Genetic mutations in lung cancer cells

Stop Smoking With EFT

The Painless Stop Smoking Cure

Get Instant Access

Apart of chromosomal aberrations single gene mutations can appear in lung cancer cells. These mutations can be revealed with molecular biology techniques. Mentioned mutations do not often appear simultaneously in one cancer cell (less than 3% of tumour cells). They concern genes important for correct proliferation, differentiation and cell growth such as oncogenes and genes for signal proteins involved in a complicated network of intracellular signal transmission (predominantly genes for tyrosine and threonine-serine kinases).

The most important kind of genetic disturbances observed in NSCLC cells are point mutations (single nucleotide substitutions), small (few to a few dozen base pairs) deletions or insertions and formation of fusion genes as a result of translocation of gene fragments, usually within a single chromosome. Some of these alterations change the structure of proteins (sense mutations) which play an important role in oncogenesis, others shift the expression of oncogenes and suppressor genes, while some remain silent. Such processes lead to protein malfunction: they can increase or decrease protein expression or cause differences in normal enzyme activity.

Accumulation of driver mutations in different genes is detected depending on history of tumour exposure to carcinogens. Failure of DNA repair and progressive genetic instability leads to appearance of mutation that drives cancer development, its growth and metastases [4]. Molecular type of lung cancer is partially consistent with histological type of tumour. Although frequency of occurrence of some driver mutations is extremely rare, in only 20% of NSCLC tumours important mutations are not detected. Small cell lung cancer is less characterised in terms of incidence of genetic mutations. Until 2011, 1738 mutated genes and tens of thousands of different types of mutations were identified in NSCLC [2, 5, 6, 7]. Figure 1 shows the percentage of tumours with identified mutations in all histological types of NSCLC.

Figure 1. The percentage of NSCLC tumours with identified mutations in different genes (EGFR gene amplification and polysomy, as well as p53 gene abnormalities which are common in NSCLC tumours have not been included on the graph).

NSCLC is a heterogeneous aggregate of histological subtypes, which traditionally have been grouped together because of similarities of treatment outcome. Ideally, a tumour classification system should include morphologic and genetic distinctions between tumour types, which will help to define specific subset of patients responsive to certain molecularly targeted treatment. In terms of genetic mutations squamous cell carcinomas are the least described. Mutations have not been detected in over 50% of already screened tumours (Fig. 2). On the other hand adenocarcinoma cases are definitely better described and in only 20% of tumours screening fails to describe any mutations. Among 10-15% of non-smokers (but also light-smokers and former smokers) adenocarcinoma might develop regardless of tobacco smoking. In these cases in almost all tumours different genetic mutations have been found, mostly in epidermal growth factor receptor (EGFR) and KRAS genes as well as presence of EML4-ALK fusion gene (Fig. 3). Accumulated evidence suggested that lung cancer in ever smokers and never smokers follow distinct molecular pathways and may therefore respond to distinct therapy. One could speculate than non-small cell lung cancer in ever and never smokers are two distinct disorders regarding their molecular level and the manner of treatment planning [5, 6, 7, 8, 9, 10, 11, 12].

The most frequent irregularity found among squamous cell carcinoma patients is an amplification of gene for fibroblast growth factor receptor type 1 (FGFR) and p53 gene abnormalities. These disturbances could overlap with other mutations. In SCC it is extremely rare to detect EGFR, PTEN, ERBB2 (HER2), PIK3CA, DDR2 or BRAF mutations, which are more typical for adenocarcinoma [5, 6, 7].

RÎHDM2-NFE1

AKT1 mut

RÎHDM2-NFE1

AKT1 mut

Figure 1. The percentage of NSCLC tumours with identified mutations in different genes (EGFR gene amplification and polysomy, as well as p53 gene abnormalities which are common in NSCLC tumours have not been included on the graph).

Figure 2. The percentage of SCC tumours with identified mutations in different genes (p53 gene abnormalities which are common in SCC tumours have not been included on the graph)

Figure 3. The percentage of AC tumours with identified mutations in different genes (EGFR gene amplification and polysomy have not been included on the graph).

