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In 2012, 8.2 million people died of cancer an estimated 14.6% of all deaths worldwide. The number of cancer diagnoses globally is projected to increase 57% (approximately 8 million new cases) between now and 2030, influenced in part by an aging population. That same year, in 2012, the World Health Organization announced cancer had officially replaced heart disease as the primary cause of death in many developed and developing countries worldwide ( This fact is fueling increased demand for research and public health campaigns to fight cancer both here at home and abroad. This article probes the discoveries leading up to the invention of whole-genome sequencing used widely today.

The History of Cancer

Today cancer is recognized as a disease originating from the genome; however, recognition of that fact was slow to come. Despite James Watson and Francis Crick's famous publication of molecular biology's central dogma, which explained how information flows from DNA to RNA to protein, in 1958 [1], it wasn't until 1973 when the first concrete clue was found, which appeared to show that cancer has genetic origins. In fact, it was Dr. Janet Rowley, who while studying chronic myeloid leukemia, proposed that one specific chromosomal translocation, the Philadelphia chromosome, was linked to this particular cancer [2]. Nearly 10 years later in 1982, Reddy and colleagues published their findings indicating a single point mutation changing guanosine to thymidine in HRAS resulted in bladder cancer [3]. This seminal discovery provided direct evidence to support the notion that cancer can be the result of genetic alterations of, otherwise, normal genetic material. Their findings ushered in an era of vigorous research aimed directly at cataloging entire lists of genes that could, when certain mutations or aberrations were expressed, promote the development of certain types of human cancers.

Cancer researchers pressed on, continually accumulating new knowledge on the basic mechanisms of the disease. By 2004, they had attained an inventory of genes associated with cancer, which included 291 entries, or approximately 1% of the entire coding sequence. And what was the most common type of variation they found then, at the dawn of the genomic era? They found it was translocation, which led to the formation of oncogenic fusion proteins [4].

The completion of the human genome project swept cancer research into the genomics era, which made it possible, at least in principle, to determine the precise somatic mutations that can lead to the formation of any tumor [5]. By comparing the DNA sequence from a tumor biopsy with a reference sequence, researchers unlocked the full potential of bioinformatics to process bulk Costco-sized information. In practice, it was much more complicated and required the development and use of sophisticated next-generation sequencing (NGS) platforms.

The time between the completion of a human reference genome in 2003 and the successful conclusion of the HapMap project (a Phase III clinical trial, which sought to inventory genes and categorize the normal range of common human variations among genes) in 2009, our understanding of what constitutes normal genetic variation, as well as the genetic phenotypes of disease, rapidly improved [6].

Advancements in Cancer Genome Projects

We have accumulated a staggering among of knowledge about mutations over the past 40 years. Yet, comparisons with the human reference genome seem to indicate that the cancer genome incorporates anything from single point mutations to the translocation of wholesale chromosome regions [7].

The newer NGS technologies have enabled the systematic cataloging of cancer genomes thanks to national and international efforts. The Cancer Genome Atlas (TCGA,, the International Cancer Genome Consortium (ICGC), the International Cancer Genome Project (, Therapeutically Applicable Research to Generate Effective Treatments (, are some of the projects seeking to catalog every single mutation in a wide variety of adult and pediatric cancers [8,9,10]. These projects make their data publicly available so that the wider cancer research community can benefit off the resource.

Just in the past 5 years, we've seen how this wellspring of information is having a profound effect on our understanding of cancer biology, and is allowing clinicians to cast a wider net among cancer patients.

We are beginning to see how genome sequencing can make a real difference in the lives of cancer patients and their families, says author Richard K. Wilson, PhD, director of Washington University's Genome Institute and a leader in the field of cancer genome sequencing [11].

Both studies underscore the value of whole-genome sequencing as a diagnostic tool. We could not have identified these mutations using conventional tests or targeted sequencing approaches because they involved unexpected structural changes to the DNA, which can only be found by looking across the entire genome.

Advances in technology have enabled scientists to sequence the genomes of cancer patients at a cost and speed that was unimaginable even a few years ago. Still, as the cost of whole-genome sequencing continues to fall, researchers expect that it will become the standard method by which scientists search for rare, inherited cancer mutations.

But Wilson cautions that it's not yet practical to routinely sequence cancer patients' genomes because the cost is still relatively high, and scientists don't yet fully understand the breadth of genetic changes that drive cancer development. Select cases like these, however, offer a glimpse of the way personalized genome sequencing can transform the way doctors diagnose and treat cancer patients and their families.

In essence, the accumulated result of these studies provided researchers with an unmatched statistical prowess to discover the majority of somatically reprogrammed (mutated) genes that contribute to a cancer's phenotype. So really, the fruit of their labor has been the formation of a reliable genetic parts list for many types of cancer. The task at hand for researchers today, is to come up with new strategies that make use of the parts list in ways that can effectively improve cancer patient care.


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[7] Meyerson M, Gabriel S, Getz G. Advances in understanding cancer genomes through second-generation sequencing. Nature Reviews Genetics, 2010. 11:685-96.

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[9] Downing JR, Wilson RK, Zhang J, et al. The Pediatric Cancer Genome Project. Nature, 2012. 44:619-22.

[10] Garraway LA, Lander ES. Lessons from the cancer genome. Cell, 2013. 153:17-37.

[11] Decoding Cancer Patients' Genomes is a Powerful Diagnostic Tool. The Genome Institute. Washington University in St. Louis' School of Medicine. 2014.