Ultra high-throughput DNA sequencing strategies are already being used to study human genomes. The potential usefulness of such data for clinical practice is of great interest, and is the subject of a current PHG Foundation project. Early examples of how whole-genome sequencing (WGS) can be used for diagnosis and choice of therapy were recently presented at the Personal Genomes conference at Cold Spring Harbor Laboratory.
The case of a female patient with acute promyelocytic leukemia (APL) was presented. Most APL patients have a chromosomal translocation resulting in the fusion of the PML and RARA genes and production of a PML-RARA fusion protein, which can be effectively targeted by a specific drug ATRA (all–trans retinoic acid).
Normal analysis of the patient in question did not reveal the presence of the translocation, so she was not treated with ATRA. However, rapid sequence analysis and comparison of tumour and control (skin) samples from this patient revealed a novel chromosomal change creating a PML-RARA fusion protein. The patient was then given treatment with ATRA, with good results; there are plans to sequence the genomes of other atypical cancer patients in the future.
Another centre presented the case of a man with a rare tumour, an adenocarcinoma of the tongue, for which no established treatment protocol existed [Jones SJ et al. (2010) Genome Biol. 11(8):R82.]. The genomes of the tumour and normal DNA from this patient were sequenced, and researchers then compared key genomic features of the cancer (such as somatic mutations, and copy number alterations, and gene expression data), with drug target information from the DrugBank database. They found that several genes encoding proteins targeted by a specific class of drugs were either amplified or highly expressed in the tumour. The patient was treated with these drugs and showed a good response.
Examples were also presented of the use of WGS in other types of serious disease to inform treatment, such as exome-sequencing of a child with a severe form of inflammatory bowel syndrome.
Despite the promise of these approaches, doctors were quick to point out that no therapy was selected based solely on the findings of genome sequencing, but the additional information was of value in some cases where standard diagnosis or treatment had not been successful. It is also important to note that, whilst the cost of whole genome sequencing continues to plummet, the analysis and interpretation of the data it produces to inform clinical management is a complex matter.