Figure 3. The percentage of AC tumours with identified mutations in different genes (EGFR gene amplification and polysomy have not been included on the graph).

Among patients with adenocarcinoma the most often detected irregularities are in EGFR gene, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene and p53 gene. In nonsmoking Caucasian population activating mutations in EGFR gene appear with frequency of over 50%. The most common mutations in this gene are: small (9-21 base pair) deletions in exon 19 (48% of detected mutations) and missense mutations in exon 21 (L858R, 41% of detected mutations). Substitutions in exon 18-21 or insertions and duplications in exon 20 are rare but they also appear [2, 9, 13].

Mutations in exon 18-21 of EGFR gene concern tyrosine kinase domain of the EGF receptor. Overexpression of EGFRs' tyrosine kinase function leads to hyperphosphorylation of intracellular signalling proteins of Pi3K/Akt or RAS/RAF/MAPK pathways without having to activate the receptor with its specific ligand - the EGF. The activation of Pi3K/Akt pathway results in stimulation of transcription factors such as STAT or excessive proliferation of cancer cells. Mutations in EGFR gene are most common in papillary AC, less frequent in adenocarcinoma with „lepidic predominant" growth and least frequent in solid AC [2, 13].

Mutations in KRAS gene are also common and are detected in 15-25% of adenocarcinoma cases. KRAS gene, which is coding a low molecular weight guanosine triphosphatase (GTPase) is considered to be the most frequently mutated oncogene in lung AC arising in patients with history of smoking. Most KRAS mutations involve replacing glycine with other amino acids such as valine, aspartic acid and glutamic acid in codon 12. Less frequent mutations consider codon 13 and 61. The emergence of the mutation causes the reduction of GDPase activity with subsequent potent activation of mitogenic and proliferative signalling through the RAF/MEK/ERK/MAPK cascade. Mutations in KRAS gene are most common in solid mucinous adenocarcinoma and in acinar adenocarcinoma [2, 5, 6, 7].

Among other mutations detected in more than 2% of adenocarcinomas are EML4-ALK fusion gene, substitution V600E in BRAF oncogene, substitutions in codon 542, 545 and 1047 of PIK3CA oncogene, insertion in exon 20 of ERBB2 gene, polysomy of FGFR1 gene and amplification of cMET gene. Both anaplastic large cell lymphoma kinase (ALK) and echinoderm microtubule associated protein 4 (EML4) genes are located in chromosome 2p and fusion of both involves small inversions within this region. EML4-ALK fusion results in constitutive activation of ALK kinase. EML4-ALK fusion gene is prevalent in lung adenocarcinoma (2-4%), especially in signet ring cell carcinoma (<15%), in younger patients and in never- or light smokers. EML4-ALK fusion gene is mutually exclusive with EGFR and KRAS gene mutations. Recently, new fusion genes have been discovered in lung adenocarcinomas, including fusion of kinesis family member 5B (KIF5B) with ret proto-oncogene (RET) and fusion of coiled-coil domain containing protein 6 (CCDC6) with RET as well as fusions of ALK with c-ros oncogene 1 receptor tyrosine kinase (ROS1) [2, 5, 6, 7, 14, 15].

Information about the mutations mentioned above come from large databases such as Catalogue of Somatic Mutations in Cancer (COSMIC), My Cancer Genome, The Cancer Genome

Atlas and the results obtained by the American Lung Cancer Mutation Consortium (LCMC) [5, 6, 7, 16].

Was this article helpful?

0 0
The Smoker's Sanctuary

The Smoker's Sanctuary

Save Your Lungs And Never Have To Spend A Single Cent Of Ciggies Ever Again. According to a recent report from the U.S. government. Centers for Disease Control and Prevention, more than twenty percent of male and female adults in the U.S. smoke cigarettes, while more than eighty percent of them light up a cigarette daily.

Get My Free Ebook


Post a comment