Distribution of <i>KRAS</i>, <i>DDR2</i>, and <i>TP53</i> gene mutations in lung cancer: An analysis of Iranian patients

<div><p>Purpose</p><p>Lung cancer is the deadliest known cancer in the world, with the highest number of mutations in proto-oncogenes and tumor suppressor genes. Therefore, this study was conducted to determine the status of hotspot regions in <i>DDR2</i> and <i>KRAS</i> genes for the first time, as well as in <i>TP53</i> gene, in lung cancer patients within the Iranian population.</p><p>Experimental design</p><p>The mutations in exon 2 of <i>KRAS</i>, exon 18 of <i>DDR2</i>, and exons 5–6 of <i>TP53</i> genes were screened in lung cancer samples, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) using PCR and sequencing techniques.</p><p>Results</p><p>Analysis of the <i>KRAS</i> gene showed only a <i>G12C</i> variation in one large cell carcinoma (LCC) patient, whereas variants were not found in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) cases. The <i>Q808H</i> variation in the <i>DDR2</i> gene was detected in one SCC sample, while no variant was seen in the ADC and LCC subtypes. Variations in the <i>TP53</i> gene were seen in all NSCLC subtypes, including six ADC (13.63%), seven SCC (15.9%) and two LCC (4.54%). Forty-eight variants were found in the <i>TP53</i> gene. Of these, 15 variants were found in coding regions <i>V147A</i>, <i>V157F</i>, <i>Q167Q</i>, <i>D186G</i>, <i>H193R</i>, <i>T211T</i>, <i>F212L</i> and <i>P222P</i>, 33 variants in intronic regions rs1625895 (HGVS: <i>c</i>.<i>672+62A>G</i>), rs766856111 (HGVS: <i>c</i>.<i>672+6G>A</i>) and two new variants (<i>c</i>.<i>560-12A>G</i> and <i>c</i>.<i>672+86T>C</i>).</p><p>Conclusions</p><p>In conclusion, <i>KRAS</i>, <i>DDR2</i>, and <i>TP53</i> variants were detected in 2%, 2.17% and 79.54% of all cases, respectively. The frequency of <i>DDR2</i> mutation is nearly close to other studies, while <i>KRAS</i> and <i>TP53</i> mutation frequencies are lower and higher than other populations, respectively. Three new putative pathogenic variants, for the first time, have been detected in Iranian patients with lung cancer, including <i>Q808H</i> in <i>DDR2</i>, <i>F212L</i>, and <i>D186G</i> in coding regions of <i>TP53</i>. In addition, we observed five novel benign variants, including <i>Q167Q</i>, <i>P222P</i> and <i>T211T</i> in coding sequence, and <i>c</i>.<i>560-12A>G</i> and <i>c</i>.<i>672+86T>C</i>, in intronic region of <i>TP53</i>. Mutations of <i>KRAS</i> and <i>DDR2</i> were found in LCC and SCC subtypes, respectively, whereas mutations of <i>TP53</i> were seen in SCC and ADC subtypes with higher frequencies and LCC subtype with lower frequency. Therefore, Iranian lung cancer patients can benefit from mutational analysis before starting the conventional treatment. A better understanding of the biology of these genes and their mutations will be critical for developing future targeted therapies.</p></div

Frequency and type of coding variants in <i>KRAS</i>, <i>DDR2</i>, and <i>TP53</i> genes in lung tumor samples.

<p>Frequency and type of coding variants in <i>KRAS</i>, <i>DDR2</i>, and <i>TP53</i> genes in lung tumor samples.</p

The data of observed variations based on HGVS38 in non-coding sequence.

<p>The data of observed variations based on HGVS38 in non-coding sequence.</p

The PCR products on the gel agarose electrophoresis.

<p>The PCR products on the gel agarose electrophoresis.</p

Analysis of <i>TP53</i> gene mutations in lung cancer samples.

<p>(a) <i>D186G</i> mutation in coding sequence (b) <i>F212L</i> mutation in coding sequence (c) <i>c</i>.<i>560-12A>G</i> mutation in intronic region (d) <i>c</i>.<i>672+86T>C</i> mutation in intronic region.</p

Analysis of the lung cancer samples for <i>KRAS</i>, <i>DDR2</i> and <i>TP53</i> gene mutations.

<p>(a) percentage of <i>KRAS</i>, <i>DDR2</i> and <i>TP53</i> mutations in different subtypes of lung cancer; (green: SCLC, blue: SCC, pink: ADC). (b) <i>G12C</i> mutation in <i>KRAS</i> and (c) <i>Q808H</i> mutation in <i>DDR2</i>.</p

The data of observed variations based on HGVS38 in coding sequence.

<p>The data of observed variations based on HGVS38 in coding sequence.</p

Correlations between <i>TP53</i> mutational status and clinicopathological parameters.

<p>Correlations between <i>TP53</i> mutational status and clinicopathological parameters.</p

The predictions of variants effect based on in silico tools.

<p>The predictions of variants effect based on in silico tools.</p