Whole-Genome Sequencing Analysis Identifies a Distinctive Mutational Spectrum in an Arsenic-Related Lung Tumor Victor D. Martinez, PhD, Kelsie L. Thu,

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Whole-Genome Sequencing Analysis Identifies a Distinctive Mutational Spectrum in an Arsenic-Related Lung Tumor Victor D. Martinez, PhD, Kelsie L. Thu, BSc, Emily A. Vucic, BSc, Roland Hubaux, PhD, Marta Adonis, PhD, Lionel Gil, PhD, Calum MacAulay, PhD, Stephen Lam, MD, Wan L. Lam, PhD Journal of Thoracic Oncology Volume 8, Issue 11, Pages 1451-1455 (November 2013) DOI: 10.1097/JTO.0b013e3182a4dd8e Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Lung squamous-cell carcinoma from an arsenic-exposed patient. A, Hemotoxylin and eosin stained section is shown at ×200 magnification. B, Total number of mutations (in blue) and those affecting CDSs (in red) are shown. In both cases, the highest number of mutations were C>T/G>A transitions. In CDS regions C>T/G>A and G>C/C>G exhibit almost equal numbers of mutations. CDS, coding DNA sequence. Journal of Thoracic Oncology 2013 8, 1451-1455DOI: (10.1097/JTO.0b013e3182a4dd8e) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 As-LUSC displays a low CDS mutational load: Box-and-whisker plots (min/25th percentile/median/75th percentiles/max) comparing somatic nonsynonymous mutations affecting CDS in the As-LUSC (49 mutations, red line) with 171 LUSC tumors from: lifelong NSs, FSs, and CSs. NS, never smoker; FS, former smoker; CS, current smoker; LUSC, lung squamous-cell carcinoma; As-LUSC, arsenic-related LUSC; CDS, coding DNA sequence; TCGA, The Cancer Genome Atlas. Journal of Thoracic Oncology 2013 8, 1451-1455DOI: (10.1097/JTO.0b013e3182a4dd8e) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 As-LUSC displays a distinct mutational profile compared with other LUSC. A, Mutational spectrum of the As-LUSC compared with 171 LUSC tumors from TCGA, ordered by smoking status. Each vertical column represents a tumor. B, Comparison of the two most distinct mutation types observed in As-LUSC tumor (labeled in red on the x axis) with the 171 LUSC. Only 86 of the 171 TCGA LUSCs were labeled on the figure because of space constraints. C, Fraction of T>G/A>C and C>A/G>T transversions between As-LUSC and other LUSC. Black horizontal lines in groups represent median and minimum and maximum values. NS, never smoker; FS, former smoker; CS, current smoker; LUSC, lung squamous-cell carcinoma; As-LUSC, arsenic-related LUSC; TCGA, The Cancer Genome Atlas. Journal of Thoracic Oncology 2013 8, 1451-1455DOI: (10.1097/JTO.0b013e3182a4dd8e) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 As-LUSC exhibits a different mutational profile compared with squamous lung tumors from never smokers. A, Comparison of T>G/A>C and C>A/G>T transversions between As-LUSC and seven LUSC from never smokers. B, Comparison of T>G/A>C and C>A/G>T transversions in As-LUSC and seven LUSC from never smokers (compared as individual groups). Black horizontal lines in groups represent median and min/max values. LUSC, lung squamous-cell carcinoma; As-LUSC, arsenic-related LUSC; TCGA, The Cancer Genome Atlas; NS, never smoker. Journal of Thoracic Oncology 2013 8, 1451-1455DOI: (10.1097/JTO.0b013e3182a4dd8e) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions