Association between hypoxic volume and underlying hypoxia-induced gene expression in oropharyngeal squamous cell carcinoma

Abstract

Background:Hypoxia imaging is a promising tool for targeted therapy but the links between imaging features and underlying molecular characteristics of the tumour have not been investigated. The aim of this study was to compare hypoxia biomarkers and gene expression in oropharyngeal squamous cell carcinoma (OPSCC) diagnostic biopsies with hypoxia imaged with 64Cu-ATSM PET/CT.Methods:64Cu-ATSM imaging, molecular and clinical data were obtained for 15 patients. Primary tumour SUVmax, tumour to muscle ratio (TMR) and hypoxic volume were tested for association with reported hypoxia gene signatures in diagnostic biopsies. A putative gene signature for hypoxia in OPSCCs (hypoxic volume-associated gene signature (HVS)) was derived.Results:Hypoxic volume was significantly associated with a reported hypoxia gene signature (rho=0.57, P=0.045), but SUVmax and TMR were not. Immunohistochemical staining with the hypoxia marker carbonic anhydrase 9 (CA9) was associated with a gene expression hypoxia response (rho=0.63, P=0.01). Sixteen genes were positively and five genes negatively associated with hypoxic volume (adjusted P<0.1; eight genes had adjusted P<0.05; HVS). This signature was associated with inferior 3-year progression-free survival (HR=1.5 (1.0–2.2), P=0.047) in an independent patient cohort.Conclusions:64Cu-ATSM-defined hypoxic volume was associated with underlying hypoxia gene expression response. A 21-gene signature derived from hypoxic volume from patients with OPSCCs in our study may be linked to progression-free survival.

Clinical update on head and neck cancer: molecular biology and ongoing challenges

“…Positron emission tomography (PET)/computer tomography (CT) using hypoxia-specific radiotracers, combined with assessment of endogenous or exogenous hypoxia markers could provide a reliable clinical method for both detection and measurement of tumour hypoxia during treatment 126,128 . In HNSCC, PET imaging using the hypoxia radiotracer 18 F-MISO has been investigated, demonstrating successful identification of HNSCC patients who benefited from addition of Tirapazamine with prediction of recurrence after radiotherapy 129 .…”

Inside the hypoxic tumour: reprogramming of the DDR and radioresistance

“…Therefore, the implications of these alterations in hypoxia are not yet defined. Perhaps, like we have done with hypoxia as a single parameter 18 , what the research community needs is a genomic or proteomic signature of hypoxic-radioresistance against which we can compare effects of various alterations.…”

“…To more precisely tackle resistance induced by hypoxia researchers have also sought to lower the threshold of treatability of hypoxic tumours by use of sensitizers 15 – 17 . As a third arm in our battle plan, research has also gone into developing methods to detect hypoxia, including the use of specialised imaging techniques (PET/CT scanning combined with hypoxia-detecting radionuclides) often studied in tandem with genetic signatures seeking to genotypically define these tumours 18 , 19 .…”

STIM1 overexpression in hypoxia microenvironment contributes to pancreatic carcinoma progression

“…Hypoxia is a common microenvironmental feature within a tumor mass, which contributes to tumor growth and metastasis, especially in PDAC 15 . Hypoxia-inducible factor-1 (HIF-1), consisting of highly regulated HIF-1α and a constitutively expressed HIF-1β, is one of the most important transcription factors, which can mediate many adaptive physiologic responses 16 . In PDAC, HIF-1α expression level is up-regulated and associated with tumor progression, fibrotic focus, angiogenesis, cell migration, and hepatic metastasis 17-22 .…”