Abstract
BackgroundHypertrophy of the nucleolus is a distinctive cytological feature of malignant cells and corresponds to aggressive behaviour. This study aimed to identify the key gene associated with nucleolar prominence (NP) in breast cancer (BC) and determine its prognostic significance.MethodsFrom The Cancer Genome Atlas (TCGA) cohort, digital whole slide images identified cancers having NP served as label and an information theory algorithm was applied to find which mRNA gene best explained NP. Dyskerin Pseudouridine Synthase 1 (DKC1) was identified. DKC1 expression was assessed using mRNA data of Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1980) and TCGA (n = 855). DKC1 protein expression was assessed using immunohistochemistry in Nottingham BC cohort (n = 943).ResultsNuclear and nucleolar expressions of DKC1 protein were significantly associated with higher tumour grade (p < 0.0001), high nucleolar score (p < 0.001) and poor Nottingham Prognostic Index (p < 0.0001). High DKC1 expression was associated with shorter BC-specific survival (BCSS). In multivariate analysis, DKC1 mRNA and protein expressions were independent risk factors for BCSS (p < 0.01).ConclusionDKC1 expression is strongly correlated with NP and its overexpression in BC is associated with unfavourable clinicopathological characteristics and poor outcome. This has been a detailed example in the correlation of phenotype with genotype.
Highlights
Breast cancer (BC) is the most common cancer diagnosed in women worldwide, accounting for approximately 1 in 10 new cancer diagnoses each year and is the second most common cause of death[1,2] due to cancer
High DKC1 expression was associated with shorter breast cancer (BC) specific survival (BCSS)
DKC1 expression is strongly correlated with nucleolar prominence (NP) and its overexpression in BC is associated with unfavourable clinicopathological characteristics and poor outcome
Summary
Breast cancer (BC) is the most common cancer diagnosed in women worldwide, accounting for approximately 1 in 10 new cancer diagnoses each year and is the second most common cause of death[1,2] due to cancer. Especially histological grade, have been well validated to have a strong prognostic value and their assessment helps in prognostic stratification of BC patients for treatment decisions[3]. In the Nottingham cohort, nucleolar prominence (NP) has recently been shown to be a significant predictor for patient outcome as well as of being highly correlated with tumour grade. Since the NP is a distinctive morphological attribute, it is hypothesised to possibly serve as a substitute for the highly subjective pleomorphism component score of the Nottingham BC grading[4]. It is deemed imperative to explore the correlations between the nucleolar phenotype and genotype. This study aimed to identify the key gene associated with nucleolar prominence (NP) in breast cancer (BC) and determine its prognostic significance
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