Highly heterogeneous genomic landscape of uterine leiomyomas by whole exome sequencing and genome-wide arrays Svetlana A. Yatsenko, M.D., Priya Mittal,

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Highly heterogeneous genomic landscape of uterine leiomyomas by whole exome sequencing and genome-wide arrays Svetlana A. Yatsenko, M.D., Priya Mittal, Ph.D., Michelle A. Wood-Trageser, Ph.D., Mirka W. Jones, M.D., Urvashi Surti, Ph.D., Robert P. Edwards, M.D., Anil K. Sood, M.D., Aleksandar Rajkovic, M.D., Ph.D. Fertility and Sterility Volume 107, Issue 2, Pages 457-466.e9 (February 2017) DOI: 10.1016/j.fertnstert.2016.10.035 Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Whole genome array CGH (aCGH) in UL samples L56 and L58. (A) Whole genome profile in L58. Black scatter plot shows the average log2 ratio for the aCGH probes that are arranged from the short to the long arm of each chromosome. Chromosomes are listed at the bottom. Copy number losses involving chromosomes 1p, 2p, 6, 8p, 13q, 17p, and 22q (red shaded areas) encompass multiple subunits of the Mediator complex. Components of Mediator corresponding to the head, middle, tail, or the dissociable CDK8 kinase module (CKM) are depicted by pink, blue, yellow, and gray color, respectively. (B) Whole genome profile demonstrates gross chromosomal alterations (black arrows) in L56 with normal karyotype. Fertility and Sterility 2017 107, 457-466.e9DOI: (10.1016/j.fertnstert.2016.10.035) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Figure 2 Landscape of genomic aberrations detected by karyotype, microarray, and WES analyses in 31 cases negative for MED12 exon 2 mutations. Genes coding for subunits of the Mediator complex (in red) and other genes (FH and HMGA2 in blue), implicated in UL pathogenesis, are shown through the human genome. Red lines to the right of the idiograms indicate loss of chromosomal material, and black lines indicate gain of chromosomal material. Black triangles represent translocation breakpoints in tumor samples. Stars indicate gene mutations. Fertility and Sterility 2017 107, 457-466.e9DOI: (10.1016/j.fertnstert.2016.10.035) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Figure 3 Genomic alterations in MED12-positive ULs revealed by karyotype in 31 cases. Red star at Xq13.1 indicates MED12 mutation. Fertility and Sterility 2017 107, 457-466.e9DOI: (10.1016/j.fertnstert.2016.10.035) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 1 ULMs. (A) Histology of a human ULM. (B) Mutation analysis of MED12 exon 2. Chromatogram peaks displaying the MED12 exon 2 c.131G>C single nucleotide variant in an LM. Fertility and Sterility 2017 107, 457-466.e9DOI: (10.1016/j.fertnstert.2016.10.035) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 2 Pie chart showing the distribution of somatic clinically relevant genomic alterations identified to date in human ULs. Gross numerical and structural chromosomal abnormalities are detected by karyotype in ∼50%–60% of the samples. In our study, up to ∼65% of karyotypically normal samples were found to have large or submicroscopic genomic alterations detected by microarray. Fertility and Sterility 2017 107, 457-466.e9DOI: (10.1016/j.fertnstert.2016.10.035) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions