Abdul K. Siraj, Tariq Masoodi, Rong Bu, Shaham Beg, Saif S

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Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis Abdul K. Siraj, Tariq Masoodi, Rong Bu, Shaham Beg, Saif S. Al-Sobhi, Fouad Al-Dayel, Mohammed Al-Dawish, Fowzan S. Alkuraya, Khawla S. Al-Kuraya The American Journal of Human Genetics Volume 98, Issue 6, Pages 1170-1180 (June 2016) DOI: 10.1016/j.ajhg.2016.04.014 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 Correlation of Somatic Mutation Density with Clinical Parameters (A) Somatic mutation density (in MB) in the 101 PTC exome cohort. The maximum mutation density is 1.2 MB, and the median is 0.21 nonsynonymous somatic mutations per MB. Synonymous mutation density is compared with non-synonymous mutation density. (B) Correlation of non-synonymous mutation density with MACIS score for mortality risk, which is significant (p = 0.001). (C) Correlation of non-synonymous mutation density with risk of recurrence (p = 0.38). (D) Correlation of non-synonymous mutations with individual’s age (p = 0.008). One outlier case was excluded for figure presentation in (B), (C) and (D). P values were estimated by Student’s t test. The American Journal of Human Genetics 2016 98, 1170-1180DOI: (10.1016/j.ajhg.2016.04.014) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Frequency and Types of Mutation in 24 Genes Detected by Exome Sequencing Different types of mutations are colored differently. The majority of mutations are missense (blue); there are two stop-gains (red), three in-frame deletions (yellow color), and one frame-shift mutation (brown). The genes with a frequency of 1% share two somatic mutations except that CRTAM shows two single nucleotide changes within the same codon. The American Journal of Human Genetics 2016 98, 1170-1180DOI: (10.1016/j.ajhg.2016.04.014) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 Survival Analysis of Individuals Cohort Kaplan Meier survival plot showing statistically significant poor survival of (A) TG-mutated cases compared to TG wild-type cases in the overall cohort (p = 0.0005) and (B) significant poor survival of TG-mutated cases in the MAPK-positive cohort as compared to MAPK-positive individuals without TG mutation (p < 0.0001). The American Journal of Human Genetics 2016 98, 1170-1180DOI: (10.1016/j.ajhg.2016.04.014) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 4 Increasing Proportion of TG-Mutated Cases in a Different PTC Cohort (A) TG mutation in overall PTC cohort (3%). (B) TG mutation in an independent metastatic PTC cohort (12.7%). (C) TG mutation in available metastatic tissues (36.4%). The American Journal of Human Genetics 2016 98, 1170-1180DOI: (10.1016/j.ajhg.2016.04.014) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 5 TG Mutations Identified in Metastatic Tissue Samples Sequencing traces of four TG mutations identified in metastatic tissue samples. Three mutations, c.2530G>A (B), c.4604A>G (C), and c.454C>T (D), were not detected in corresponding PTC primary tumor tissue by Sanger sequencing. Lower panels show sequencing traces of mutations identified in metastatic tissue samples, and top panels show sequencing traces for corresponding normal examples. The American Journal of Human Genetics 2016 98, 1170-1180DOI: (10.1016/j.ajhg.2016.04.014) Copyright © 2016 American Society of Human Genetics Terms and Conditions