2018 Scholar Xiaoyan Jia, PhD, a postdoctoral fellow in Human Genetics and member of the Kitzman Lab, is lead author of a study testing genetic variants for Lynch syndrome risk.

Xiaoyan (Isaac) Jia, PhD

In his proposal for a 2018 Precision Health Scholars award, Xiaoyan (Isaac) Jia described a case study focused on Lynch syndrome, and a method of testing thousands of genetic variants in parallel, to see which of these variants definitively contributed to Lynch syndrome risk. In January 2021, these findings were published in the American Journal of Human Genetics.

Lynch syndrome is a common familial/hereditary cancer syndrome caused by an inherited mutation in a mismatch repair (MMR) gene. About one in 300 people carries a risk variant for the syndrome, and can have up to an 80% lifetime risk of colorectal or endometrial cancer. Although testing exists for MMR gene mutations, the majority of variants revealed in clinical genetic testing are “variants or uncertain significance,” or VUS, which cannot be definitively ruled in or ruled out as contributing to Lynch syndrome risk.

To address this problem, Jia and the study team—which includes Precision Health member Jacob Kitzman, PhD, Assistant Professor of Human Genetics and Computational Medicine and Bioinformatics—employed a high-throughput genomics approach to test nearly all possible genetic variants of MSH2, the MMR gene most commonly associated with Lynch syndrome.

“Functional studies using cell or animal models…traditionally take years to complete, and can only examine one or a few variants at a time,” says Kitzman. “Our high-throughput approach synthesized and tested nearly every possible genetic variant in the key Lynch Syndrome gene MSH2, equivalent to conducting nearly 17,000 functional studies in parallel.”

By treating cells carrying these MSH2 variants with the compound 6-thioguanine (or 6-TG), the team could determine which variants cause loss of function in the gene, and to what degree; from this, each variant was given a “loss-of-function score.” When compared against bioinformatics algorithms used to predict Lynch syndrome risk, these scores were “substantially more accurate than the algorithms at classifying these known variants,” said Kitzman.

Jia’s Scholar Award made this work possible. “My Precision Health Scholars Award directly funded this research project,” says Jia. “Funding from Precision Health helped us scale the approach into ‘production mode,’ to cover nearly every possible variant in MSH2. The funding also supported my ability to present… at two high-profile research conferences: American Society of Human Genetics and Gordon Research Conference on Human Genetics and Genomics.”

Through this work, Jia hopes to “build a pipeline of methods extensible to other human disease genes.” “The tools we developed for this study,” he says, “can be adapted to study genes involved in other cancers and, more generally, in human genetic disorders.”

In addition, the findings can potentially be implemented into clinical practice to aid in early diagnosis and preventive medical interventions. “We are excited to collaborate with clinicians at U-M and beyond to evaluate how our results can be incorporated to assist variant interpretation in clinical practice,” says Kitzman.