BASIS

Breast Cancer Somatic Genetics Study

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 Obiettivo del progetto (Objective)

'All cancers arise due to somatically acquired mutations in their genomes which alter the function of key cancer genes. Understanding these critical mutational events underlying cancer development is paramount for advancing prevention, early detection, monitoring and treatment of the disease. Breast cancer is the most common class of cancer diagnosed in women worldwide with more than one million cases diagnosed annually. It is responsible for >400,000 deaths per year making it the leading cause of cancer deaths in women and is the most common cause of all deaths in women aged >40yrs. Breast cancer is a heterogeneous disease with a number of subtypes. We propose here to generate complete catalogues of somatic mutations in 500 breast cancers, of the ERve HER2- subclass, under the International Cancer Genome Consortium model by high coverage, shotgun genome sequencing of both tumour and normal DNA. All classes of mutations are expected to be detected including base substitutions, insertions, deletions, copy number changes and rearrangements. These catalogues of mutations will afford us statistical power to identify cancer genes that are mutated at a frequency of greater than 3% in this class of breast cancer. Complementary catalogues of epigenomic changes (genome-wide DNA methylation) will be generated for the same cancer samples together with transcript expression profiles. Integrated analyses of these data will be carried out and compared to parallel datasets from other classes of breast cancer and other types of cancer. The potential clinical utility of these findings for detection and monitoring of minimal residual disease will be investigated. Finally, data will be made rapidly available to all scientific researchers with minimal restrictions. The results of this exhaustive and comprehensive set of studies will have an enormous impact on our understanding of the causes and biology of breast cancer and will lead to major advances in detection, prevention and treatment of breast cancer'

Introduzione (Teaser)

All cancers arise due to somatically acquired mutations in cell genomes that alter the function of key cancer genes. Understanding these critical events is paramount for advancing prevention, early detection, monitoring and treatment of cancer.

Descrizione progetto (Article)

With more than one million cases diagnosed annually, breast cancer is the most common class of cancer diagnosed in women worldwide and is responsible for more than400,000 deaths per year making it the leading cause of cancer deaths in women. The identification of cancer genes and exploration of their function is fundamental to understanding cancer biology. Some of the proteins encoded by mutated cancer genes have become targets for the development of novel effective therapies.

Recent technological advances made sequencing large numbers of cancer genomes a realistic goal. The EU-funded 'Breast cancer somatic genetics study' (http://www.basisproject.eu (BASIS)) project intends to comprehensively study 400 breast cancer cases of the ER+, HER2- subclass which accounts for 40% of all breast cancers.

Scientists will document all classes of mutations in chromosomes including base substitutions, insertions, deletions, copy number changes and translocations present in these 400 patient samples. These catalogues will allow the identification of cancer genes that are mutated at a frequency of greater than 3% in this class of cancer. They will also identify signatures of past mutagenic processes and so provide insights into the aetiology of the disease. Complementary catalogues of epigenetic changes (DNA methylation) will be generated for the same patient samples together with mRNA and miRNA expression profiles.

All types of breast cancer cases were submitted for a full pathological review to verify the quality and classification of cancer samples. Cases that were confirmed as ER+HER2- with a tumour cellularity of 70% or more were allocated to the BASIS project. Pathologists reviewed more than 2000 cases and scored the tumours according to agreed parameters. The consortium has completed the experimental protocols required to generate the raw genome, epigenetic and transcriptomic profiles of the cancers.

The first 125 cases have been subjected to mutation analyses through mutation calling algorithms that have been specifically developed for the project. The consortium has also completed the initial transcriptomic and epigenetic analyses. Good quality data have been produced successfully from 60 RNA samples. Additionally, DNA methylation profiles have been completed for approximately 140 samples. Results of the analysis of the initial cohort of samples were published in high impact journals.

The success of BASIS will have enormous impact on understanding breast cancer pathogenesis and will lead to major advances in its detection, prevention and treatment.