Copy number of 8q24.3 drives HSF1 expression and patient outcome in cancer: an individual patient data meta-analysis

Abstract

Abstract Background The heat-shock transcription factor 1 (HSF1) has been linked to cell proliferation and survival in cancer and has been proposed as a biomarker for poor prognosis. Here, we assessed the role of HSF1 expression in relation to copy number alteration (CNA) and cancer prognosis. Methods Using 10,287 cancer genomes from The Cancer Genome Atlas and Cbioportal databases, we assessed the association of HSF1 expression with CNA and cancer prognosis. CNA of 8q24.3 was categorized as diploid (reference), deletion (fewer copies), gain (+ 1 copy) and amplification (≥ + 2 copies). Multivariate logistic regression modeling was used to assess 5-year survival among those with a first cancer diagnosis and complete follow-up data (N = 9568), categorized per anatomical location and histology, assessing interaction with tumor stage, and expressed as odds ratios and 95% confidence intervals. Results We found that only 54.1% of all tumors have a normal predicted 8q24.3 copy number and that 8q24.3 located genes including HSF1 are mainly overexpressed due to increased copies number of 8q24.3 in different cancers. The tumor of patients having respectively gain (+ 1 copy) and amplification (≥ + 2 copies) of 8q24.3 display a global increase of 5-year mortality (odds ratio = 1.98, 95% CI 1.22–3.21) and (OR = 2.19, 1.13–4.26) after full adjustment. For separate cancer types, tumor patients with 8q24.3 deletion showed a marked increase of 5-year mortality in uterine (OR = 4.84, [2.75–8.51]), colorectal (OR = 4.12, [1.15–14.82]), and ovarian (OR = 1.83, [1.39–2.41]) cancers; and decreased mortality in kidney cancer (OR = 0.41, [0.21–0.82]). Gain of 8q24.3 resulted in significant mortality changes in 5-year mortality for cancer of the uterus (OR = 3.67, [2.03–6.66]), lung (OR = 1.76, [1.24–2.51]), colorectal (OR = 1.75, [1.32–2.31]) cancers; and amplification for uterine (OR = 4.58, [1.43–14.65]), prostate (OR = 4.41 [3.41–5.71]), head and neck (OR = 2.68, [2.17–3.30]), and stomach (OR = 0.56, [0.36–0.87]) cancers. Conclusions Here, we show that CNAs of 8q24.3 genes, including HSF1, are tightly linked to 8q24.3 copy number in tumor patients and can affect patient outcome. Our results indicate that the integration of 8q24.3 CNA detection may be a useful predictor for cancer prognosis.

Keywords

• Copy number alteration
• 8q24.3
• HSF1
• Individual patient data meta-analysis
• Patient outcome