Major
Biological Sciences
Advisor
Howlett, Niall G.
Advisor Department
Cell and Molecular Biology
Date
5-2015
Keywords
genomics; Human Genome Project; The Cancer Genome Atlas; breast cancer; ovarian cancer
Abstract
The field of genomics originated in the 1970’s starting with the sequencing of small organisms’ genomes such as the bacterium, Haemophilus influenzae, and the yeast, Saccharomyces cerevisiae. A genome is the complete ordered sequence of DNA bases (A, C, G, and T) comprising all of the protein- and RNA-coding genes, as well as all of the regulatory sequences necessary for the construction of an organism. Over time, scientists sequenced the genomes of larger and more complex organisms, eventually leading to the sequencing of the human genome. The Human Genome Project (HGP) was initiated in 1990 and took over ten years to complete. A draft sequence of all 3 billion human base pairs was published in 2003 and paved the way for even more complex genomic research projects. One of the more significant projects to evolve from the HGP is The Cancer Genome Atlas (TCGA). The success of the HGP led to major advances in DNA sequencing technologies, enabling genomes to be sequenced faster, cheaper, and more efficiently. TCGA set about to utilize these next-generation sequencing technologies to sequence the genomes of as many cancers as possible to try to determine if there are any significant commonalities in the DNA between tumors of the same cancers as well as similarities in the genomes between different types of cancer. Through their findings they hoped they could better understand the changes in cancer genomes to provide a foundation for improvement in treatment, detection and prevention of cancer.
Breast cancer is one of the most common cancers to affect women ranking as the second leading cause of cancer deaths with an estimated 292,130 new cases, both invasive and non-invasive, and 40,290 deaths in 2015. Ovarian cancer ranks as the fifth leading cause of cancer deaths in women, with an estimated 21,290 new cases and 14,180 deaths in 2015. Due to the high prevalence and mortality of breast and ovarian cancer, TCGA set out to comprehensively characterize the molecular signatures of these cancers. To do this, TCGA performed whole genome and exome sequencing, DNA methylation analysis, chromosome copy-number variation analysis, and mRNA, miRNA, and protein expression analysis on normal and tumor samples from multiple affected individuals. It was seen that genes including PIK3CA, MAP3K1, TP53, PTEN, FOXA1, BRCA1, and BRCA2, among others, were commonly mutated and/or amplified in breast cancer tumor samples. Ovarian cancer tumor samples also displayed a high frequency of mutations in BRCA1 and BRCA2 along with mutations in genes such as RB1, NF1, CSMD3 and CDK12. Through TCGA’s study on breast cancer, it was discovered that there are four distinct molecular subtypes of breast cancer based on variations in mRNA expression: Luminal A, Luminal B, HER2-enriched, and Basal-like. Similarly, TCGA researchers determined that at least four expression subtypes exist in high-serous ovarian cancer (HGS-OvCa) based on mRNA and miRNA expression including immunoreactive, differentiated, proliferative, and mesenchymal.
Through TCGA findings, there is hope that new treatments can become available for treating these cancers in ways that can target specific pathways that any of the genes are involved in. It is possible that new diagnostic methods and therapeutic approaches can be discovered for a variety of cancers including both breast and ovarian.
The Cancer Genome Atlas