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    • In our study Small cell lung cancer SCLC accounts for about

    2018-11-09

    Small-cell lung cancer (SCLC) accounts for about 15% of all lung tumors and has a 5-year survival below 5%. While SCLC tumors are initially sensitive to chemotherapy, they invariably relapse with a resistant and deadly disease. We and others have found that, contrary to lung adenocarcinomas and squamous-cell lung carcinomas, mutations in therapeutic targets are rare in SCLC (George et al., 2015; Peifer et al., 2012; Rudin et al., 2012). TP53 is inactivated in virtually all SCLC cases, and TP53 mutations are known to be an early event in the development of this disease. Given the almost uniform presence of TP53 mutations in SCLC, we have investigated to what extent mutations in this gene can be identified in the cfDNA of patients with SCLC tumors. In addition, we have also assessed two independent series of non-cancer controls to evaluate the specificity of the approach.
    Material and Methods
    Results The characteristics of the cases and controls are shown in Table 1. We detected 31 TP53 mutations in 25 SCLC patients (49%, 25/51). When the 51 initial SCLC cases were stratified by stage, we found that 35.7% (5/14) of the stage I–II and 54.1% (20/37) of the stage III–IV, carried detectable TP53 mutations in their cfDNA (Fig. 1b). While statistically significant in cases versus controls (p-value=6×10), 18 TP53 mutations were detected in 14 of the Russian non-cancer controls (11.4%, 14/123). The significance was also maintained when stratifying by stage (stage I–II versus controls, p-value=0.012; stage III–IV versus controls, p-value=1×10). We replicated these observations in an independent series of 102 controls, and found a comparable proportion of TP53 mutated samples (10.8%, 13 TP53 mutations in 11 controls). Similarly to what is expected for TP53 mutations present in cancer, most of the mutations in cases and controls altered In our study coding for the TP53 DNA-binding domain, which is critical for the transactivation activity of this gene (Fig. 1c). We next evaluated the characteristics of the mutations found in cases versus controls. Chi-square test analysis showed that there was a statistically significant difference between the mutational pattern found in cases versus controls (p-value=0.008). The fraction of nonsense, indel, or splicing mutations found in the cases was similar to that previously reported for SCLC tumors (George et al., 2015) (35.5% versus 37% respectively), whereas this proportion was slightly lower in controls (22.2% in the Russian, and 7.7% in the replication controls; Fig. 1d). We used the IARC TP53 database to classify the missense mutations in functional, partially functional, or non-functional based on the in vitro transcriptional activity of the resulting protein. Most missense mutations found in SCLC tumors (George et al., 2015) (92.6%) and cfDNA from cases (100%) were classified as resulting in a non-functional protein. However, controls had a higher proportion of missense mutations that retained some transcriptional activity (~30%; Fig. 1d). We also compared the allelic fractions (AFs) of the TP53 mutations found in the cfDNA of cases and controls. The AFs for a given mutation were similar in the two independent libraries, demonstrating the reproducibility of the assay (Table S3, S4, and S5). The AFs for the cases ranged from 0.12% to 84.81% (median 4.6%). In the Russian controls the AFs ranged from 0.19% to 84.94% (median 1.2%), and in the replication controls they ranged from 0.02% to 63.74% (median 0.5%) (Fig. 1e). The statistically significant difference in the AFs between cases and controls (p-value=4×10) is explained by the presence of late-stage SCLC tumors, since the median AF of the TP53 mutations detected in the five stage I–II SCLC (0.9%) is not statistically different from that found in controls (p-value=0.64), while it differed from the median AF of stage III-IV SCLC tumors (8.2%; p-value=2×10; Fig. 1e).