Homing in on cancer’s code

Malak Abedalthagafi first encountered the young patient while she was fighting a losing battle against glioblastoma. She had begun treatment at the age of 5, undergoing surgery and an aggressive course of radiation and chemotherapy, but less than six months later, the cancer had returned. “She had relapsed as if nobody had ever touched the tumour,” says Abedalthagafi, a genomics researcher at KACST.

Although hope was fading for the girl, Abedalthagafi and colleagues believed genome sequencing might reveal a cause of the tumour, and possibly a vulnerability, based on the family’s history of cancer. “The family had lost another child at the age of 8 to an unusual lymphoma,” she says.

Their investigation identified a mutation in a gene that normally repairs genetic damage. This also allowed doctors to match the child with an immunotherapy compatible with that mutation. “She is now 7, and in remission,” says Abedalthagafi.

Such stories are still uncommon, but Abedalthagafi and her colleagues at KACST are spearheading an ambitious effort to make genomic medicine a core component of cancer care in Saudi Arabia. Building on the Saudi Human Genome Program, which launched in 2014, their team is striving to identify genetic factors that contribute to disease risk in the Saudi population, and to accelerate the use of this data in healthcare.

Family first

This programme is now in its second phase, following an initial series of studies focused on relatively simple ‘monogenic’ hereditary diseases. These are developmental disorders in which a clearly defined set of manifestations, such as blindness or neurological defects, can be traced back to a single causative gene mutation.

Cancer is a greater challenge because most tumours carry a myriad of mutations, although in many cases the root cause lies with just one or two ‘driver’ mutations. Some cancers are also hereditary, with powerful genetic risk factors that pass through families. According to Abedalthagafi, the Saudi population has a distinctive cancer profile that suggests the presence of genetic risk factors that might be different from those commonly found in other populations. “For example, thyroid cancer is the second most common cancer in Saudi Arabia in women, whereas in the United States it’s the fifth,” she says. “I also see a lot of women who get breast cancer in their 30s and 40s.”

The KACST team initially focused on identifying heritable risk factors in families with an established history of malignancy. They set out to recruit a cohort of 1,000 these patients, and performed a variety of targeted genomic analyses in order to identify mutated genes that might be causative. Of the patients analyzed to date, 20–40 percent have been found to carry a gene alteration that is likely to contribute to familial tumour formation or progression. The data have also yielded some surprises. “I had a family of nine members, all of whom carried a mutation reported to be common in a particular ethnic subgroup. However, this family has no such ancestry,” says Abedalthagafi, “Three or four of them developed colon cancer in their 30s.”

Through these findings, clinicians can get a handle on the nature of a patient’s particular tumour. They could also inform currently healthy individuals of future risk, or offer insights in the context of family planning.

Based on an identified subset of around 7,000 known Saudi mutations, Abedalthagafi explains, KACST has developed a chip to look for them. The test allows couples to plan a family based on the insights. “We want to do a similar thing with cancer,” she adds.

A larger landscape

The KACST team has since scaled up their efforts. They are expanding their focus to non-inherited cancers, which are associated with ‘somatic’ mutations that arise as people age, or as a result of environmental factors. “At this stage, we think 25-30 percent of all of the newly diagnosed cancer cases in Saudi Arabia are attributable to familial causes,” says Abedalthagafi. This means that up to 75 percent of tumours arise spontaneously from mutations scattered throughout the genome.

Accordingly, Abedalthagafi and colleagues are now casting a wider net. The first phase of the programme focused on panels of known genes, or analyses of the exome — the subset of genomic regions that are transcribed and translated to produce proteins. For phase two, her team is exploring the whole genome, combing through datasets up to 100 times larger than those from exome sequencing. “We will be using this to look at the larger genomic landscape for common cancers in Saudis, starting with liver, thyroid and breast cancer,” she says.

In testing for inherited disorders, a simple blood sample will suffice, but cancer genome sequencing requires samples of both tumour tissue and adjacent healthy tissue for comparison. For this reason, KACST is now partnering with clinical centres across Saudi Arabia, as well as experts in computational analysis of biological ‘big data’ at the King Abdullah University of Science and Technology (KAUST). Abedalthagafi’s team is also pursuing international collaborations with experts at Harvard Medical School specializing in tumours, as well as organizations like deCODE Genetics in Iceland. “They [deCODE Genetics] have experience in working with ethnically homogeneous populations like ours,” she says.

Abedalthagafi is optimistic that the next phase of cancer genomics research at KACST will offer more opportunities for translation to improved care. As shown by the case of the young glioblastoma patient, certain mutations can be informative in terms of helping clinicians select treatment, and many drug companies are now seeking possible genomic signatures of efficacy during the clinical trial process. “We want to take this a step further, and work with big pharma companies to see how we can develop the next generation of therapies for specific diseases in Saudi or Arab populations,” she says.

Next-generation medicine

Abedalthagafi acknowledges that these are still early days. “This will not be a very easy task, but the rewards promise to be immense,” she says.

For one, the distinct genetic profile of the Saudi population could uncover biological insights that would not be accessible in other cohorts. Abedalthagafi cites the example of an ongoing study into a form of liver cancer that is relatively rare outside the peninsula. “It’s an unusual liver cancer that happens to be common among Saudis, and they don’t even have a predisposition – none of the normal risk factors, like hepatitis,” she says.

KACST’s efforts may also offer a powerful lure for international pharmaceutical players, and precision medicine was one of the major themes at the Future Investment Initiative meeting held in Riyadh in October 2018.

But above all, there is the long-term goal of building capacity to make sequencing a routine part of the diagnostic process, and a means for measurably improving the quality of healthcare. “It’s very exciting when you can save a person by this kind of approach,” says Abedalthagafi. “Publication and discovery are nice, but we really want to translate this to help our people.”

1. Abedalthagafi, M. et al. Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency. The Oncologist 23, 1401-1406 (2018). | article
2. Abedalthagafi, M. Precision medicine of monogenic disorders: Lessons learned from the Saudi human genome. Frontiers in Bioscience, Landmark, 24, 870-889, March 1, (2019) | article