Meet the Girl with Gene NUP214-ABL1

When Myrrah Shapoo arrived at Columbia University Medical Center last year with a form of cancer that wouldn’t respond to chemotherapy, a team of physicians and scientists working on a new precision-medicine initiative faced their ultimate test.

by David J. Craig Published Summer 2016
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The doctors’ only suggestion was that the Shapoos take their daughter to the United States — specifically, to New York–Presbyterian/Columbia University Medical Center — where a group of pediatric oncologists was developing a new, personalized approach to treating cancer by conducting an extremely detailed analysis of each patient’s DNA. “We were told that Myrrah’s disease might somehow be treatable, but that it would require an unusually in-depth investigation to figure out how,” says Rubina, who is a television journalist and documentary filmmaker. “This was our only chance.”

Two days later, on a Friday afternoon, Sajid requested a long-term leave from his job and booked two tickets to New York. He and Myrrah left that weekend. His wife would remain in New Delhi with their newborn son, Hayder, and Myrrah’s twelve-year-old brother, Ruhayl.

“This was the darkest hour for me,” says Sajid. “I’d always been the one in our family refusing to entertain bad thoughts about Myrrah’s prognosis. But now I struggled to keep myself together for my wife and for my little girl.”

New Terrain

In 2014, the pediatric oncology unit at Columbia University Medical Center became one of the first in the world to offer whole-exome sequencing to every child with cancer in its care. Whole-exome sequencing is a method of DNA profiling that reveals the exact sequence of all thirty million nucleotides — adenine, thymine, guanine, and cytosine molecules — that constitute a person’s nineteen thousand genes.

Because using this technology is expensive and time-consuming, and because it generates an overwhelming amount of data, physicians rarely use whole-exome sequencing as a diagnostic tool. Typically, oncologists simply want to know whether the person has any of a handful of genetic mutations whose roles in cancer are well understood. This is accomplished with karyotyping (the method that scientists at Apollo Hospital had used) and with slightly more sensitive computer-based genetic tests that scan a person’s DNA for limited numbers of mutations that have been proven to cause cancer.

Columbia’s pediatric oncologists, however, sought to look more comprehensively across all genes, with the hope of discovering ways they might save children with forms of cancer that were deemed incurable. Working alongside data scientists, cell biologists, molecular pathologists, and other medical researchers, they were determined to embrace whole-exome sequencing in all its complexity.

Oncologists Prakash Satwani and Maria Luisa Sulis

“By looking not only at the genes whose contributions to cancer are already well established for a given condition, but at the countless others that researchers have identified as potentially being involved in other forms of cancer, we knew we could gain an unprecedented level of insight into each child’s disease,” says Andrew Kung, the chief of pediatric hematology, oncology, and stem-cell transplantation at CUMC. “If a child didn’t respond to the standard treatment regimen, we’d have all the information we could possibly want at our fingertips when considering alternative approaches.”

Kung envisioned a network of clinicians and researchers working side by side, seamlessly integrating information the researchers gleaned from whole-exome sequencing into treatment decisions on a daily basis. He dubbed his new program Precision in Pediatric Sequencing (PIPseq).

When Kung launched PIPseq with the support of Lee Goldman, the chief executive of CUMC, and Stephen Emerson, the director of CUMC’s Herbert Irving Comprehensive Cancer Center, he knew it would be a gamble. Assessing the significance of the countless possible mutations scattered across a single person’s nineteen thousand genes was an ambitious task, usually undertaken only as part of a major research project aimed at identifying genes associated with a particular disease. In clinical situations, whole-exome sequencing was used sparingly. Health-insurance companies almost never paid for it, and few studies had even attempted to quantify the potential clinical payoff of analyzing DNA on this scale.

“It was a chicken-or-egg dilemma,” says Kung. “Since no hospital had ever made a serious attempt to show what comprehensive sequencing could achieve in the clinic if used routinely, its benefits were unproven.”

But Kung, who had been recruited to Columbia from Harvard in 2012 in part to advance the use of genomics in pediatric oncology, believed that his division had an opportunity to help shape the future of medicine. It was only a matter of time, he was convinced, before this type of highly sophisticated genetic sequencing became cheap enough, fast enough, and easy enough to use routinely, not only for the diagnosis and treatment of cancer but for a wide variety of conditions. He saw that research on human genetics was already having profound intellectual implications, causing scientists to rethink the definitions of many diseases. It had revealed, for example, how cancers that started in different parts of the body sometimes shared the same physiological roots and were responsive to the same medicines. He anticipated that genetics research would also have disruptive effects on how medical institutions are organized. Gone would be the days when physicians operated more or less independently from laboratory scientists, learning about medical breakthroughs at annual conferences and then going back to their clinics to ponder the findings. He envisioned a hospital in which physicians would be in constant conversation with geneticists, cellular biologists, and molecular pathologists. Kung thought that CUMC, which was making major investments in its genomics research and clinical programs under the umbrella of its recently established Institute for Genomic Medicine, was ideally positioned to figure out how these new types of collaborations should work. His bosses agreed, and in the fall of 2014, Columbia University Medical Center began offering DNA sequencing and analysis to the family of every pediatric cancer patient, on the understanding that CUMC would pick up the estimated $8,000 tab if the family’s insurance company declined to pay.

“I think that many other institutions were waiting for genetic sequencing to become cheaper and easier,” says Kung. “My colleagues and I thought that CUMC should chart the way forward, even if we had to absorb the costs.”

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Outstanding article. Grateful that there are so many individuals dedicated towards finding the various cures for cancer. This research is different and exciting. Talk about thinking out of the box! Thank you!

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