Posted on June 27, 2017
Mitchell Machiela, Sc.D., M.P.H., a newly-appointed Earl Stadtman tenure-track investigator in the Laboratory of Genetic Susceptibility (LGS), studies the role of germline variation and somatic mosaicism in cancer risk. He joined the Laboratory of Translational Genomics (LTG) as a postdoctoral fellow in 2012, transitioned to LGS in 2015, and was promoted to research fellow in 2016.
Dr. Machiela is leading studies of large-scale genetic mosaicism to investigate the causes of acquired mosaic alterations and their impact on cancer risk. Genetic mosaicism results from a DNA mutation that is present in some of the body's cells but not in others. A person with mosaicism has a mixture of normal and mutated cells.
“Mosaicism is a somatic event, meaning a mutation occurs sometime in life after fertilization. It is not an inherited genetic variant,” Dr. Machiela said. “We define mosaicism quite broadly; it can be limited to a one base pair change in your genome different from what you inherited. Or, it can be as large as an entire chromosome that is lost or duplicated.” Read more about DCEG research on genetic mosaicism.
Dr. Machiela and collaborators have published a number of studies estimating the frequency and distribution of mosaicism in existing genotyped collections of blood and buccal DNA. Now, he is utilizing an unparalleled set of genotype data – 200,000 DCEG samples, 500,000 genotyped samples from the UK Biobank, and a merged international mosaicism consortium of over 1 million samples – to expand the size and scope of his research on mosaicism and cancer risk.
In addition, Dr. Machiela is developing improved approaches for detecting genetic mosaicism. “Previous studies have focused on detecting mosaic events larger than 2 megabases in size and affecting cellular proportions of 10% or greater,” he said. “This is a conservative threshold to ensure detected events have a high true positive rate. We are now exploring ways to use haplotype data to improve the array-based detection of events affecting a smaller proportion of cells.”
Relatively little is known of the mechanisms that initiate and select for mosaic alterations. Results from previous work suggests inherited germline variation (e.g. at TCL1A) or environmental exposures (e.g. smoking) may predispose to mosaicism. Dr. Machiela is utilizing genotyped samples from the UK Biobank and other datasets to examine endogenous and exogenous factors influencing acquisition of detectible mosaicism.
In recent studies, Dr. Machiela and colleagues found evidence to suggest that mosaicism increases cancer risk for hematologic malignancies and select solid tumor subtypes. He is expanding this work to examine the influence of mosaicism on cancer risk in various populations and tissue types.
Dr. Machiela also conducts and analyzes genetic association studies to better understand the genetic architecture of different cancers (e.g. pediatric and common adult cancers). He is expanding association studies to incorporate whole-exome/genome sequencing data, and combining data on germline and somatic variation to better understand cancer genetic etiology and improve risk prediction.
Specifically, he is leading a genome-wide association study on Ewing sarcoma (ES) to identify susceptibility regions and elucidate the underlying genetic architecture of ES. “Pediatric cancers like ES provide a unique opportunity to study a homogenous tumor with potentially larger genetic contribution to risk,” Dr. Machiela said.
Dr. Machiela is also the creator of a web-based tool, LDlink, which interactively explores linkage disequilibrium across population groups from the 1000 Genomes Project. LDlink is tailored for investigators interested in mapping disease susceptibility loci by generating output linking correlated alleles and highlighting putative functional variants.
Named after Earl Stadtman, a noted biochemist at the National Heart, Lung, and Blood Institute, the Stadtman program is a trans-NIH recruitment initiative designed to attract the most talented early-career scientists to NIH.