Mitchell J. Machiela, Sc.D., M.P.H.

Stadtman Investigator

Integrative Tumor Epidemiology Branch


9609 Medical Center Dr.
Room SG/7E108
Rockville, MD 20850

+1 240 760 6518

Research Topics

Dr. Mitchell Machiela’s research is focused on understanding the role of inherited variation and acquired mutations in cancer risk. He is leading studies of large-scale genetic mosaicism to investigate the causes of acquired mosaic chromosomal alterations and their impact on cancer risk. He also conducts and analyzes genetic association studies to investigate the underlying genetic architecture of different cancers (e.g., pediatric and adult cancers).

Genetic Mosaicism

Genetic mosaicism results from an acquired 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. Dr. Machiela has published findings that estimate the frequency and distribution of mosaicism in existing genotyped populations of blood and buccal DNA. His research utilizes existing genotype data from DCEG studies and merged international consortia to enable well-powered investigations of mosaicism and cancer risk.

Relatively little is known of the mechanisms that initiate and select for mosaic alterations. Results from his 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 DCEG special exposure and disease populations to examine endogenous and exogenous factors influencing acquisition of detectible mosaicism.

Acquired mosaic alterations have abundant potential to inform cancer etiology and drive oncogenic change. Dr. Machiela has found evidence suggesting mosaicism increases cancer risk for hematologic malignancies and select solid tumor subtypes. His research program continues to examine the influence of mosaicism on cancer risk in special exposure populations and various tissue types.

Genetic Architecture of Cancer

Dr. Machiela and colleagues have published several genome-wide association studies (GWAS) of common adult cancers. He is working to better understand the genomic architecture of cancer by performing genetic association studies in pediatric cancers and combining data on germline and somatic variation to better understand cancer genetic etiology and improve risk prediction.

Pediatric cancers like Ewing sarcoma (ES) provide a unique opportunity to study a homogenous tumor with potentially larger genetic contribution to risk. Dr. Machiela is leading a GWAS on ES to identify susceptibility regions and elucidate the underlying genetic architecture of ES. Findings from this ES GWAS have led to further regional sequencing to investigate germline-somatic interactions with ES fusion oncoproteins. Dr. Machiela also performs pan-cancer GWAS on adult malignancies in the PLCO study and is developing the DCEG GWAS Explorer as a platform to examine, visualize, and share PLCO GWAS summary statistics across several traits.

Dr. Machiela is the creator of a web-based tool, LDlink, which interactively explores linkage disequilibrium across 1000 Genomes population groups. LDlink is tailored for investigators interested in mapping disease susceptibility loci by generating output linking correlated alleles and highlighting putative functional variants. He is also the creator of AuthorArranger, an online tool that helps researchers and consortia create and format title pages for journal submission.


Dr. Machiela received his M.P.H. in epidemiology from the University of Michigan and his Sc.D. in epidemiology from the Harvard T.H. Chan School of Public Health. His doctoral thesis focused on germline genetics and prostate cancer risk. Dr. Machiela joined the Laboratory of Translational Genomics as a postdoctoral fellow in 2012 and transitioned to the Laboratory of Genetic Susceptibility in 2015. In 2016, he was promoted to research fellow. Dr. Machiela was appointed to the position of Earl Stadtman Tenure-Track Investigator in 2017.

Selected Publications

  1. Liu A, Genovese G, Zhao Y, Pirinen M, Zekavat SM, Kentistou KA, Yang Z, Yu K, Vlasschaert C, Liu X, Brown DW, Hudjashov G, Gorman BR, Dennis J, Zhou W, Momozawa Y, Pyarajan S, Tuzov V, Pajuste FD, Aavikko M, Sipilä TP, Ghazal A, Huang WY, Freedman ND, Song L, Gardner EJ, FinnGen, Estonian Biobank Research Team, Breast Cancer Association Consortium, Million Veteran Program, Sankaran VG, Palotie A, Ollila HM, Tukiainen T, Chanock SJ, Mägi R, Natarajan P, Daly MJ, Bick A, McCarroll SA, Terao C, Loh PR, Ganna A, Perry JRB, Machiela MJ. Genetic drivers and cellular selection of female mosaic X chromosome loss. Nature. 2024.
  2. Lee OW, Rodrigues C, Lin SH, Luo W, Jones K, Brown DW, Zhou W, Karlins E, Khan SM, Baulande S, Raynal V, Surdez D, Reynaud S, Rubio RA, Zaidi S, Grossetête S, Ballet S, Lapouble E, Laurence V, Pierron G, Gaspar N, Corradini N, Marec-Bérard P, Rothman N, Dagnall CL, Burdett L, Manning M, Wyatt K, Yeager M, Chari R, Leisenring WM, Kulozik AE, Kriebel J, Meitinger T, Strauch K, Kirchner T, Dirksen U, Mirabello L, Tucker MA, Tirode F, Armstrong GT, Bhatia S, Robison LL, Yasui Y, Romero-Pérez L, Hartmann W, Metzler M, Diver WR, Lori A, Freedman ND, Hoover RN, Morton LM, Chanock SJ, Grünewald TGP, Delattre O, Machiela MJ. Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding. Am J Hum Genet. 2023;110(3):427-441.
  3. Brown DW, Zhou W, Wang Y, Jones K, Luo W, Dagnall C, Teshome K, Klein A, Zhang T, Lin SH, Lee OW, Khan S, Vo JB, Hutchinson A, Liu J, Wang J, Zhu B, Hicks B, Martin AS, Spellman SR, Wang T, Deeg HJ, Gupta V, Lee SJ, Freedman ND, Yeager M, Chanock SJ, Savage SA, Saber W, Gadalla SM, Machiela MJ. Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis. Nat Commun. 2022;13(1):5284.
  4. Zekavat SM, Lin SH, Bick AG, Liu A, Paruchuri K, Wang C, Uddin MM, Ye Y, Yu Z, Liu X, Kamatani Y, Bhattacharya R, Pirruccello JP, Pampana A, Loh PR, Kohli P, McCarroll SA, Kiryluk K, Neale B, Ionita-Laza I, Engels EA, Brown DW, Smoller JW, Green R, Karlson EW, Lebo M, Ellinor PT, Weiss ST, Daly MJ, Biobank Japan Project, FinnGen Consortium, Terao C, Zhao H, Ebert BL, Reilly MP, Ganna A, Machiela MJ, Genovese G, Natarajan P. Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection. Nat Med. 2021;27(6):1012-1024.
  5. Machiela MJ, Grünewald TGP, Surdez D, Reynaud S, Mirabeau O, Karlins E, Rubio RA, Zaidi S, Grossetete-Lalami S, Ballet S, Lapouble E, Laurence V, Michon J, Pierron G, Kovar H, Gaspar N, Kontny U, González-Neira A, Picci P, Alonso J, Patino-Garcia A, Corradini N, Bérard PM, Freedman ND, Rothman N, Dagnall CL, Burdett L, Jones K, Manning M, Wyatt K, Zhou W, Yeager M, Cox DG, Hoover RN, Khan J, Armstrong GT, Leisenring WM, Bhatia S, Robison LL, Kulozik AE, Kriebel J, Meitinger T, Metzler M, Hartmann W, Strauch K, Kirchner T, Dirksen U, Morton LM, Mirabello L, Tucker MA, Tirode F, Chanock SJ, Delattre O. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. Nat Commun. 2018;9(1):3184.

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This page was last updated on Friday, June 14, 2024