International Cancer Genome Consortium

Breast cancer is the most common class of cancer diagnosed in women worldwide with more than one million cases diagnosed annually, is responsible for >400,000 deaths and is the leading cause of cancer deaths in women. The aetiology of most breast cancer cases is unknown. However, endocrine factors, inherited susceptibility and mutagenic exposures such as X-irradiation are all known to influence risk of the disease.

Histological, immunohistochemical, mRNA expression and genomic analyses have indicated that breast cancer is a heterogeneous disease composed of multiple biological subtypes. We have adopted a pragmatic working classification of breast cancer based on histology combined with immunohistochemistry for a limited biomarker set including estrogen receptor (ER), progesterone receptor (PR) and HER2. This classification is outlined below.

The European Commission have funded this proposal, known as “BASIS”, which focuses on ER+ve, HER2-ve ductal-type breast cancers (both PR+ and PR-) which constitute the largest subgroup in this classification scheme and account for ~40% breast cancer cases.

Classification scheme of breast cancer
• ER-, HER2-, PR- (triple negative, most of which are “basal” tumors)
• ER-, HER2+ tumors
• ER+, HER2+ tumors
• ER+, HER2-, PR+ tumors; ductal-type
• ER+, HER2-, PR- tumors; ductal-type
• Invasive lobular carcinoma
• “Rare” histological special types

We propose to generate comprehensive catalogues of somatic mutations in 500 ER+, HER2-breast cancers under the ICGC model by high coverage, shotgun genome sequencing of both tumor and normal DNA. All classes of mutations are expected to be detected including base substitutions, insertions, deletions, copy number changes, translocations and other chromosomal 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. They will also carry signatures of past mutagenic processes operative in the development of each cancer and thus provide insights into the aetiology of the disease.

Complementary catalogues of epigenomic changes (genome-wide DNA methylation) will be generated for the same 500 cancer samples together with mRNA and miRNA expression profiles. Integrated analyses of these data will be carried out and compared to parallel datasets from other classes of breast cancer as well as other types of cancer.

The ICGC Breast Cancer Working Group will be overseeing this study and others focusing on other breast cancer subtypes and is funded through a number of sources including the Wellcome Trust (triple negative cases), Breakthrough Breast Cancer (triple negative cases), and the Institut Nationale du Cancer (HER2+ve cases) in addition to this European Commission FP7 funded proposal on ER+ve, HER2-ve breast cancer.

Michael Stratton