Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters-fluke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3' untranslated region deletion as a mechanism of FGFR2 upregulation. Integration of noncoding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores-mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.Significance: Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes. Cancer Discov; 7(10); 1116-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1047.

Self-Assembled Resonance Energy Transfer Keys for Secure Communication over Classical Channels.

Modern authentication and communication protocols increasingly use physical keys in lieu of conventional software-based keys for security. This shift is primarily driven by the ability to derive a unique, unforgeable signature from a physical key. The sole demonstration of an unforgeable key, thus far, has been through quantum key distribution, which suffers from limited communication distances and expensive infrastructure requirements. Here, we show a method for creating unclonable keys by molecular self-assembly of resonance energy transfer (RET) devices. It is infeasible to clone the RET-key due to the inability to characterize the key using current technology, the large number of input-output combinations per key, and the variation of the key's response with time. However, the manufacturer can produce multiple identical devices, which enables inexpensive, secure authentication and communication over classical channels, and thus any distance. Through a detailed experimental survey of the nanoscale keys, we demonstrate that legitimate users are successfully authenticated 99.48% of the time and the false-positives are only 0.39%, over two attempts. We estimate that a legitimate user would have a computational advantage of more than 10(340) years over an attacker. Our method enables the discovery of physical key based multiparty authentication and communication schemes that are both practical and possess unprecedented security.