Functional cancer genomics

Published on October 29, 2015   44 min

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Other Talks in the Series: Cancer Genetics

Hello. I am Roderick Beijersbergen from the Netherlands Cancer Institute in Amsterdam. And I will be talking to you today about functional cancer genomics.
In the past decade, rapid progress in the ability to analyze full genomes of cancers has pointed out that individual tumors may contain hundreds and thousand of mutations across the entire genome. Some tumors, such as colorectal cancer, lung cancer and melanoma, have frequently even up to a 100,000 mutations. Although the majority of these mutations will not directly affect the coding region of genes, and thus, not lead to abnormal proteins, estimates are that 10 to 100 mutations expressed in coding regions will result in the expression of mutant proteins with aberrant functions. These abnormal proteins and the biological pathways and mechanisms they control play important roles in the development of cancer and response to cancer therapies. It's an enormous challenge for oncology research to map and understand the role of each of these genetic alterations for the diagnosis, prognosis and treatment of cancer. In addition to the large numbers of mutations found in different tumor types, it has also become clear that within one tumor type, for example lung cancer, different mutational spectra can be found in individual patients.
This slide shows significantly mutated genes in 178 tumors of one type, in this example, squamous cell lung cancer. Although the frequency of the mutations of the tumor suppressor gene TP53 is high, with more than 80 percent mutation frequency, for other genes, even though they are significantly mutated, this mutation rate is much lower. This indicates that among different tumors, different mutations exist, even within one tumor type. This heterogeneity among different tumors, even from the same tumor type, complicates the interpretation and use of this genetic information for the treatment of cancer. However, more in-depth analysis of all the pathways involved, for example, in cell proliferation, growth, and survival, which can be due to different mutations within the same phenotypic outcome can highlight all the pathways and provide potential therapeutic targets for this type of cancer.
Molecular target agents, for example, drugs that inhibit specific proteins in signaling pathways, in processes associated with tumor growth and survival, are now commonly used in patients for the treatment of cancer. However, it is important that these targets are indeed essential for a specific tumor, also in the context of other mutations present in the same tumor. The gene-centered analysis of core cellular pathways in these examples, of PI(3) kinase pathway, receptor targets in kinase signaling, and the RAS MAP kinase pathway, that will present potential therapeutic targets in these squamous cell lung cancers, revealed alterations in one of the components of these pathways in at least 69 percent of the tumors. These alterations are not restricted to mutations, but can also represent deletions or amplifications and overexpression, more specifically, in 47 percent of tumors, one of the components of the PI(3) kinase pathway was altered, and the receptor targets in kinase signaling effected by events such as epidermal growth factor receptor amplification, BRAF mutation or fibroblast growth factor receptor amplification or mutation, occurred in 26 percent of tumors. Important to note here is that the alterations in PI(3) kinase pathway genes were mutually exclusive with EGFR mutations and amplifications, indicating that these cells depend on one pathway or another. Although the dependence of lung squamous cell cancer on many of these individual alterations remain to be defined functionally, these observations do suggest the potential use of target therapies for this type of cancer.
The molecular classification of cancer with respect to mutations that affect potential drivers has already resulted in the implementation of genotype-driven cancer therapy. This means that the therapy of choice can be based on the presence of a specific molecular alteration in a given tumor, and which can be inhibited by a small molecular antibody. For adenocarcinoma in the lung, mutations in EGFR and KRAS are highly prevalent, and drugs have been developed that either target the protein directly, for example, erlotinib and gefitinib targeting EGFR, or indirectly downstream of the mutated protein such as MEK inhibition in KRAS mutant cancer. In addition, other genetic alterations such as amplification of the HER2 receptor, mutation of BRAF and PI(3) kinase, the catalytic subunit if of the PI(3) kinase enzyme can be targeted by small molecule inhibitors. Apart from mutations or amplification, translocations can also act as drivers in cancers. This is illustrated by the presence of the EML4-ALK kinase fusion in lung adenocarcinoma. An ALK inhibitor called crizotinib can be used for cancer carrying such a translocation and shows promising clinical response. The majority of patients have a reduction in tumor size upon crizotinib treatment. However, despite some great success with genotype-driven therapy of cancer, most notably in hematological malignancies carrying the BCR-ABL translocation treated with Gleevec or Imatinib, it has also become evident that in many cases, patients either do not respond to the corresponding target therapy, or rapidly develop resistance leading to progressive disease.

Functional cancer genomics

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