of the U.S. established in the mid-twentieth

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INTRODUCTION & HISTORY CONT’D

U.S Surgeon General’s 1964 report on the health effects of tobacco smoking. Following the report, cigarette use started to decline in North America and parts of Europe, and with it, so did the incidence of lung cancer.

Although tobacco smoking remains the primary cause of lung cancer worldwide, 60% of new lung cancers in the U.S occur in former ≌smokers, many of whom quit decades ago, or never smokers.

Moreover one in five women and one in 12 men diagnosed with lung cancer have never smoked.

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WHY LUNG CANCER IS MATTER?

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WHY LUNG CANCER IS MATTER?

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WHY LUNG CANCER IS MATTER?

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Lung cance

r is m

ore co

mm

on in m

en than

women

WHO GETS THIS CANCER?

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WHO DIES FROM THIS CANCER? Fi

rst l

eadi

ng c

ause

of c

ance

r de

ath

in U

S

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CLASSIFICATION OF LUNG CANCER

There are two main categories of lung cancer : • non-Small cell lung cancer

Common : Squamous cell carcinoma (epidermoid carcinoma). Large cell carcinoma Adenocarcinoma

Less Common : Pleomorphic Carcinoid tumor Salivary gland carcinoma Unclassified carcinoma

• Small cell lung cancer : • Small cell carcinoma (oat cell cancer)• Combined small cell carcinoma

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non-Small cell lung cancer(NSCLC)

• NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC).

• Representing 80% to 85% of cases:

Adenocarcinoma (40% of lung cancers). Squamous cell carcinoma (25% of lung cancers). Large cell carcinoma (10% of lung cancers)

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• Subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of :

EGFR and downstream MAPK and PI3K signaling pathways.

These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors

Adenocarcinoma

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Adenocarcinoma, cont’d

• All mutations in adenocarcinoma are mutually exclusive, except for those involving PI3KCA and BRAF mutations, EGFR mutations, or ALK translocations

• EGFR and ALK mutations predominate in adenocarcinomas that develop in nonsmokers (fewer than 100 cigarettes in a lifetime)

• KRAS and BRAF mutations are more common in smokers or former smokers.

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Squamous cell carcinoma

• Is most commonly found in men and is strongly associated with smoking.

• Chromosome deletions : 3p, 9p (site of the CDKN2A gene), and 17p (site of the TP53 gene) are early events in tumor evolution, being detected at an appreciable frequency in the histologically normal respiratory mucosal cells of smokers.

• Squamous cell carcinomas show the highest frequency of TP53 mutations of all histologic types of lung carcinoma (60% to 90%)

• Loss of expression of the retinoblastoma (RB) : 15%

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Large cell carcinoma

• Large cell carcinoma is an undifferentiated malignant epithelial tumor that lacks the cytologic features of other forms of lung cancer.

• Clinically, large cell carcinoma is significantly associated with smoking.

• TP53 mutations are highly enriched in this tumor type.• Approximately 40% of large cell carcinomas contain an activating

KRAS mutation.• Other reported alterations include mutations in BRAF and NRAS.

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Small cell carcinoma

• Most aggressive of lung tumors, metastasizing widely and virtually always proving to be fatal.

• Despite its divergent histologic features shares many molecular features with squamous cell carcinoma.

• Shows the strongest association with smoking; only about 1% occurs in nonsmokers

• Loss-of-function aberrations involving TP53 (75% to 90% of tumors), RB (close to 100% of tumors), and chromosome 3p deletions.

• Also common is amplification of genes of the MYC family.29

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microRNA-Mediated Regulation• As We know, miRNAs are a class of non–protein-encoding small RNAs

capable of regulating gene expression : directly cleaving a targeted mRNA inhibiting translation by interacting with the 3′ UTR of a target mRNA.

• There is currently a strong research focus on microRNAs as potential diagnostic(early diagnosis) and prognostic biomarkers and therapeutic targets for lung cancer.

• For detection of miRNA profiles we can use peripheral blood and sputum.

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• Aberrant expression of miRNAs has been found to play an important role in the pathogenesis of lung cancer

• miRNAs can function as either TSGs or oncogenes.• Restoration of aberrantly expressed miRNAs can be achieved in vitro

and in vivo using miRNA mimics (for expression miRNAs) or ⬇miRNA inhibitors (for expression miRNAs). ⬆

• Concurrent inhibition or overexpression of miRNAs with conventional therapies has resulted in an increased response to EGFR TKIs, radiotherapy, and chemotherapy.

microRNA-Mediated Regulation cont’d

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(oncomir)

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• The let-7 family is a cluster of miRNAs that function as TS , frequently underexpressed in lung tumors, associate with poor prognosis.

• Let-7 regulates multiple oncogenes: RAS, MYC, and HMGA2 via binding to the let-7 binding sites in 3′ UTRs.

• An example of important oncogenic miRNA in lung cancer is RAS-regulated miR-21 which promotes cellular growth, invasion and metastasis by targeting multiple genes with tumor suppressive effects such as negative regulators of the RAS/RAF/MAPK pathway, pro- apoptotic, and anti-metastatic genes.

microRNA-Mediated Regulation cont’d

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Aberrant methylation is an early event in lung cancer

pathogenesis and is detectable in DNA circulating

in the blood, many studies have investigated methylation status as a biomarker for risk assessment, early detection,

disease progression, and prognosis in lung cancer

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Why molecular features is important?

Targeted therapy : Which Patient , What Therapeutic Protocol ? (Predictive purpose)

Prognostic purpose Therapeutic Targets : New Targets for Drug

Discovery The More Important : Early Detection

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Transformation to SCLC from NSCLC can occur at any time during active treatment. The specific moment when the transformation occurs has not been elucidated. After EGFR-specific TKI treatment, resistant pluripotent cells can accumulate

genetic alterations (such as the loss of RB1 and TP53), which give them a distinct epigenetic state and capability of differentiation in a lineage that does not require EGFR signaling, such as SCLC. 49

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REFERENCES

• The Molecular Basis of Cancer 4th ed 2015, John Mendelsohn, MD, Chapter 32

• The Molecular Basis of Human Cancer 2nd ed 2017, Chapter 28

• Robbins & Cotran Pathologic Basis of Disease 9th ed 2015, Chapter 15

• Harrison's Principles of Internal Medicine 19th ed 2015, Part 7, Chapter 107

• http://www.cancer.gov/types/lung

• doi:10.1038/nrdp.2015.9

• doi: 10.21037/tlcr.2016.07.10

• doi:10.1038/nrc.2016.56

• http://dx.doi.org/10.1016/j.path.2016.04.003

• http://dx.doi.org/10.1016/S0140-6736(16)30958-8

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REFERENCES

• doi: 10.1158/0008-5472.CAN-10-1346

• doi:10.1038/nrclinonc.2015.90

• doi:10.1126/scitranslmed.aaf6282

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