Cholangiocarcinoma (CCA)

1    Gu, T. L., X. Deng, F. Huang, M. Tucker, K. Crosby, V. Rimkunas, Y. Wang, G. Deng, L. Zhu, Z. Tan, Y. Hu, C. Wu, J. Nardone, J. MacNeill, J. Ren, C. Reeves, G. Innocenti, B. Norris, J. Yuan, J. Yu, H. Haack, B. Shen, C. Peng, H. Li, X. Zhou, X. Liu, J. Rush, and M. J. Comb. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. (2011). PLoS One. 6: e15640. pdf 3780,  DDR1 and CCA (cholangiocarcinoma). In BB2013Sep.  FIG-ROS1    Cholangiocarcinoma, also known as bile duct cancer, is the second most common primary hepatic carcinoma with a median survival of less than 2 years. The molecular mechanisms underlying the development of this disease are not clear. To survey activated tyrosine kinases signaling in cholangiocarcinoma, we employed immunoaffinity profiling coupled to mass spectrometry and identified DDR1, EPHA2, EGFR, and ROS tyrosine kinases, along with over 1,000 tyrosine phosphorylation sites from about 750 different proteins in primary cholangiocarcinoma patients. Furthermore, we confirmed the presence of ROS kinase fusions in 8.7% (2 out of 23) of cholangiocarcinoma patients. Expression of the ROS fusions in 3T3 cells confers transforming ability both in vitro and in vivo, and is responsive to its kinase inhibitor. Our data demonstrate that ROS kinase is a promising candidate for a therapeutic target and for a diagnostic molecular marker in cholangiocarcinoma. The identification of ROS tyrosine kinase fusions in cholangiocarcinoma, along with the presence of other ROS kinase fusions in lung cancer and glioblastoma, suggests that a more broadly based screen for activated ROS kinase in cancer is warranted.

2    Saborowski, A., M. Saborowski, M. A. Davare, B. J. Druker, D. S. Klimstra, and S. W. Lowe. Mouse model of intrahepatic cholangiocarcinoma validates FIG-ROS as a potent fusion oncogene and therapeutic target. (2013). Proc Natl Acad Sci USA. 110: 19513-8. pdf 3888.    Cholangiocarcinoma is the second most common primary liver cancer and responds poorly to existing therapies. Intrahepatic cholangiocarcinoma (ICC) likely originates from the biliary tree and develops within the hepatic parenchyma. We have generated a flexible orthotopic allograft mouse model of ICC that incorporates common genetic alterations identified in human ICC and histologically resembles the human disease. We examined the utility of this model to validate driver alterations in ICC and tested their suitability as therapeutic targets. Specifically, we showed that the fused-in-glioblastoma-c-ros-oncogene1 (FIG-ROS1(S); FIG-ROS) fusion gene dramatically accelerates ICC development and that its inactivation in established tumors has a potent antitumor effect. Our studies establish a versatile model of ICC that will be a useful preclinical tool and validate ROS1 fusions as potent oncoproteins and therapeutic targets in ICC and potentially other tumor types.

3    Davare, M. A., A. Saborowski, C. A. Eide, C. Tognon, R. L. Smith, J. Elferich, A. Agarwal, J. W. Tyner, U. P. Shinde, S. W. Lowe, and B. J. Druker. Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. (2013). Proc Natl Acad Sci USA. 110: 19519-24. pdf 3963. interesting, is related to pdf 3888 (mouse model of cholangio)    The rapidly growing recognition of the role of oncogenic ROS1 fusion proteins in the malignant transformation of multiple cancers, including lung adenocarcinoma, cholangiocarcinoma, and glioblastoma, is driving efforts to develop effective ROS1 inhibitors for use as molecularly targeted therapy. Using a multidisciplinary approach involving small molecule screening in combination with in vitro and in vivo tumor models, we show that foretinib (GSK1363089) is a more potent ROS1 inhibitor than crizotinib (PF-02341066), an ALK/ROS inhibitor currently in clinical evaluation for lung cancer patients harboring ROS1 rearrangements. Whereas crizotinib has demonstrated promising early results in patients with ROS1-rearranged non-small-cell lung carcinoma, recently emerging clinical evidence suggests that patients may develop crizotinib resistance due to acquired point mutations in the kinase domain of ROS1, thus necessitating identification of additional potent ROS1 inhibitors for therapeutic intervention. We confirm that the ROS1G2032R mutant, recently reported in clinical resistance to crizotinib, retains foretinib sensitivity at concentrations below safe, clinically achievable levels. Furthermore, we use an accelerated mutagenesis screen to preemptively identify mutations in the ROS1 kinase domain that confer resistance to crizotinib and demonstrate that these mutants also remain foretinib sensitive. Taken together, our data strongly suggest that foretinib is a highly effective ROS1 inhibitor, and further clinical investigation to evaluate its potential therapeutic benefit for patients with ROS1-driven malignancies is warranted.

