An Overview of the Molecular Biology of Lung Cancer

Jill E. Larsen

Monica Spinola

Adi F. Gazdar

John D. Minna

Lung cancer cells have defects in the regulatory circuits that govern normal cell proliferation and homeostasis. Hanahan and Weinberg¹ described the “hallmarks of cancer” as six essential alterations in cell physiology that collectively dictate malignant growth. These acquired capabilities found in lung cancers are self-sufficiency of growth signals, insensitivity to growth-inhibitory (antigrowth) signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. Transformation from a normal to malignant lung cancer phenotype is thought to arise in a multistep fashion, through a series of genetic and epigenetic alterations, ultimately evolving into invasive cancer by clonal expansion. ² These progressive pathological changes in the bronchial epithelium—known as preneoplastic or premalignant lesions—occur primarily as one of three distinct morphological forms: squamous dysplasia, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.³ Bronchial squamous dysplasia and carcinoma in situ (CIS) are the recognized preneoplastic lesions for squamous cell carcinoma; atypical adenomatous hyperplasia (AAH), a putative preneoplastic lesion, for a subset of adenocarcinomas; and neuroendocrine cell hyperplasia for neuroendocrine lung carcinomas.³ These preneoplastic lesions, however, account for the development of only a subset of lung cancers; for example, the precursor lesion for the most common neuroendocrine carcinoma of the lung, small cell lung carcinoma (SCLC), is unknown. Tumors are believed to become increasingly malignant with time, initiating tumorigenesis from possibly only a handful of mutations followed by additional (and different) mutations and epigenetic changes acquired during clonal expansion, where cells possessing in vivo growth advantage become dominant.²

The identification and characterization of these molecular changes in lung cancer is of fundamental importance for improving the prevention, early detection, treatment, and palliation of this disease. The overall goal is to translate these findings to the clinic by using molecular alterations as (a) biomarkers for early detection, (b) targets for prevention, (c) tools for new molecular approaches, (d) signatures for personalizing prognosis and therapy selection for each patient, and (e) targets to specifically kill or inhibit the growth of lung cancer in patients.

Lung cancer arises from neoplastic changes to epithelial cells in the lung. However, it is not known whether all lung epithelial cells are susceptible to malignant transformation or only a subset of these cells; specifically, a major question is whether the changes need to take place in lung epithelial cells with stem cell-like properties. Lung cancer is a heterogeneous disease clinically, biologically, histologically, and molecularly. The underlying causes of this heterogeneity are unknown and could reflect changes occurring in cells with various potential for differentiation (e.g., squamous or adenomatous) or represent different molecular changes occurring in the same target lung epithelial cells. This heterogeneity and molecular complexity contributes to the difficulty in unraveling the pathogenesis of lung cancer. Multiple oncogenes, tumor suppressor genes (TSGs), signaling pathway components, and other cellular processes are involved in the molecular pathogenesis of lung cancer. This chapter will review molecular aberrations in lung cancer and the multiple pathways through which it develops.

The two main disease categories of lung cancer, non-small cell lung cancer (NSCLC) (representing 80% to 85% of cases) and SCLC (representing 15% to 20%), are generally classified based on differences in histological, clinical, and neuroendocrine characteristics. NSCLC and SCLC can also differ molecularly with many genetic alterations exhibiting subtype specificity (summarized in Table 5.1). Additionally, molecular studies of NSCLC have also revealed considerable differences between the subtypes of NSCLC, particularly the two most common subtypes: adenocarcinoma and squamous cell carcinoma.

