GENETIC ASPECTS OF LUNG CANCER
Cherneva R1, Dimova I2,*
*Corresponding Author: Dr. Ivanka Dimova, Department of Medical Genetics, Medical University, 2 Zdrave str., Floor 13, 1431 Sofia, Bulgaria; Tel./Fax: +359-2-952-03-57; E-mail: idimova73@yahoo.com
page: 9

MOLECULAR-GENETIC ABERRATIONS

Oncogenes. Oncogenes are derived from normal genes (proto-oncogenes) that code for proteins, which play key roles in physiological cellular processes. Proto-oncogenes are abnormally activated in cancer tissues. Of importance in lung cancer are RAS, MYC, EGFR, HER-2/neu.

      RAS. There are three types of RAS oncogenes (HRAS, NRAS, KRAS) in the human genome that code a protein called p21. Each is active when bound to GTP and inactive when bound to GDP. Normal RAS proteins have a GTP-ase activity that leads to their inactivation. Point mutations associated with tumors result in the loss of GTP-ase activ­ity.

      KRAS mutations are present in approximately 20% of NSCLC, and in 30-50% of adenocarcinoma [10]. In lung cancer 90% of RAS mutations affected the KRAS gene and 80% of these are in codon 12, the predominant mutation being a G→T transversion. These mutations have a nega­tive impact on a patientís survival, particularly for adeno­carcinomas [10]. They are almost never met in SCLC [11]. KRAS mutations are found in 15-50% of atypical adeno­matous hyperplasia (AAH), in 16.7% of bronchoalveolar carcinomas and in 10% of invasive adenocarcinomas [12]. KRAS mutations are not an early event in the multistep carcinogenesis of adenocarinomas. They are frequently observed in tumors from smokers [13], and are not found together with EGFR or HER-2 mutations [14].

      MYC is a proto-oncogene that is commonly affected in lung carcinogenesis. Amplification of the gene is an early event and is related to tumor formation and progression [15].The amplifications of the myc family genes are an early event in lung carcinogenesis. L-myc, c-myc and N-myc are not affected together which shows that each of them is responsible alone as a proto-oncogene in lung car­cinogenesis. Myc amplification is typical for SCLC. C-myc and L-myc amplifications are also seen in NSCLC. A trans­genic transfer of c-myc in cell lines is associated with the variant phenotype of the SCLC, which has shorter dou­bling times [16]. C-myc causes downregulation of c-kit; a tyrosine kinase receptor activated by stem hemopoietic ligand [17]. As this is not true for N-myc and L- myc, it is suggested that tumors with c-myc amplification have dif­ferent behavior patterns [17]. The amplification of L-myc is associated with lack of expression of HLAII as it causes downregulation of class II transactivator, thus explaining the low concentration of cytotoxic T-lymphocytes in SCLC tissue [18]. N-myc alterations are commonly present in SCLC. In contrast to the other two oncogenes, it is not found in NSCLC, and is thought to be connected with the neuroendocrine traits of the cells [19].

      EGFR is a member of a family of four related recep­tors ErbB1, ErbB2, (HER-2/neu), ErbB3, ErbB4. These receptors have a common structure that consists of an N-terminal ligand binding extracellular domain, a single transmembrane helix, and an intracelular tyrosine kinase domain with a C-terminal tail. In normal lung epithelium expression of EGFR is found in the basal layer where pro­liferation occurs. In response to tobacco smoke, progres­sive atypical changes are noted in the bronchial epithelium, followed by squamous metaplasia with mild through mod­erate and severe dysplasia and carcinoma in situ. EGFR expression is increased in severe dysplasia compared to moderate and mild dysplasia, normal or metaplastic epithe­lium, suggesting that the EGFR pathway plays an impor­tant role in lung carcinogenesis [20]. EGFR is commonly expressed in adenocarcinoma (40-60%), in virtually all cases of squamous cell carcinoma, in approiximately 65% of large cell carcinoma, but is not expressed in small cell carcinoma [21]. Dysregulated EGFR signaling occurs in the presence of mutated receptor EGFRvIII that lacks the extracellular domain of EGFR because of an inframe dele­tion and leads to an overactivation of the receptor tyrosine kinase [22]. A large study of the tyrosine kinase domain for mutations showed that lung cancer is the only epithe­lium tumor in which mutations within the tyrosine kinase domain could be detected [23]. The lung cancer EGFR mutations are somatic in origin and are common in non smokers, more often in females than in males, in adeno­carcinoma type [23]. KRAS mutations are also typical for adenocarcinomas but the simultaneous presence of both of these are never found [23]. This shows that the patho­genesis of adenocarcinoma is different.

      EGFR gene amplification was found in only 9% of lung cancers [24]. A high gene copy number was associ­ated with a poorer prognosis while EGFR over expression was not consistently connected with a poor outcome [24].

