Breast Cancer Genetics

Breast cancer is a genetic disease that develops when one or more cells within the tissue of the breast start to grow without normal controls. Some breast cancers are caused by germline mutations within breast cancer susceptibility genes such as BRCA1 or BRCA2. Mutations in these genes may be inherited, they are found in all cells of affected individuals, and typically confer a lifetime risk of breast cancer. However, these inherited forms are rare. Most breast cancers are caused by genetic changes that are found only in the cancer cells and acquired during lifetime. Additional genetic changes will typically accumulate in cells of the primary tumour, and will further influence growth advantage.

In recent years, genome-wide microarray profiling technologies have allowed identification of clinically distinct breast cancer subtypes based on the types of genes that are expressed in the cancer cells. These findings reinforce the notion that genetic markers have potential to be applied for breast cancer diagnosis with the same confidence that they are currently used to characterise distinct subtypes of leukaemia or sarcoma. However, gene expression profiling is both expensive and technically demanding to a level that is not currently amenable to most routine diagnostic settings. Thus, although there is a major shift in the breast cancer paradigm that cannot be ignored, there are practical hurdles that limit feasibility to translate important findings into routine diagnostics.

Image from Walker et al, Cancer Genet Cytogenet. 2007 Oct 15;178(2):94-103

Simpler, more stable and less costly approaches are needed to distinguish the newly recognised breast cancer subtypes. These approaches include immunohistochemistry (IHC), fluorescent in situ hybridisation (FISH) or polymerase chain reaction (PCR), all of which are presently used to enhance routine diagnostic pathology practice. However, success of these applications would rely on the use of appropriate marker panels, which in turn depends on knowledge of biologically relevant genes. In this regard, more research is needed to extend present understanding of the gene networks most relevant to normal breast cell development and to breast malignancy. Procedures such as IHC, PCR and FISH also yield very limited information about the overall genetic composition of cancer cells compared with global profiling by microarray analysis. A different type of microarray technology platform known as array comparative genomic hybridisation or “array CGH” is now allowing scientists to analyse chromosomal DNA of human cells with sensitivity and at ultra-high resolution not previously possible using conventional cytogenetic methods. In contrast to labile RNA used for expression profiling, tumour DNA is stable, relatively easy to transport, and can be obtained from archival paraffin tissue blocks.

Array CGH has identified specific segments of DNA, known as “copy number variants” (CNVs) or “structural variants”, that may be lost, gained or altered in structure in the genomic make-up of some individuals but not in others. More than 17,000 such variants have been identified so far, but still very little is understood about their health relevance. When inherited or otherwise congenitally present in all cells of an individual from birth, some configurations of these CNVs may predispose to particular clinical syndromes or to cancer development. Conversely, when acquired during lifetime, CNVs may mark genetic changes of relevance to the cause and progression of malignancy. To this end, array CGH has been applied now for

the identification of DNA copy number changes in the affected tissues of many different types of cancer. Extending a wealth of knowledge learned through the application of conventional cytogenetics, especially karyotyping, array CGH is revealing DNA copy number variations specific to different cancer subtypes, and which are strong biological indicators for diagnosis, for more accurate prognosis and new drug development.

Our Study

We have been applying FISH, CGH, and high resolution microarray technologies in a prospective study designed to identify molecular events which may be of clinical significance to patients who have breast cancer of ductal origin. Close collaboration between clinical oncologists, surgeons, histopathologists and researchers is ensuring optimal documentation of relevant clinical parameters at diagnosis, during post-operative treatment, and through disease recurrence, and of proper histopathological characterisation, tissue sampling and storage for genetic analysis.

Understanding the genetic differences between different breast cancer subtypes will improve the accuracy of diagnosis, enable better prognostic stratification and inevitably lead to the development of more effective treatment options.

Image from Walker et al, Genes Chromosomes Cancer. 2008 May;47(5):405-17