Total-Genome Analysis of BRCA1/2-Related Invasive Carcinomas of the Breast Identifies Tumor Stroma as Potential Landscaper for Neoplastic Initiation

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Total-Genome Analysis of BRCA1/2-Related Invasive Carcinomas of the Breast Identifies Tumor Stroma as Potential Landscaper for Neoplastic Initiation Frank Weber, Lei Shen, Koichi Fukino, Attila Patocs, George L. Mutter, Trinidad Caldes, Charis Eng The American Journal of Human Genetics Volume 78, Issue 6, Pages 961-972 (June 2006) DOI: 10.1086/504090 Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of a family with HBOC segregating BRCA variants. The pedigree is shown across 4 generations, with affected members (with breast cancer) indicated by blackened circles. The proband (arrow) was diagnosed with breast cancer at age 49 years, and testing showed her as wild type for both BRCA genes. Other affected family members (stars) tested positive for the BRCA1 Ser1040Asn and BRCA2 Ser2483Gly variants. The American Journal of Human Genetics 2006 78, 961-972DOI: (10.1086/504090) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 2 Frequency of LOH/AI observed in the epithelium and stroma in HBOC-related breast cancer compared with sporadic breast cancers. Frequency of LOH/AI (Y-axes) is plotted on a markerwise level (X-axes). The average LOH/AI frequency of markers in the epithelium (top panel) and stroma (bottom panel) are shown for 51 cases of HBOC-related breast cancer (blue dots) and 134 cases of sporadic breast cancer (red dots). The bold horizontal lines indicate LOH/AI frequencies averaged over all markers. The American Journal of Human Genetics 2006 78, 961-972DOI: (10.1086/504090) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 3 Unsupervised hierarchical cluster analysis. Average linkage and the dissimilarity measure of proportion of discordant LOH/AI between samples are used. The analysis was based on the presence or absence of LOH at 371 informative loci for 51 HBOC-related breast carcinoma epithelial samples and the matching 51 stromal samples (for a total of 102 end branches). The numbers at each end branch indicate germline deleterious mutations in BRCA1 (1) or BRCA2 (2) or unclassified variants of these genes (uv1 and uv2, respectively). The stars indicate those samples for which the stroma and epithelium of one case cluster directly together. Note the clustering of BRCA1 samples near the left (black bar; see text for details). wt = Wild type. The American Journal of Human Genetics 2006 78, 961-972DOI: (10.1086/504090) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 4 Two-dimensional scaling of 51 HBOC-related breast cancer cases. Each case is represented by combining the stroma and malignant epithelium from the same patient. Samples were obtained from individuals with germline mutations in BRCA1 (black dots) or BRCA2 (red dots), with variants in BRCA1 (BRCA1uv [green dots]) or BRCA2 (BRCA2uv [blue dots]), or without mutations or variants in either gene (yellow dots). Note the clustering of samples with BRCA1 mutations to the left of the diagonal line. The American Journal of Human Genetics 2006 78, 961-972DOI: (10.1086/504090) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 5 Multidimensional scaling of LOH/AI patterns from 35 patients with deleterious BRCA1/2 mutations. The LOH/AI patterns from epithelium (EP; left panel) and stroma (ST; right panel) of individuals with germline mutations in BRCA1 (black dots) and BRCA2 (red dots) were analyzed separately in the context of the pattern of LOH/AI observed in sporadic breast cancers (green dots). Note that the stromal LOH/AI pattern differentiates BRCA1 and BRCA2 mutation-positive breast cancers from sporadic breast cancers. The American Journal of Human Genetics 2006 78, 961-972DOI: (10.1086/504090) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 6 Unsupervised cluster analysis by LOH/AI status in a combined stromal and epithelial data set for HBOC-related breast cancers and sporadic breast cancers. HBOC breast cancers are labeled at the end branches with “DM” (deleterious mutation) and “non-DM” (comprising those with variants of unknown significance and those without detectable mutations). The bar below the cluster plot visualizes the separation of HBOC breast cancers (black and gray bars) from sporadic breast cancers (white bars). The American Journal of Human Genetics 2006 78, 961-972DOI: (10.1086/504090) Copyright © 2006 The American Society of Human Genetics Terms and Conditions