Methylation alteration of SHANK1 as a predictive, diagnostic and prognostic biomarker for chronic lymphocytic leukemia.

// Eleonora Loi 1 , Loredana Moi 1 , Antonio Fadda 1 , Giannina Satta 2 , Mariagrazia Zucca 3 , Sonia Sanna 3 , Shadi Amini Nia 2 , Giuseppina Cabras 4 , Marina Padoan 5 , Corrado Magnani 5 , Lucia Miligi 6 , Sara Piro 6 , Davide Gentilini 7 , 8 , Maria Grazia Ennas 3 , Melissa C. Southey 9 , 10 , Graham G. Giles 11 , 12 , Nicole Wong Doo 11 , 13 , Pierluigi Cocco 2 and Patrizia Zavattari 1 1 Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy 2 Department of Medical Sciences and Public Health, Occupational Health Unit, University of Cagliari, Cagliari, Italy 3 Department of Biomedical Sciences, Cytomorphology Unit, University of Cagliari, Cagliari, Italy 4 Unit of Hematology, A. Businco Oncology Hospital, Cagliari, Italy 5 Department of Medical Sciences, Unit of Medical Statistics and Cancer Epidemiology, University of Eastern Piedmont, Novara, Italy 6 Institute of Oncology Studies and Prevention, Florence, Italy 7 Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy 8 Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Milan, Italy 9 Precision Medicine, Monash University, Melbourne, Melbourne, Australia 10 Department of Clinical Pathology, The University of Melbourne, Melbourne, Australia 11 Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Australia 12 Centre for Epidemiology & Biostatistics, The University of Melbourne, Melbourne, Australia 13 Concord Hospital Clinical School, The University of Sydney, Sydney, Australia Correspondence to: Patrizia Zavattari, email: pzavattari@unica.it Keywords: cancer methylation alteration; predictive biomarkers; diagnostic biomarkers; prognostic biomarkers; SHANK1 Received: March 14, 2019     Accepted: June 21, 2019     Published: August 13, 2019 ABSTRACT Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the clonal expansion of malignant B cells. To predict the clinical course of the disease, the identification of diagnostic biomarkers is urgently needed. Aberrant methylation patterns may predict CLL development and its course, being very early changes during carcinogenesis. Our aim was to identify CLL specific methylation patterns and to evaluate whether methylation aberrations in selected genes are associated with changes in gene expression. Here, by performing a genome-wide methylation analysis, we identified several CLL-specific methylation alterations. We focused on the most altered one, at a CpG island located in the body of SHANK1 gene, in our CLL cases compared to healthy controls. This methylation alteration was successfully validated in a larger cohort including 139 CLL and 20 control in silico samples. We also found a positive correlation between SHANK1 methylation level and absolute lymphocyte count, in particular CD19+ B cells, in CLL patients. Moreover, we were able to detect gains of methylation at SHANK1 in blood samples collected years prior to diagnosis. Overall, our results suggest methylation alteration at this SHANK1 CpG island as a biomarker for risk and diagnosis of CLL, and also in the personalized quantification of tumor aggressiveness.