CENP-A Subnuclear Localization Pattern as Marker Predicting Curability by Chemoradiation Therapy for Locally Advanced Head and Neck Cancer Patients

Abstract

Effective biomarkers predictive of the response to treatments are key for precision medicine. This study identifies the staining pattern of the centromeric histone 3 variant, CENP-A, as a predictive biomarker of locoregional disease curability by chemoradiation therapy. We compared by imaging the subnuclear distribution of CENP-A in normal and tumoral tissues, and in a retrospective study in biopsies of 62 locally advanced head and neck squamous cell carcinoma (HNSCC) patients treated by chemoradiation therapy. We looked for predictive factors of locoregional disease control and patient’s survival, including CENP-A patterns, Ki67, HPV status and anisokaryosis. In different normal tissues, we reproducibly found a CENP-A subnuclear pattern characterized by CENP-A clusters both localized at the nuclear periphery and regularly spaced. In corresponding tumors, both features are lost. In locally advanced HNSCC, a specific CENP-A pattern identified in pretreatment biopsies predicts definitive locoregional disease control after chemoradiation treatment in 96% (24/25) of patients (OR = 17.6 CI 95% [2.6; 362.8], p = 0.002), independently of anisokaryosis, Ki67 labeling or HPV status. The characteristics of the subnuclear pattern of CENP-A in cell nuclei revealed by immunohistochemistry could provide an easy to use a reliable marker of disease curability by chemoradiation therapy in locally advanced HNSCC patients.

CENP-A Regulation and Cancer

“…Thus, in line with the hypothesis that centromeric regions are robust and stable chromosomal loci ( Krijger and de Laat, 2013 ), CENP-A labelling as foci at the nuclear periphery reflects a fundamental feature of centromeres organization and distribution in healthy cells. By contrast, in human tumor tissues, this discrete CENP-A subnuclear localization is drastically altered and, for invasive neoplastic lesions, similar to that detected in the cultured cell lines of tumoral origin ( Verrelle et al, 2021 ). Interestingly, CENP-A subnuclear localization in breast lesions reveals distinct information.…”

“…To date, however, much of our knowledge comes from data collected in mammalian cultured cells. In these proliferating cells, CENP-A marks the centromere of the mitotic chromosomes and, during interphase, these marks are detected as numerous foci dispersed throughout the nucleus ( Dunleavy et al, 2009 ; Lacoste et al, 2014 ; Verrelle et al, 2021 ). Importantly, these cultured cells derived from tumors provide a CENP-A localization in interphase that cannot necessarily reflect the situation in normal cells.…”

“…Furthermore, in the cell nuclei of human normal solid tissues, CENP-A is detected in 9–18 foci corresponding to the clustering of the centromeres from 2 to 5 distinct chromosomes. These foci, homogenous in size and shape, localize equidistantly at the nuclear periphery and, in fewer cases, at the periphery of the nucleolus ( Figure 5 ) ( Verrelle et al, 2021 ). This very distinct organization represents a general feature shared by distinct cell types originating from various progenitors and along various different differentiation pathways irrespective of the fact that cells could be circulating or in tissues.…”

“…Interestingly, CENP-A subnuclear localization in breast lesions reveals distinct information. In healthy tissues, the normal reference pattern compares to benign lesions ( Verrelle et al, 2021 ). By contrast, in neoplastic lesions, CENP-A foci localization in a regular distribution at the nuclear periphery is disrupted and clustering is altered or lost (smaller and many more foci) ( Figure 5 ).…”

Exploration of a Novel Prognostic Nomogram and Diagnostic Biomarkers Based on the Activity Variations of Hallmark Gene Sets in Hepatocellular Carcinoma

“…The AUC values of the two genes in RNA expression levels reached over 0.9 in four of the five independent cohorts and reached over 0.95 in protein levels in the immunohistochemistry validation cohort. The role of CENPA in some cancer types like prostate cancer ( 32 ), colon cancer ( 33 ), breast cancer ( 34 ), gastric cancer ( 35 ), and head and neck cancer ( 36 ) was widely reported. Although the carcinogenicity of CENPA in HCC has been explored by a few bioinformatic analyses ( 37 , 38 ), the CENPA -mediated molecular mechanisms in HCC remain not so clear.…”