      ErbB2 (HER-2/Neu) is an EGFR. As this receptor does not have its own ligand it provides signal transduction by forming homo- or heterodimers with other receptors [25]. It seems that ErbB2 is the preferred co-receptor of ErbB3, ErbB4 and Erb1 [25]. ErbB2 is rarely expressed in SCLC but is detectable in 20% of NSCLC [26]. The expression of ErbB2 is associated with a worse prognosis [27].

      Tumor Suppressor Genes. Several studies have re­vealed the presence of TSG, localized in 3p, which are commonly involved in lung cancer [28]. There is evidence that smoking causes allele loss in many different sites of lung tissue and breakpoints in 3p21.3 TSG [29]. Such cells proliferate and when they experience loss of the second allele or inactivation of another TSG gene, an invasive carcinoma develops. Sequential carcinogenesis applies in NSCLC since genetic alterations lead to morphological changes; hyperplasia (small del3p), dysplasia (large del3p), Ca in situ (complete loss of 3p), and tumor (inacti­vation of other TSG) [30]. In contrast, in SCLC, no inter­mediate pathological stages are seen: normal cells acquire genetic changes that lead to tumor development [31]. The results from research of TSG have highlighted the genes mentioned below.

      Retinoic Acid Receptor-β (RAR-β) is located on 3p24 and encodes a retinoic acid receptor that is expressed in many normal tissues. The RAR-β receptor gene is epigenet­ically silenced through methylation of its promoter in lung tumors. It is inactivated in 72% of SCLC and in 41% of NSCLC [31]. Methylation-specific polymerase chain reac­tion (MS-PCR) showed that this gene is inactivated mainly by cigarette smoking. Binding to its receptor, retinoic acid inhibits transcription of AP-1 and thus inhibits prolifera­tion and induces apoptosis [30]. When silenced, the gene does not code a receptor and the retinoic acid cannot exert its effects.

      FHIT (fragile histidine triad) is a gene that codes for a small protein located on chromosome 3p14.2. This is the most common fragile site in the human genome. In lung cancer patients and in their relatives, 3p14.2 fragility was three times more frequent than in the control group, thus leading to genome instability [32]. Aphidocolin- induced fragility of the locus is also different among individuals thus confirming that though common, fragile sites are with individual frequency in population determining the indi­vidual susceptibility to lung cancer [32]. FHIT rarely un­dergoes missense or point mutations but is mostly silenced by methylation [33].

      P53, located on 17p13.1, has a leading role in the cell cycle by inhibiting G1 to S transition through induction of p21 and facilitating apoptosis and DNA repair by inducting BAX and DNA repair enzymes. It is the gene most com­monly mutated in the human genome, and its mutation frequency in NSCLC being 50% and in SCLC 80% [34]. Typical and atypical carcinoids contain normal p53, while in many high-grade neuroendocrine tumors it is inactivated [35]. Mutations of p53 have been detected in dysplastic and premalignant lesions in the lung [36]. Mutation of p53 is an early event in lung cancer and occurs before micro invasion [37]. Specific point mutations in lung cancer are associated with tobacco exposure and the formation of DNA adducts [38]. Typical of lung cancer is a GC→TA transversion [38]. Other mutations occur in radon-induced cancer showing carcinogen specificity of mutations. The mutated p53 protein is consistently associated with a poor­er prognosis [39].

      RB1 is involved in regulation of the cell cycle (phos­phorylation of Rb interacts with transcription factor E2F, that regulates the G0/G1 phase) and in growth arrest. The gene is mutated in 17% [40] of NSCLC and in 80-100% of SCLC [40]. Typical and atypical carcinoids show no and low rate of Rb1 inactivation, respectively [41]. In contrast, high grade neuroendocrine tumors have a high rate of inac­tivation. In lung cancer, mutations specifically destroy the formation of tertiary structure and do not target the region of phosphorylation. The mutations of Rb1 are a late event in lung carcinogenesis as they are not seen in preneoplastic lesions and early stage cancers. In neuroendocrine tumors, Rb1 loss is associated with a poorer prognosis [35].

            P16 (CDKN2) is a TSG located on 9p21 and is a mem­ber of the CDK complex inhibitors that specifically blocks the interaction of CDK4/CDK6 with Cyclin D1, thus in­hibiting phosphorylation of Rb and release of E2F, and regulating the G1/S transition. Decreased p16 is a charac­teristic feature of NSCLC, it occurs in 75% of the squa­mous carcinomas and in 54% of the adenocarcinomas [42]. A reciprocal pattern of Rb and p16 inhibition exists in lung cancers [43]. In SCLC, Rb is lost in 90% and p16 is re­tained. In NSCLC the opposite is true. In neuroendocrine tumors there is also an inverse relation. The most common mutations of this gene seem to be as follows: promoter methylation (methylation of the CpG islands of the pro­moter region of the gene), loss of heterozygosity (LOH), homozygous deletion is predominant in smokers [44



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