Dara S. Ross, Ahmet Zehir, Donavan T

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Next-Generation Assessment of Human Epidermal Growth Factor Receptor 2 (ERBB2) Amplification Status Dara S. Ross, Ahmet Zehir, Donavan T. Cheng, Ryma Benayed, Khedoudja Nafa, Jaclyn F. Hechtman, Yelena Y. Janjigian, Britta Weigelt, Pedram Razavi, David M. Hyman, José Baselga, Michael F. Berger, Marc Ladanyi, Maria E. Arcila The Journal of Molecular Diagnostics Volume 19, Issue 2, Pages 244-254 (March 2017) DOI: 10.1016/j.jmoldx.2016.09.010 Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 1 A: Square-root–transformed coverage value of each probe against the GC content of the probe shows the reduced coverage at high end of GC content (left panel). Loess normalization removes the dependency of coverage across different GC profiles (right panel). B: Example of a normalized log2 transformed fold change of coverage (log-ratio) values across all the captured regions in MSK-IMPACT assay. Circular binary segmentation algorithm is used to segment the data into discreet data points. Red lines indicate segmented regions determined by circular binary segmentation algorithm. C: Ordered log-ratio values are clustered on the basis of distance, and the cluster closest to 0 is selected as the null distribution (left panel). All other clusters are then tested against a model parameterized by the null distribution. Curves represent the distribution of each fit of different clusters (right panel). The Journal of Molecular Diagnostics 2017 19, 244-254DOI: (10.1016/j.jmoldx.2016.09.010) Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 2 A: The range of fold change values for breast and gastroesophageal cases, separated according to the HER2 IHC result (score, 0 or 1, 1 to 2, 2, 2 to 3, and 3) and HER2 FISH result. The solid vertical line and dashed vertical line represent a fold change of 1.5 and 2.0, respectively. B: Receiver operating characteristics curve for different threshold values. For lower values of threshold, pipeline calls everything as amplified (AMP), which are all false positives (x axis); for higher values of cutoff threshold, our ability to call real events as amplified decreases. Threshold of 1.5 is the best in terms of sensitivity and specificity. EQUIV, equivalent; NA, not applicable. The Journal of Molecular Diagnostics 2017 19, 244-254DOI: (10.1016/j.jmoldx.2016.09.010) Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 3 Representative ERBB2 amplified case. A: Each dot represents a probe set, and the values on the y axis show the normalized log2 transformed fold change of coverage of tumor versus normal. ERBB2 fold change (FC) of 2.95. Additional amplification calls (cytoband, FC): PRDM1 (6q21, 3.0), ROS1 (6q22.1, 3.0), MYC (8q24.21, 2.8), CCND1 (11q13.3, 2.5), FGF19/4/3 cluster (11q13.3, 2.5), PAK1 (11q13.5, 2.5), and SPOP (17q21.33, 2.5). B: Hematoxylin and eosin–stained section of invasive carcinoma. C: HER2 immunohistochemical-stained slide showing strong and complete membranous staining in the invasive tumor cells (score, 3). D: HER2 FISH (red signal, HER2; green signal, CEP17). HER2/CEP17 ratio, 5.2; average HER2 CN, 9.9. Original magnification, ×200 (B and C). The Journal of Molecular Diagnostics 2017 19, 244-254DOI: (10.1016/j.jmoldx.2016.09.010) Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions

Figure 4 Concurrent somatic alterations in validation data set. The oncoprint displays the most common somatic alterations in the data set. Each column is a sample, and each row is a gene. Alterations are represented with various colors. GE, gastroesophageal; SCNA, somatic copy number alteration. The Journal of Molecular Diagnostics 2017 19, 244-254DOI: (10.1016/j.jmoldx.2016.09.010) Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology Terms and Conditions