Prognostic value of DICER and CA9 expression in patients with anal squamous cell carcinoma treated with definitive chemoradiotherapy

BACKGROUND: The levels of the microRNA-processing enzyme DICER and the hypoxia associated marker carbonic anhydrase 9 (CA9) critically influence tumor growth, aggressiveness, and response to therapy. However, their prognostic value in patients treated with definitive chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC) remains elusive. PATIENTS AND METHODS: DICER and CA9 were scored in a cohort of a total of 95 ASCC patients by multiplex immunofluorescence and next-generation sequencing for DICER on pre-treatment biopsies. They were correlated with patients' histopathological characteristics and clinical endpoints locoregional failure-free survival (LRFFS), distant metastases-free survival (DMFS), disease-free survival (DFS) and overall survival (OS). RESULTS: We observed a significant inverse correlation between DICER and CA9 expression. In contrast, DICER and CA9 expression did not correlate with age, gender, T/N stage, and grading. High levels of DICER protein and mRNA were prognostic for superior LRFFS (p = 0.006) and DFS (p = 0.014), while elevated levels of CA9 were associated with decreased LRFFS (p = 0.008) and decreased DFS (p = 0.023), respectively. In multivariate analyses, DICER levels remained significant for LRFFS and DFS (p = 0.020, and p = 0.033). A combined DICER high and low CA9 variable indicated a subgroup of patients most likely to respond to CRT with improved LRFFS (p = 0.002) and DFS (p = 0.006). CONCLUSION: These data indicate that elevated pretreatment levels of CA9 and low levels of DICER are correlated with an unfavorable clinical outcome in patients with ASCC treated with definitive CRT. The superior prognostic power of DICER+ CA9 suggests that DICER and hypoxia may have non-redundant roles in these malignancies.