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Targeted Therapy Challenges:More Cancer Genes Discovered, Mutational Burdens Defined

Jane de Lartigue, PhD
Published: Friday, Jun 13, 2014
Targeted Therapies Even as technological advances make it possible to sequence DNA on a large scale at relatively lower costs and in shorter time-frames, emerging evidence from the world’s top research laboratories suggests that scientists are still a long way from having a complete catalog of cancer genes.

And, as a wealth of data accumulates, it is becoming increasingly clear that the sheer variety and frequency of mutations plays a complex role in malignancies, underscoring the challenges of molecularly targeted anticancer strategies.

Recent research from the Broad Institute of MIT and Harvard highlights both of these developments. Researchers announced the discovery of 33 genes whose roles in promoting cancers had not been previously identified and described how the burden of mutations differs among tumor types.

The implications for therapies include the need for novel analytic techniques and fresh approaches to multigene targeting.

Therapeutic Development in the Genomic Era

The renowned German biologist Theodor Boveri suspected the genetic origins of cancer more than a century ago, but it took almost 70 years for his suspicions to be confirmed. Now it is well understood that the majority of cancers arise as a result of the acquisition of a series of alterations to their genome, which lead to the dysregulation of key cellular processes.

During the past several decades, significant headway has been made in uncovering the genetic alterations that play a role in the development and progression of cancer and in identifying scores of oncogenes, which promote oncogenesis, and tumor suppressors, which keep it in check. Researchers have identified both driver mutations that are causally implicated in oncogenic development and passenger mutations that, as the name suggests, are just along for the ride and are likely a result of the genetic disarray of cancer, rather than the cause of it (Figure).

Figure. Snapshot of Cancer Genomic Landscape

Snapshot of Cancer Genomic Landscape

References
1An O et al [published online March 7, 2014]. Database. doi:10.1093/database/bau015.
2Vogelstein B et al. Science. 2013;339(6127):1546-1558.



All of the nearly 140 driver mutations identified to date are linked to one or more cellular pathways or processes, the realization of which led to the idea of cancer “hallmarks”—that is, essential changes that normal cells undergo on the path to becoming malignant tumor cells. While the contributions of many of these hallmark processes to cancer seemed intuitive, genomic sequencing has revealed new, unexpected contributions of cellular processes governing epigenetic regulation, chromatin modification, metabolism, and others that were not previously suspected to be involved in cancer.

The Cancer Gene Catalog: Close to Completion?

Candidate cancer genes are discovered by sequencing tumor samples and comparing the findings with matched normal samples, based on the presence of a greater number of somatic mutations than expected.

The process was initially time-consuming and expensive, but advancements in sequencing technology in the past decade, particularly the introduction of massively parallel sequencing, have brought about a 1 million–fold decrease in the cost and increased the capacity of DNA sequencing, such that it is now possible to sequence a genome for $1000 and to sequence more than 600 gigabases (Gb) per run.

Mutation Burden by Tumor Type

Mutation Burden by Tumor Type

This graphic depicts the median frequencies of somatic mutations in the exome (horizontal lines) across multiple tumor types from the lowest frequencies, left, to the highest frequencies, right, as measured in mutations per megabase (Mb). The dots represent tumor-normal pairs. The colored panel at bottom illustrates the distribution of 6 possible base-pair substitutions in key at left.

Broad Institute of MIT and Harvard. Reprinted with permission.



Major international efforts are currently under way to catalog the cancer genome, including those by The Cancer Genome Atlas and the International Cancer Genome Consortium, and there is a growing interest in pan-cancer analyses. Promising results from many of these studies were reported in 2013. Currently, roughly 10% of the known genes in the human genome have been identified as or are suspected to be cancer genes. But an important question remains: How far are we from a complete picture?


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