Perspective Chapter: Molecular Pathology of Lung Cancer

*Shivani Gandhi, Ishani Gupta, Reetika Menia and Raman Kumar*

#### **Abstract**

Lung cancers, due to delays in diagnosis and availability of limited treatment resources, have become the leading cause of cancer-related death globally. With the recent advances in the identification of molecular mechanisms and profile of lung cancer, the understanding of novel characteristics of the molecular pathology of lung cancers as well as knowledge of driver mutations has been enhanced that has led to the development and success of targeted strategies against lung cancer. Diagnosis and treatment of this heterogeneous group of cancer have been revolutionized with the advent of the identification of genetic alterations. This chapter will summarize the etiopathogenesis, current knowledge depicting the series of events associated with the development of lung cancer, the molecular mechanism of most common and relevant genetic alterations in lung cancer along with a brief about the use of targeted therapies in lung cancer patients.

**Keywords:** molecular, pathology, lung cancers, molecular mechanism, tumor suppressor genes

#### **1. Introduction**

Lung cancer is one of the most frequently diagnosed cancers worldwide and is the leading cause of cancer-related mortality, late diagnoses being one of the commonest reasons for this. A total of 13% of new cases of cancer as well as 19% of deaths related to cancer are attributed to lung cancers globally. A total of 1.8 million new cases of lung cancer were estimated in the year 2012. Cancer-related mortality due to lung cancer is common in men, with the highest number of cases being reported from Mizoram in both males and females (age-adjusted rate 28.3 and 28.7 per 100,000 population in males and females, respectively). A total of 6.9% of all new cases of cancer and 9.3% of deaths related to cancer are constituted by lung cancer alone in India in both men and women. The 5-year survival rate is less than 15%, despite significant advances in both diagnostic and therapeutic approaches [1–3].

With the identification of the molecular profile of lung cancer, the understanding of molecular pathology has also been enhanced. Many genetic alterations in the cancer stem cells have been revealed with the help of molecular studies and these cancer stem cells play an important role to produce clones of cancer cells to form tumor mass. Many genetic driver mutations have been identified with the help of

combined genomic and transcriptomic sequencing studies and these driver mutations undergo stepwise accumulation resulting in the development of lung cancer. Molecular-targeted therapies have been identified to predict the response in patients of lung cancers to these targeted therapies with the advent and identification of driver mutations. The identification and knowledge of the molecular pathology of lung cancers have further led to the modification in the histological classification of cancers of the lung. A huge success rate has been observed in the development as well as approval of the targeted therapies and approach with the improved understanding in the identification of the genetic signature and the pathogenesis of molecular mechanism in approximately 20% of squamous cell carcinoma (SCC) and 60% of adenocarcinoma of lung. Dramatic response rates along with improved progression-free survival (PFS) have been observed with the use of targeted therapies in patients of lung cancers harboring mutations of genes like epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene. Therefore, molecular testing is now being routinely used to guide the clinical care of lung cancer patients to predict one's therapeutic response [4–9].

Lung cancers have been classified into several histological subtypes based on the molecular profiles and targetable genetic alterations in lung cancer. It is a heterogeneous disease that shows variation in clinical features and biological behavior. Heterogeneity in the molecular mechanism reflects the molecular changes that occur in different subtypes of lung cancer. Genetic abnormalities associated with the development of cancer include a gain of function mutation of oncogenes like EGFR, BRAF, KRAS, AKL, MET, HER-2, loss of function mutation of tumor suppressor genes like TP53, PTEN, STK11, expression of growth factor, and their receptors. Targeted therapies are highly dependent upon molecular pathology; thus, the thorough understanding and knowledge of the molecular mechanism of different types of lung cancer is an integral part to understand the biological behavior and predict the response of cancer to the targeted therapy. With the identification of genetic mutations involved in particular cancer, the biological behavior of lung cancer can be determined which is essential for the diagnostic and therapeutic strategies that can target molecular aberrations.

In addition to the well-known genetic alterations in lung cancer that have been previously identified such as BRAF, EGFR & KRAS, many other genetic alterations such as ERBB2, RET, JAK2, DDR2 that occur in low frequency but are recurrent have also been identified with the help of genomic studies that have led to the development of targeted approach against lung cancers [10–13].
