Image courtesy of Andrew Armstrong.
Whole genome sequencing—reading all three billion letters of a person’s genome—was first accomplished by the Human Genome Project in 2003 after more than a decade of research. But now, with the advent of massive parallel sequencing methods, the human genome can now be sequenced in a matter of days.
A recent case study conducted by Yale and the Duke and Weill Cornell Schools of Medicine is one of the first to publish the completed whole genome sequence of a patient to inform future personalized medicine treatment for prostate cancer. In the near future, the patient hopes to create a page that shares his motivation for self-identification, his germline, and his somatic sequencing information. This creates a “unique case where clinical and genetic information are linked” and “[sets] the stage for further patients to share and link their own data,” said Andrew Armstrong, co-first author of the study.
Targeted gene panels, which sequence only the most commonly mutated genes in cancers or other conditions, are used more frequently in medicine due to their lower cost. They operate within a smaller pool of known genes whose mutations have been shown to drive cancers. Whole genome sequencing, in contrast, looks at every letter in the entire genome, so it remains quite expensive and is not generally a viable clinical option. However, examining whole genome sequencing enables researchers to analyze the potential effects of noncoding sequences—which do not produce protein and comprise over ninety-eight percent of the genome. The function of these non-protein-coding sequences in the genome is “not well understood,” said Xiaotong Li, a co-first author and the study’s bioinformatician.
In this case, the whole genome sequencing was not integral to finding a cancer driver mutation, which would have been found with targeted sequencing. However, the patient’s whole genomic information was useful for inferring the aging and clock-related mutational signatures that may have caused his cancer-related mutation over time. “[Future] whole genomic approaches may speed the discovery of cancer causes and prevention as well as treatment by more fully using this information and processing it with clinical outcomes to broaden the impact of personalized medicine,” Armstrong said. He hopes this is the first of many cases in which genomic sequencing data becomes available and tied to clinical outcomes.
Armstrong and Li formed close relationships with the patient. Li described this journey as a “uniquely rewarding experience.” “I was impressed by how genomics analysis can help us better understand cancer treatment and benefit personalized medicine,” Li said.
If possible, Armstrong encourages patients to seek out whatever sequencing options they might have access to, whether that be targeted gene panels or another method. “By empowering patients to ask their doctors about sequencing options, we can help inform treatment and genetic counseling in ways that will continue to facilitate discovery,” Armstrong said.
Armstrong, A. J., Li, X., Tucker, M., Li, S., Mu, X. J., Eng, K. W., … & Gerstein, M. (2021). Molecular medicine tumor board: Whole-genome sequencing to inform on personalized medicine for a man with advanced prostate cancer. Prostate Cancer and Prostatic Diseases, 1-8.