TABLE 5.1 Common Genetic Alterations Found in Lung Cancer^a

			NSCLC (%)
Gene		SCLC (%)	All	Adenocarcinoma	Squamous Cell	References
Oncogenic Alterations
Mutation
	BRAF	Rare	1-3	1-5	3	¹⁷⁷,¹⁷⁸
	EGFR	Rare	∽20	10-40	Rare	¹⁷⁷,¹⁷⁹,¹⁸⁰,¹⁸¹,¹⁸²
	ErbB2 (HER-2)	Rare	2	4	Rare	¹⁷⁷,¹⁸³
	KRAS	Rare	10-30	15-35	<5	¹⁷⁷,¹⁸⁴,¹⁸⁵,¹⁸⁶
	MET	13	21	14	12	⁶
	PIK3CA	Rare	1-5	2-3	2-7	⁵⁶,¹⁸⁷,¹⁸⁸,¹⁸⁹
Amplification
	EGFR	Rare	20-30	15	30	⁶
	ErbB2 (HER-2)	5-30	2-23	6	2	⁶,¹⁸³,¹⁹⁰,¹⁹¹
	MDM2		6-24	14	22	¹⁹²
	MET		7-21	20	21	¹⁹³,¹⁹⁴
	MYC	18-30	8-22			¹⁹⁵,¹⁹⁶,¹⁹⁷,¹⁹⁸
	NKX2-1 (TITF-1)	Rare	12-30	10-15	3-15	⁶,¹⁴,¹⁵
	PIK3CA	∽5	9-17	6	33-36	⁶,⁵⁶
Increase in protein expression
	CRK		8-30	8-30		¹⁹⁹
	BCL2	75-95	10-35			¹⁸⁶,²⁰⁰,²⁰¹
	CCND1	0	43	35-55	30-35	⁸⁵,²⁰²
	CD44	Rare	Common	3	48	²⁰³
	c-KIT	46-91	Rare			²⁰⁴,²⁰⁵,²⁰⁶,²⁰⁷,²⁰⁸,²⁰⁹,²¹⁰
	EGFR	Rare	50-90	40-65	60-85	²⁹,³⁰,³¹,³²,¹⁸⁶
	ErbB2 (HER-2)	<10	20-35	16-38	6-16	¹⁸³,¹⁸⁶,²⁰⁷,²¹¹,²¹²,²¹³
	MYC	10-45	<10			⁵⁰,²¹⁴,²¹⁵,²¹⁶
	PDGFRA	65	2-100	100	89	²¹⁷,²¹⁸,²¹⁹,²²⁰
Tumor-Suppressing Alterations
Mutation
	CDKN2A (p16)	<1	10-40			¹⁸⁶
	LKB1	Rare	30	34	19	⁶,¹⁸⁶
	p53	75-90	50-60	50-70	60-70	¹⁸⁶,²²¹,²²²,²²³
	PTEN	15-20	<10			¹⁸⁶
	Rb	80-100	20-40			¹⁸⁶,²²⁴,²²⁵,²²⁶
Deletion/LOH^b
	CDKN2A (p16)	37	75-80			⁸⁴,²²⁷,²²⁸
	FHIT	100	55-75			²²⁷,²²⁸,²²⁹
	p53	86-93	74-86			²²⁷,²²⁸
	Rb	93	62			²²⁷,²²⁸
Loss of protein expression
	CAV1	95	24			²³⁰
	CDKN2A (p14^ARF)	65	40-50			⁸⁴,²³¹
	CDKN2A (p16)	3-37	30-79	∽55	60-75	²²⁷,²²⁸
	FHIT	80-95	40-70			¹⁸⁶,²²⁷,²²⁸
	PTEN		25-74	77	70	⁶⁰,²³¹
	Rb	90	15-60	23-57	6-14	²²⁸
	TUSC2 (FUS1)	100	82	79	87	²³²
Tumor-acquired DNA
Methylation
	APC	15-26	24-96			⁹³,⁹⁴,²³³
	CAV1	93	9			²³⁰
	CDH1	60 40	20-35			⁹⁴,²³³,²³⁴,²³⁵
	CDH13	15-20	45			⁹³,⁹⁴
	CDKN2A (p14^ARF)	nd^b	6-8			⁹⁴
	CDKN2A (p16)	5, 0	15-41	21-36	24-33	²³⁶,²³⁷,²³⁸
	DAPK1	nd	16-45			⁹⁴,²³³,²³⁹
	FHIT	64	37			⁹³,⁹⁴
	GSTP1	16	7-12, 15			⁹⁴,²⁴⁰
	MGMT	16	16-27, 10			⁹⁴,²³³
	PTEN		26	24	30	⁶⁰
	RARβ	45-70	40-43			⁹³,⁹⁴,²⁴¹
	RASSF1A	72-85	15-45	31	43	⁹⁰,⁹⁴,⁹⁶,²³³,²⁴²,²⁴³
	SEMA3B	nd	41-50	46	47	⁹⁰,⁹¹
	TIMP3	nd	19-26			⁹⁴
Telomeres
	Telomerase activity	75-100	50-80	65-85	80-90	¹¹,¹²,¹³,¹⁸⁶,²⁴⁴
Chromosomal Aberrations
	Large-scale loss	1p, 3p, 4p, 4q, 5q, 8p, 10q, 13q, 17p	3p, 5q, 8p, 9p, 13q, 17p, 18q, 19p, 19q, 21q, 22q	2q, 3p, 4q, 8p, 9p, 9q, 10p, 10q, 13q, 15q, 18, 20	3p, 4q, 9p, 10p, 10q, 18, 20	²⁴,²⁵,⁵⁵,²²⁷,²⁴⁵,²⁴⁶,²⁴⁷,²⁴⁸
	Focal deletions		2q22.1, 3p14.2, 3q25.1, 5q11.2, 7q11.22, 9p23, 9p21.3, 10q23.31, 11q11, 13q12.11, 13q14.2, 13q32.2, 18q23, 21p11.2			¹⁵,¹⁷¹,¹⁷²
	Large-scale gain	3q, 5p, 8q, 18q	1q, 3q, 5p, 6p, 7p, 7q, 8q, 20p, 20q	5p, 7p, 7q, 8q, 11q, 19, 20q	2q, 3q, 5p, 7, 8q, 11q, 13q, 19, 20q	²⁴,²⁵,⁵⁵,²²⁷,²⁴⁵,²⁴⁶,²⁴⁷,²⁴⁸
	Focal amplifications		1p36.32, 1p34.3, 1q32.2, 1q21.2, 2p24.3, 2q11.2, 2q31.1, 3q26.31, 5p15.33, 5p15.31, 5p14.3, 5q31.3, 6p21.1, 7p11.2, 8p12, 8q21.13, 8q24.21, 10q24.1, 10q26.3, 11q13.3, 12p12.1, 12q13.2, 12q14.1, 12q15, 14q13.3, 14q32.13, 16q22.2, 17q12, 18q12.1, 19q12, 19q13.33, 20q13.32, 22q11.21			¹⁵,¹⁷¹,¹⁷²
^and, not determined.^bLOH, loss of heterozygosity.

