Epigenetic down-regulation of SOX2 is an independent poor prognostic factor for hypopharyngeal cancers

Abstract

Aims

We recently reported that a small subset (7%) of oesophageal squamous cell carcinomas completely lacking SOX2 expression had unique clinicopathological features and a dismal prognosis. The present study aimed to elucidate whether the findings obtained in oesophageal cancers are applicable to hypopharyngeal or oropharyngeal squamous cell carcinomas (HPSCCs or OPSCCs, respectively).

Methods and Results

The study cohort consisted of consecutive patients with HPSCC (n=130) and OPSCC (n=65) who underwent surgery without preoperative therapy. On immunostaining, SOX2 was almost entirely negative in 10/130 HPSCCs (8%) and 7/65 OPSCCs (11%). No significant differences were observed in clinicopathological features, including the p16 status, between SOX2-positive and SOX2-negative cancers. However, patients with SOX2-negative HPSCC had significantly worse overall and recurrence-free survivals than those with SOX2-positive cancer, while such prognostic relationship was not confirmed in patients with OPSCC. In a multivariate analysis, the loss of SOX2 expression appeared to be an independent poor prognostic factor for patients with HPSCC. In a sequencing analysis, no mutation was found in SOX2. Since SOX2 is known to contain an extensive CpG island before the transcription start site, methylation-specific PCR for the SOX2 promoter was performed. Methylated alleles were found in 9/10 SOX2-negative HPSCCs but none of SOX2-retained cases.

Conclusions

Similar to oesophageal cancers, a small subset (8%) of HPSCCs characteristically almost lacking SOX2 expression appeared to be aggressive neoplasms with high recurrence rates. Promoter hypermethylation was determined to be a major mechanism underlying epigenetic SOX2 silencing.

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