The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor-mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.

Cholangiocarcinoma is an intractable cancer, with limited therapeutic options, in which the molecular mechanisms underlying tumor development remain poorly understood. Identification of a novel driver oncogene and applying it to targeted therapies for molecularly defined cancers might lead to improvements in the outcome of patients. We performed massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients without KRAS/BRAF/ROS1 alterations and identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In reverse-transcriptase polymerase chain reaction (RT-PCR) screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%), rarely in colorectal (1/149) and hepatocellular carcinoma (1/96), and none in gastric cancer (0/212). The rearrangements were mutually exclusive with KRAS/BRAF mutations. Expression of the fusion kinases in NIH3T3 cells activated MAPK and conferred anchorage-independent growth and in vivo tumorigenesis of subcutaneous transplanted cells in immune-compromised mice. This transforming ability was attributable to its kinase activity. Treatment with the fibroblast growth factor receptor (FGFR) kinase inhibitors BGJ398 and PD173074 effectively suppressed transformation. Conclusion: FGFR2 fusions occur in 13.6% of intrahepatic cholangiocarcinoma. The expression pattern of these fusions in association with sensitivity to FGFR inhibitors warrant a new molecular classification of cholangiocarcinoma and suggest a new therapeutic approach to the disease. (HEPATOLOGY 2014;59:1427-1434 C holangiocarcinoma (CC) is a highly malignant invasive carcinoma that arises through malignant transformation of cholangiocytes.1 It is an intractable tumor with poor prognosis, whose incidence and mortality rates are high in East Asia and have been rapidly increasing worldwide.1,2 CC can be subdivided into intrahepatic (ICC) and extrahepatic (ECC) types, which show distinct etiological and clinical features.2 ICC is the second most common primary hepatic malignancy after hepatocellular carcinoma, and is associated with hepatitis virus infection. Somatic mutations of KRAS and BRAF are the most common genetic alterations in CC.3,4 Surgical resection is the only curative treatment for CC, and no standard chemotherapy regimens have been established for inoperative cases or those showing recurrence after surgical resection. 5,6

SUMMARY Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted-sequencing to validate significantly mutated genes in additional 112 cancers. The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype. We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes (TP53, KRAS, APC and others). Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion.

This study was conducted in healthy Japanese subjects to examine the effects of age and gender on the relationship between the risk factors for cardiovascular disease (CVD) and augmentation index (AI), and the effects of clusters of those risk factors on AI. Radial arterial pressure wave analysis was used to obtain AI in 3675 men and 2919 women. AI was found to be higher in women than in men, and age-related increase in AI showed an attenuated curve in subjects aged X50 years. A step-wise multivariate linear regression analysis showed that mean blood pressure and smoking are independent significant variables related to AI in men regardless of age, and in women aged o50 years, but not in women aged X50 years. A general linear model univariate linear regression analysis showed that mean blood pressure and smoking had a significant interaction for their relation with AI in men, but not in women. In conclusion, among the risk factors for CVD, smoking and blood pressure were found to be independent factors related to increase in AI. Although age-related attenuation of increase in AI was confirmed in Japanese subjects, these risk factors may act to increase AI even in elderly subjects, at least in part. However, the effects of these factors on AI may differ based on gender, and these factors may act synergistically to increase AI in men. On the contrary, these factors may act independently in young women to increase AI without interaction, whereas only the blood pressure seems to increase AI in elderly women. Keywords: age; augmentation index; gender; risk factors INTRODUCTION Accumulating evidence suggest that increased arterial stiffness is an independent risk for cardiovascular disease (CVD). 1-3 The augmentation index (AI) is a marker related to systemic arterial stiffness, and some studies reported that increased AI or central blood pressure estimated by AI predicts future cardiovascular events. [4][5][6] Some studies reported that CVD risk factors affect AI. 7-11 The age-related increase in AI shows an attenuated curve in subjects aged 450 years, and AI is thought to be less sensitive in reflecting arterial stiffness in elderly subjects. 12 Although AI increases predominantly in women, the Second Australian National Blood Pressure Study (ANBP 2 study) showed that it cannot be used as a marker for predicting future CVD events in elderly women with hypertension. 13 Matsui et al. 14 examined the effects of age and gender on AI in subjects with hypertension under anti-hypertensive medication. However, their study could not avoid the influence of anti-hypertensive medication on the results. Thus, the effects of both age and gender on the relationship between the risk factors for CVD and AI in healthy individuals have not been fully clarified. Furthermore, although it is noted that a cluster of those risk factors additively or synergistically augments the progression of

This approach facilitates dissection of the IPDA on the right side of the SMA, thereby reducing operative times.