Darwinian evolution spectrum of primary triple negative breast cancers
Understanding the biology and therapeutic responses in patients with triple negative breast cancer require determination of individual tumour clonal genotypes
- Date : 10 May 2012
- Topic : Breast cancer
A new study, published in the journal Nature, reveals that triple-negative breast cancer is not one distinct single entity, but an extremely complex and evolved tumour with an unprecedented range of mutations. The study revealed groupings of genetic mutations that already have potential clinical treatment options. The research team, including scientists from BC Cancer Agency, University of British Columbia, Cross Cancer Institute of Alberta and Cancer Research UK/University of Cambridge, pinpointed that exact cellular mutations involved are important first step in understanding why patients respond differently to treatment.
Triple negative breast cancer is not just one uniform subtype of breast cancer
Named for what it isn’t, triple negative breast cancer is currently defined by three missing receptors (the estrogen receptor, progesterone receptor and ERBB2 receptor), compared to other breast cancer subtypes. Triple negative breast cancer is currently treated as if it’s a single disease, yet it’s clear from this study that patients’ tumours vary drastically across a spectrum of cellular mutations involved in the cancer’s development. Currently, triple negative breast cancer accounts for 16% of all breast cancer diagnoses and approximately 25% of breast cancer deaths.
This discovery builds on Dr. Samuel Aparicio’s landmark study of 2009, published also in Nature, and which showed for the first time how genome sequencing can be used to follow the evolution of breast cancers.
The study researchers showed in 104 triple-negative breast cancer cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2414 somatic mutations, the study researchers determined for the first time in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. They showed that triple-negative breast cancers vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype showing more variation than non-basal tumours.
Although p53, PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies were incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression.
Future sequence-guided clinical trials will require collaborations between major cancer centres able to recruit the required numbers of patients
In approximately 20% of cases studied, the tumours revealed groupings of genetic mutations that already have potential clinical treatment options in the pipeline. This leads researchers and clinicians toward a future where patients’ tumours could be sequenced as a means to better direct targeted therapies. Pinpointing the exact cellular mutations involved is an important first step in understanding why patients respond differently to treatment.
The newly discovered cancer-related genes and mutation patterns from this research could become the targets for more effective treatments or the markers for a more personalised diagnosis. Insights from mathematical and computational models of evolution in cancer patients, informed by precise genetic measurements will be required for future translational research in cancer.
The research was generously supported by the BC Cancer Foundation, Canadian Breast Cancer Foundation - BC/Yukon Region and Prairies/NWT Region, Alberta Cancer Foundation, Alberta Cancer Prevention Legacy Fund and Alberta Innovates-Health Solutions, Michael Smith Foundation for Health Research and Cancer Research UK at the University of Cambridge.
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