227whole genomes and ultra-deep sequencing of target genes. The method is not only
very sensitive, but it is also quantitative and provides a digital display of gene varia-
tion within tumors. It identifi es rare cancer-associated genetic variations at the
molecular level, potentially enabling the personalization of targeted therapies. This
technology was used to analyze mutations in fi ve exons of the EGFR gene in tumor
samples from patients with lung cancer. The EGFR gene is the target for several
new anticancer drugs called EGFR inhibitors. Thus 454 Sequencing may help to
validate the ability of EGFR mutations to predict patient responsiveness to treat-
ment with an EGFR inhibitor. Ultimately, this system will enable personalized med-
icine, such as identifying the early stages of drug resistance and facilitating a change
in treatment that is tailored to a patient’s unique genetic response.
RNA Disruption Assay™
RNA Diagnostics Inc has developed RNA Disruption Assay™ (RDA™) that
enables determination of effi cacy of chemotherapy within the fi rst three cycles and
helps in making decision about further continuation of therapy. The test is based on
the observation that in some patients chemotherapy administration results in marked
degradation of tumor RNA, indicating a positive response and tumor destruction.
Role of Genetic Variations in Susceptibility to Anticancer Drugs
Genetic variations in susceptibility to anticancer drugs has been investigated using
a genome-wide model of human lymphoblastoid cell lines from the International
HapMap consortium, of which extensive genotypic information is available (Huang
et al. 2007 ). This model integrated genotype, gene expression, and sensitivity of
HapMap cell lines to drugs. Associations were evaluated between genotype and
cytotoxicity, genotype and gene expression and gene expression of the identifi ed
candidates was correlated with cytotoxicity. The analysis identifi ed 63 genetic vari-
ants that contribute to etoposide-induced toxicity through their effect on gene
expression. These include genes that may play a role in cancer (AGPAT2, IL1B, and
WNT5B) and genes not yet known to be associated with sensitivity to etoposide.
This method can be used to elucidate genetic variants contributing to a wide range
of cellular phenotypes induced by chemotherapeutic agents.
of Cancer Cells to Drugs Non-genetic Factors for Variations in Response
of Cancer Cells to Drugs
It is well known that not all cells of a particular cell type react to cancer treatments
uniformly and genetics alone cannot explain sensitivity or resistance to chemother-
apy. In the case of apoptosis mediated by TRAIL (tumor necrosis factor
Determination of Response to Therapy