Nature Genetics published a fascinating article online on October 4 by Bass et al. identifying SOX2 amplification in lung and esophageal squamous cell carcinomas (SqCC). It is refreshing to read a good study of squamous cell carcinomas since there has been so much published recently on lung adenocarcinomas.
This is a multi-institutional study that first examined 40 esophageal SqCC and 47 lung SqCC using SNP arrays to determine copy number changes and GISTIC (Genomic Identification of Significant Targets in Cancer) to score the significance of recurrent chromosomal gains and losses in order to identify peak regions likely to harbor tumor-driving genes.
The most significant amplified peak in lung SqCC was at chromosome 3q26.33, found in 11/47 lung SqCC and 6/40 esophageal SqCC. In lung SqCC, the peak in this segment contained four genes, including SOX2; in esophageal SqCC, the peak only included SOX2. Next, the authors measured SOX2 mRNA levels by RT-PCR in 27 lung SqCC with matched SNP data cases. Cases with SOX2 amplification were found to have higher mRNA expression but they also found several cases without 3q26.33 amplification that had high SOX2 mRNA expression. The authors made similar findings with esophageal SqCC. The authors then performed an arrayed RNA interference screen targeting SOX2, neighboring genes, additional candidate genes and controls in 4 SqCC cell lines (2 lung, 2 esophageal) for differential effects on proliferation. Suppression of SOX2 had the largest differential anti-proliferative effects on 3q26.33 amplified cell lines amongst all genes tested. Further, they showed that SOX2 knockdown reduced anchorage-independent growth. These findings were confirmed with rescue of the effects of SOX2 suppression by restoring wild-type SOX2 in a mutant cell line.
Additional work shows that SOX2 amplification and mRNA levels are significantly higher in lung SqCC compared with lung adenoca (which differentially showed NKX2-1 amplification and increased mRNA levels cf. to lung SqCC). SOX2 alone could not transform immortalized tracheobronchial cells but could do so in cooperation with the epithelial isoform of FGFR2.
As it turns out SOX2 is an very interesting transcription factor intimately involved in forgut development and is required for proper differentiation of esophageal squamous mucosa and in multiple respiratory cell types.
This is a very dense paper presenting the results of multiple experiments of which I have summarized only a part. What does all this mean for the practicing pathologist or oncologist? The identification of SOX2-dependent pathways in lung squamous cell carcinomas is an exciting finding that may represent a novel therapeutic target--which has been conspicuously lacking so far in lung SqCC.