We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039).
The mutation occurred in a small cell lung cancer sample and is the first reported codon 196 TP53 mutation in both radon-associated and small cell lung cancer (SCLC) material.
To determine the association between expression of TRAIL-R2 and p53 mutation status in lung cancers, we compared the two events in 20 small-cell lung cancer (SCLC) cell lines, 20 NSCLC cell lines, and 30 primary NSCLC tumors.
The rate of co-occurring mutations of TP53 and RB1 in these Chinese SCLC patients was 74.6%, and lower than the reported Western patients (90.9%, P = 0.007).
Our data suggest that point mutations of the p53 gene are infrequent in pulmonary carcinoids thus contrasting the findings in other histological types of lung cancer, in particular small-cell lung cancer.
We have here examined ionizing radiation (IR)-induced apoptotic signaling in one IR-sensitive small cell lung carcinoma (SCLC) and one resistant non-small cell lung carcinoma (NSCLC) cell line, both harboring mutant p53.
An SNP, Val83Met, in the MTH1 (microtT homolog 1) gene encoding a triphosphatase that hydrolyzes pro-mutagenic oxidized nucleoside triphosphates, such as 8-hydroxy-dGTP and 2-hydroxy-dATP, showed the strongest and a significant association with SCLC risk [odds ratio (OR)=1.6, 95% confidence interval (CI): 1.2-2.2, P=0.004], while three other SNPs in the TP53, BLM and SNM1 genes, respectively, also showed marginal associations (0.05<P<0.1).
Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden.
While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1<sup>high</sup>/DLL3<sup>high</sup>/NOTCH<sup>low</sup>, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1<sup>low</sup>/DLL3<sup>low</sup>/NOTCH<sup>high</sup>, and an upregulation of immune-related pathways.
Using a genetically engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung, we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC.
The mutations in exon 2 of KRAS, exon 18 of DDR2, and exons 5-6 of TP53 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.
More than 90% of SCLC tumors harbor mutations in the tumor suppressor gene tumor protein p53 (p53), an important DNA damage checkpoint regulator, and these tumor cells rely predominantly on the checkpoint kinases to control DNA damage response.
Our previous study revealed that the p53 gene is frequently mutated with a distinct nucleotide substitution pattern in small cell lung cancer specimens in Japanese patients.
The molecular drivers of neuroendocrine carcinoma are best defined in small cell lung cancer, which shows near-universal genomic alterations in TP53 and RB1.
The TSG p53 is mutated in more than 90% of SCLCs and more than 50% of NSCLCs; the retinoblastoma TSG is inactivated in over 90% of SCLC but only 15% of NSCLCs, and p16, the other component of the retinoblastoma/p16 pathway, is almost never abnormal in SCLC but is inactivated in more than 50% of NSCLCs.
Despite the fact that many of the genetic alterations, including loss of heterozygocity in the 3p chromosome locus and point mutations in the tumor-suppressor genes TP53 and retinoblastoma (RB1), occur in nearly all histopathologic types of lung cancer, the frequency and the "timing" of their occurrence seems to differ between small-cell lung cancer (SCLC) cells, that are characterized by neuroendocrine differentiation, and non-small-cell lung cancer (NSCLC) cells.