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Malachi and Obi Griffith: Scientific Curiosity, Personal Drive

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Recommended by: Rick Wilson and Elaine Mardis, Washington University in St. Louis

For twin brothers Malachi and Obi Griffith, their drive toward understanding the cancer genome is more than just scientific curiosity, it's personal. A few weeks before they graduated from high school, their mother died from breast cancer.

"It was a big event at a seminal moment," Obi says.

The two now work at WashU's Genome Institute and are developing an informatics pipeline for clinical cancer sequencing. We're "trying to derive medically useful information out of all that sequence data," Malachi says. The pipeline is being designed to combine whole-genome, transcriptome, and exome sequencing data to find molecular events that suggest clinical action, he says.

This type of analysis is different from other cancer genome informatics strategies, Malachi says, because those are often more focused on understanding the biology of the tumor rather than what clinical actions can be taken.

"To work on clinical cancer sequencing analysis is to really try to shift your focus, to what do we know now, what information can we gather to suggest something clinically relevant," he says.

Obi says one of the main challenges has been in applying their work in the clinic and establishing connections between the researchers on the genomics and informatics side and those on the clinical and translational side.

Looking ahead

In the next five years, Malachi predicts that a catalog of common cancer mutations will be completed. Already, significant progress has been made in cataloging SNVs, although there is still work to be done on characterizing insertions, deletions, other structural variations, copy-number changes, and genes fusions, he says. Additionally, this catalog of mutations will likely lead to a "redefinition in the way we think about cancer," so that cancer is defined on a molecular basis as opposed to the tissue site of origin.

"It's definitely a very exciting time" to be in the field, Obi adds. And as sequencing continues to get cheaper, more hospitals, academic centers, and commercial entities will begin offering cancer genome sequencing to patients. Rather than one-off examples of clinicians using sequencing to make decisions about cancer patients' treatment, it will become standard of care, he predicts.

Paper of note

Both Obi and Malachi contributed to one of the first published examples of using whole-genome sequencing to guide treatment in a 2010 Genome Biology study that was led by Steve Jones and Marco Marra at the BC Cancer Agency.

A patient presented with a rare adenocarcinoma of the tongue. He received radiation therapy, which appeared to be successful, but a follow-up examination showed that the cancer had metastasized to his lungs. After an EGFR inhibitor failed to slow the tumor growth, the team sequenced both his genome and transcriptome, which suggested he might respond to a RET inhibitor. The patient was put on sunitinib, which stabilized his disease for four months, after which he began a second round of treatment with another RET inhibitor, sorafenib, in combination with the drug sulindac. This regimen led to stabilization of the patient's disease for another three months, after which analysis of a new metastasis showed that the patient had developed new mutations conferring drug resistance.

And the Nobel goes to…

Malachi says that if he were to win the Nobel, he'd want it to be for applying an informatics approach to cancer biology. "The answer to a lot of our problems is in integrative, systematic, formulized computational analysis of data," he says.

Similarly, Obi says that if he were to win a Nobel, it would likely be on the technology side, "identifying a method for differentiating or predicting cancer occurrence," he says. Ultimately though, he says their work is focused on "improving patient outcomes in a real-world setting, and it's hard to picture how that leads to Nobel Prizes."

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