general overview
cancer genomics Cancer is a disease of the genome. High-throughput sequencing is allowing great headway to the general understanding of cancer. Several landmark studies have determined the complete DNA sequences of clinical tumour samples or cell lines and compared these to normal tissues from the same individual. At the CNAG, cancer genomics is currently one of the most active areas of research.
genome and transcriptome sequencing data have been generated for 65 and 100 of these patients, respectively.
Efforts have focused on obtaining genome or exome-wide molecular profiles of cancer for individuals with chronic lymphocytic leukaemia, bladder cancer, colon cancer, breast cancer, prostate cancer, bone cancer and other tumour types, revealing a wide range of somatic mutation loads. The results obtained support the hypothesis that there is extensive genetic heterogeneity within a given tumour type, with a high number of infrequently mutated genes and few genes with mutations of medium recurrence in a given form of cancer.
In 2012, the DNA methylome of two CLL and three mature B-cell subtypes isolated from a single donor were sequenced at single-base pair resolution (Kulis et al. 2012). The results revealed that widespread hypomethylation predominantly targeting the gene body is the major epigenetic change in the transition between naive B cells and memory B cells as well as between CLL and normal B cells. The CLL Consortium also recognised a DNA methylation signature that distinguishes the two molecular subtypes of CLL and even new subtypes of CLL with different biological features and clinical behaviours. This study represents an initial step towards the whole epigenomic characterisation of normal and neoplastic hematopoietic cells. This activity has been extended to our contribution to the EU funded project BLUEPRINT part of the IHEC (Adams et al. 2012).
The CNAG participates in the Chronic Lymphocytic Leukaemia (CLL) Genome Project, the Spanish contribution to the ICGC. CLL is a neoplasia of B lymphocytes and is one of the most common tumours in Western countries. In the last three years, the CLL Consortium, led by Dr Elias Campo from Hospital Clﾃｭnic and Dr Carlos Lopez-Otin from the University of Oviedo, has established a comprehensive catalogue of exomic genetic alterations in 300 CLL tumours. Whole
Since 2011 the CNAG has worked in close collaboration with Dr Miguel ﾃ］gel Piris and collegues at the Hospital Universitario Marquﾃｩs de Valdecillas in using sophisticated high-throughput genomic technologies for the clinical management of cancer patients through the development of individualised approaches to treatment. In 2012 more than 100 exomes were sequenced within the framework of this project.
Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia Kulis M, Heath S, Bibikova M, et al including Bayﾃｩs M, Gut M and Gut I. Nat Genet. 2012 Oct 14;44(11):1236-42. BLUEPRINT to decode the epigenetic signature written in blood Adams D, Altucci L, Antonarakis SE, Ballesteros J, Beck S, Bird A, Bock C, Boehm B et al. including Gut I. Nat Biotechnol. 2012 Mar 7;30(3):224-6. 10