EPIDEMIOLOGY AND SUSCEPTIBILITY IN LUNG CANCER

Eighty-five percent of lung cancers are caused by tobacco smoke, where exposure to carcinogens present in tobacco smoke leads to the acquisition of genetic mutations that may eventually initiate carcinogenesis. However, not all lung cancers arise in smokers, and not all smokers will develop lung cancer. Thus, inherited factors must be involved that may predispose an individual to develop lung cancer—either by increasing susceptibility to the damaging effects of carcinogen exposure or by increasing susceptibility regardless of smoking history. Worldwide, approximately 25% of lung cancer cases are not attributable to smoking.⁴ These cases occur more frequently in women, especially in Asian countries, target the distal airways, and are commonly adenocarcinomas. Coupled with molecular data that indicates strikingly different mutation patterns between known lung cancer genes such as KRAS, epidermal growth factor receptor (EGFR), and TP53 and clinical data in relation to response to targeted therapies, it has now been suggested that lung cancer in never-smokers be considered a distinct disease from the more common tobacco smoke-related lung cancer.⁴

Many studies have examined the effect of single nucleotide polymorphisms (SNPs) on the risk of developing lung cancer.⁵,⁶ The reported risk effect in these studies is generally modest and often inconsistent, explaining why none are in routine use. However, metaanalyses as well as use of whole-genome SNP microarrays may hold the key to identifying robust and possible synergistic interactions between the modest affect of multiple SNPs. Lung cancer risk was recently associated with genomic variation at 15q24/q25.1 by three separate studies simultaneously that used whole-genome SNP microarrays.⁷,⁸,⁹ Although the conclusions of the three studies differed in whether the risk is conferred directly with cancer or through nicotine addiction, the genes within this locus—which include several genes encoding nicotinic acetylcholine receptor subunits— represent important targets for further functional analyses.

GENOMIC INSTABILITY, TELOMERES, AND DNA DAMAGE IN LUNG CANCER

Malignant transformation is characterized by genetic instability that can exist at the chromosomal level (with loss or gain of genomic material, translocations, and microsatellite instability); at the nucleotide level (with single or several nucleotide base changes); or in the transcriptome (with altered gene expression). Abnormalities are typically targeted to proto-oncogenes, TSGs, DNA repair genes, and other genes that can promote outgrowth of affected cells.¹⁰ The erosion of telomeres at the end of chromosomes is also associated with genomic instability leading to chromosomal abnormalities. Telomere length regulates the replicative capacity of a cell, where progressive telomere shortening occurs with each replication. Once the telomere becomes too short, the cell will undergo cellular senescence or apoptosis. Activation of telomerase, the telomere-lengthening enzyme, in premalignant cells prevents loss of telomere ends beyond critical points and is essential for cell immortality. Although silenced in normal cells, telomerase is activated in >80% of NSCLCs and almost uniformly in SCLCs.¹¹,¹²,¹³ In normal cells, the presence of DNA damage engenders a DNA repair response, and if this is not successful, the apoptosis program is activated to remove the damaged cell. However, in premalignant and cancer cells the apoptosis program is often itself damaged, thus allowing unrepaired or misrepaired DNA damage to persist in clones of cells.

ONCOGENES AND GROWTH-STIMULATORY PATHWAYS

Many oncogenes and TSGs have been identified by mapping of copy number changes throughout the cancer genome.¹⁴,¹⁵,¹⁶,¹⁷,¹⁸,¹⁹,²⁰,²¹,²²,²³ Earlier genomic analysis technology such as karyotyping and comparative genomic hybridization (CGH) enabled low-resolution characterization of the lung cancer genome identifying whole-arm or large-scale gain or loss on nearly every chromosomal arm, but most commonly 3p, 4q, 9p, and 17p loss and 1q, 3q, 5p, and 17q gain²⁴,²⁵ (Table 5.1). However, high-resolution microarray analyses can now narrow in on these aberrant regions to detect focal amplifications and deletions often spanning only a handful of genes (Table 5.1).

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