To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.

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The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.

Erratum Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouseIn the article by Hingorani et al. (Cancer Cell 4,, there are several typographical errors in the text regarding the citation of the figures. On page 441, the sentence "In many of the older mice, the pancreata contained extensive ductal lesions, and the acinar parenchyma was largely replaced by an intense stromal, or desmoplastic, reaction comprised of inflammatory cells, fibroblasts, and collagen deposition (Figures 2I-2K)" should instead refer to Figures 2I-2L. Also on page 441, the sentence "Finally, we note that PanINs expressed only low levels of PDX-1, which can nevertheless be discerned when compared to the lack of expression in surrounding acini (Figures 2G and 2H) and to normal ducts in control animals (Figure 2I)" should refer instead to Figure 3, and thus should read "Finally, we note that PanINs expressed only low levels of PDX-1, which can nevertheless be discerned when compared to the lack of expression in surrounding acini (Figures 3G and 3H) and to normal ducts in control animals (Figure 3I)."

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