CDKN2A/p16 Inactivation Mechanisms and Their Relationship to Smoke Exposure and Molecular Features in Non–Small-Cell Lung Cancer Kit W. Tam, MD, MHS,

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CDKN2A/p16 Inactivation Mechanisms and Their Relationship to Smoke Exposure and Molecular Features in Non–Small-Cell Lung Cancer Kit W. Tam, MD, MHS, Wei Zhang, PhD, Junichi Soh, MD, PhD, Victor Stastny, BS, Min Chen, PhD, Han Sun, MS, Kelsie Thu, BSc, Jonathan J. Rios, PhD, Chenchen Yang, PhD, Crystal N. Marconett, PhD, Suhaida. A. Selamat, PhD, Ite A. Laird-Offringa, PhD, Ayumu Taguchi, MD, PhD, Samir Hanash, MD, PhD, David Shames, PhD, Xiaotu Ma, PhD, Michael Q. Zhang, PhD, Wan L. Lam, PhD, Adi Gazdar, MD Journal of Thoracic Oncology Volume 8, Issue 11, Pages 1378-1388 (November 2013) DOI: 10.1097/JTO.0b013e3182a46c0c Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 HDs of p16 in lung adenocarcinoma tumors and cell lines. Affymetrix SNP six arrays were used to generate copy number profiles for lung adenocarcinoma cell lines and clinical lung tumors. Allele-specific copy numbers were derived using the allele-specific copy number workflow in PGS software. Copy number profiles for lung cancer cell lines were generated using a panel of 72 nondiseased HapMap individuals as a baseline whereas matched nonmalignant lung tissue was used as a reference for defining copy number changes in tumors. Arrows indicate region of the p16 gene. A, Focal HD of p16 in the lung adenocarcinoma cell line, NCI-H1944. B, Lung adenocarcinoma tumor illustrating neutral p16 copy number state. C, Focal HD of p16 in a lung adenocarcinoma tumor. Both HDs in (A) and (C) occur in a background of single copy loss on chromosome 9p. Copy number states in regions of deletion do not drop right to zero because of to cancer cell heterogeneity, aneuploidy, and/or the presence of nonmalignant cells that contribute to array signals. Maximum (red) and minimum (blue) alleles are defined by copy number state. Each dot represents the smoothed copy number for 30 adjacent array probes. Copy number states (HD, single copy loss, or copy neutral) are indicated. Images were generated in PGS. Arrows indicate location of p16 gene at chromosome 9p21.3. HD, homozygous deletion; PGS, Partek Genomics Suite. Journal of Thoracic Oncology 2013 8, 1378-1388DOI: (10.1097/JTO.0b013e3182a46c0c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Methylation of p16 promoter in lung cancers and cell lines. A, Schematic diagram of CDKN2A (p14ARF-p16INK4a) genomic locus. Colored boxes represent exons of p16INK4a or p14ARF. The coding regions are shown as green, whereas the noncoding regions shown as yellow. The locations of the CDKN2A MSP probe and corresponding Illumina Methylation 450K BeadChip probes are indicated. B, The methylation status of p16 in the NSCLC cell lines by Illumina Methylation 450K BeadChip probes. The methylation β values from cell lines carrying a HD of the CDKN2A locus, DNA methylation of the CpG island in exon 1a (p16INK4a) (Meth), a point mutation in p16INK4a (Mut), or no detectable alteration of the locus (WT) are plotted. A value of 0 indicates nonmethylation of the locus; a value of 1 means complete methylation. C, The methylation status of p16 in lung cancers from TCGA data portal by Illumina Methylation 450K BeadChip probes. The methylation β values from LUSC or LUAD and nonmalignant lung tissues are plotted. Methlyation was defined as tumor samples with β scores of 0.3 or higher than the mean values for nonmalignant tissues. MSP, methylation-specific polymerase chain reaction; NSCLC, non–small-cell lung carcinoma; TCGA, The Cancer Genome Atlas; LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma; HD, homozygous deletion; WT, wild-type. Journal of Thoracic Oncology 2013 8, 1378-1388DOI: (10.1097/JTO.0b013e3182a46c0c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Expression analysis of the CDKN2A locus in NSCLC cell lines. A, Heatmap shows RNA and protein expression levels in cell lines carrying no detectable alteration of the CDKN2A locus (WT), DNA methylation of the CpG island in exon 1a (p16INK4a) (Meth), a point mutation in p16INK4a (Mut), or an HD of the locus. RNA expression was determined by qPCR. The relative mRNA levels of p16 were compared with that of nonmalignant immortalized HBECs. Protein expression was determined by mass spectrometry. *Indicates Rb mutants. B, RNA-Seq data for the CDKN2A locus for representative cell lines. The different splice variants arising from the locus are indicated. Genome-wide coverage was similar for all four lines. Peaks detected are shown to scale. No signal was detected in the HD line (NCI-H2228), p14ARF mRNA, but not p16INK4a was detected in the Mut (NCI-H1975) or Meth (NCI-H23) lines; mRNA containing exon 1a (p16INK4a) was only detected in WT line (NCI-H522). HD, homozygous deletion; NSCLC, non–small-cell lung carcinoma; HD, homozygous deletion; HBECs, bronchial epithelial cells; WT, wild-type; qPCR, quantitative polymerase chain reaction. Journal of Thoracic Oncology 2013 8, 1378-1388DOI: (10.1097/JTO.0b013e3182a46c0c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 The association between p16 inactivation and EGFR, KRAS, STK11 mutations, and smoke exposure. The frequency of p16 WT, HD, methylation, and point mutation cases in each mutation type or smoking exposure group are presented in the bar graphs for cell lines, tumors, or combined. *Indicates statistically significant value. (for cell lines, p = 0.025; for tumors, p = 0.025; for combined, p = 0.003). HD, homozygous deletion; WT, wild-type. Journal of Thoracic Oncology 2013 8, 1378-1388DOI: (10.1097/JTO.0b013e3182a46c0c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Other genetic alterations in p16-RB pathway in NSCLC cell lines. The percentages of cell lines containing RB mutations, CCND1, CDK4, and CDK6 copy number gains are plotted. Copy numbers >3 are considered as copy number gains. NSCLC, non–small-cell lung carcinoma. Journal of Thoracic Oncology 2013 8, 1378-1388DOI: (10.1097/JTO.0b013e3182a46c0c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 6 Meta-analysis of smoke exposure and p16 promoter methylation. A random-effects model was applied because of the heterogeneity of the studies selected. The square and the connecting lines indicate the OR and its CIs. The area of each square is proportional to the sample size of the study in the meta-analysis. The overall OR was 1.99 (p < 0.05) with 95% CI between 1.48 and 2.72. OR, odds ratio; CIs, confidence intervals. Journal of Thoracic Oncology 2013 8, 1378-1388DOI: (10.1097/JTO.0b013e3182a46c0c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 7 Meta-analysis of smoke exposure and p16 homozygous deletion. A fixed-effects model was used. The square and the connecting lines indicate the OR and its CIs. The area of each square is proportional to the sample size of the study in the meta-analysis. The overall OR was 0.61 (p = 0.1068) with 95% CI between 0.338 and 1.11. OR, odds ratio; CIs, confidence intervals. Journal of Thoracic Oncology 2013 8, 1378-1388DOI: (10.1097/JTO.0b013e3182a46c0c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions