Significantly mutated genes and regulatory pathways in SCLC—a meta-analysis

Abstract

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and demands effective targeted therapeutic strategies. In this meta-analysis study, we aim to identify significantly mutated genes and regulatory pathways to help us better understand the progression of SCLC and to identify potential biomarkers. Besides ranking genes based on their mutation frequencies, we sought to identify statistically significant mutations in SCLC with the MutSigCV software. Our analysis identified several genes with relatively low mutation frequency, including PTEN, as highly significant (p<0.001), suggesting these genes may play an important role in the progression of SCLC. Our results also indicated mutations in genes involved in the axon guidance pathways likely play an important role in SCLC progression. In addition, we observed that the mutation rate was significantly higher in samples with RB1 gene mutated when compared to samples with wild type RB1, suggesting that RB1 status has significant impact on the mutation profile and disease progression in SCLC.

Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer

“…Since RB1 inactivation accounts for about two-thirds of SCLC patients [21] and amplification of a MYC family gene was found in about one-fifth [31] of SCLC cases, two studies reported on these genetic changes as prone conditions for the use of aurora kinase inhibitors [16,156].…”

“…Deficiency of ‘phosphatase and tensin homolog’ (PTEN) is a frequent finding in SCLC but not in NSCLC [168]. Sundaresan et al discovered PTEN deficiencies in 7.4% of SCLC patients [21]. In n = 204 Japanese SCLC tissue samples, alterations in the PIK3CA/AKT/mTOR signaling were analyzed.…”

“…Taken together, via an allele-specific polymerase chain reaction, next-generation sequencing, or whole-exome sequencing, they found relevant amounts of RB1 (79%), TP53 (58%) and ‘phosphatidylinositol 3-kinase catalytic subunit alpha’ (PIK3CA) (27%) mutations [19]. Sundaresan et al postulated that the inactivation of the RB1 gene is associated with an increased overall mutational burden in SCLC tissues [21]. This genetic heterogeneity of SCLC is depicted in Table 1.…”

“…Thereof, inactivating mutations of the ‘cAMP response element binding protein binding protein’ (CREBBP) gene locus are frequent: The latter gene transcriptional product, Crebbp, plays a crucial role as a ubiquitous transcriptional coactivator [12]. Furthermore, in many cases, the ‘phosphatase and tensin homolog’ (PTEN) locus [21], acting in the PI3K/AKT/mTOR pathway, is altered or dysfunctional. Other than that, the upregulated gene loci of oncogenic ‘avian-myelocytomatosis viral oncogene homolog’ (MYC) family and ‘fibroblast growth factor receptor 1’ (FGFR1) are frequently found [12].…”

Bioinformatics analysis of mRNA and miRNA microarray to identify the key miRNA‑gene pairs in small‑cell lung cancer

“…SCLC resistance to conventional treatment and its high recurrence rate are primarily due to its markedly high mutation rate and genomic instability (4). A previous study revealed that TP53 and RB transcriptional corepressor 1 (RB1) were the most frequently mutated genes in SCLC, with mutation frequencies of ~85 and 57%, respectively (5). High prevalence of mutations in tumor suppressor genes TP53 and RB1, alterations in chromosome 3p, has been revealed to be significantly correlated with a poor outcome (6).…”