4    Ong, C. K., C. Subimerb, C. Pairojkul, S. Wongkham, I. Cutcutache, W. Yu, J. R. McPherson, G. E. Allen, C. C. Ng, B. H. Wong, S. S. Myint, V. Rajasegaran, H. L. Heng, A. Gan, Z. J. Zang, Y. Wu, J. Wu, M. H. Lee, D. Huang, P. Ong, W. Chan-on, Y. Cao, C. N. Qian, K. H. Lim, A. Ooi, K. Dykema, K. Furge, V. Kukongviriyapan, B. Sripa, C. Wongkham, P. Yongvanit, P. A. Futreal, V. Bhudhisawasdi, S. Rozen, P. Tan, and B. T. Teh. Exome sequencing of liver fluke-associated cholangiocarcinoma. (2012). Nat Genet. 44: 690-3. pdf 3596 in BB2013Mar, 2012-06, referred by 蔡坤志醫師.     Opisthorchis viverrini-related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini-related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 (mutated in 44.4% of cases), KRAS (16.7%) and SMAD4 (16.7%), we identified somatic mutations in 10 newly implicated genes in 14.8-3.7% of cases. These included inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%) and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%). These genes have functions that can be broadly grouped into three biological classes: (i) deactivation of histone modifiers, (ii) activation of G protein signaling and (iii) loss of genome stability. This study provides insight into the mutational landscape contributing to O. viverrini-related CCA.

5    Chan-On, W., M. L. Nairismagi, C. K. Ong, W. K. Lim, S. Dima, C. Pairojkul, K. H. Lim, J. R. McPherson, I. Cutcutache, H. L. Heng, L. Ooi, A. Chung, P. Chow, P. C. Cheow, S. Y. Lee, S. P. Choo, I. B. Tan, D. Duda, A. Nastase, S. S. Myint, B. H. Wong, A. Gan, V. Rajasegaran, C. C. Ng, S. Nagarajan, A. Jusakul, S. Zhang, P. Vohra, W. Yu, D. Huang, P. Sithithaworn, P. Yongvanit, S. Wongkham, N. Khuntikeo, V. Bhudhisawasdi, I. Popescu, S. G. Rozen, P. Tan, and B. T. Teh. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. (2013). Nat Genet. 45: 1474-8. pdf not yet.   The impact of different carcinogenic exposures on the specific patterns of somatic mutation in human tumors remains unclear. To address this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non-O. viverrini-related etiologies. Whole-exome sequencing (n = 15) and prevalence screening (n = 194) identified recurrent somatic mutations in BAP1 and ARID1A, neither of which, to our knowledge, has previously been reported to be mutated in CCA. Comparisons between intrahepatic O. viverrini-related and non-O. viverrini-related CCAs demonstrated statistically significant differences in mutation patterns: BAP1, IDH1 and IDH2 were more frequently mutated in non-O. viverrini CCAs, whereas TP53 mutations showed the reciprocal pattern. Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations, even within the same tumor type.

6    Jiao, Y., T. M. Pawlik, R. A. Anders, F. M. Selaru, M. M. Streppel, D. J. Lucas, N. Niknafs, V. B. Guthrie, A. Maitra, P. Argani, G. J. Offerhaus, J. C. Roa, L. R. Roberts, G. J. Gores, I. Popescu, S. T. Alexandrescu, S. Dima, M. Fassan, M. Simbolo, A. Mafficini, P. Capelli, R. T. Lawlor, A. Ruzzenente, A. Guglielmi, G. Tortora, F. de Braud, A. Scarpa, W. Jarnagin, D. Klimstra, R. Karchin, V. E. Velculescu, R. H. Hruban, B. Vogelstein, K. W. Kinzler, N. Papadopoulos, and L. D. Wood. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. (2013). Nat Genet. 45: 1470-3. pdf 3970.    Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.

7    Grassian, A. R., R. Pagliarini, and D. Y. Chiang. Mutations of isocitrate dehydrogenase 1 and 2 in intrahepatic cholangiocarcinoma. (2014). Current opinion in gastroenterology. pdf 3978.    PURPOSE OF REVIEW: Exome sequencing studies have recently expanded the genetic characterization of intrahepatic cholangiocarcinomas. Among a number of novel genes, isocitrate dehydrogenase (IDH) is recurrently mutated in intrahepatic cholangiocarcinomas. We review the effects of these mutations on several biochemical pathways, as well as potential changes to downstream signaling pathways. RECENT FINDINGS: Hotspot mutations in IDH isoforms 1 or 2 occur in approximately 15% of intrahepatic cholangiocarcinomas. These mutations result in elevated levels of an oncometabolite, 2-hydroxyglutarate, which is associated with higher DNA CpG methylation and altered histone methylation that accompany a block in cellular differentiation. Exploratory studies have suggested additional phenotypes associated with IDH1/2 mutations. SUMMARY: Tumors with IDH1 or IDH2 mutations may represent a distinct subtype of cholangiocarcinomas. Further studies are required to elucidate the exact role that mutant IDH1/2 and 2-hydroxyglutarate play in tumorigenesis, and what are the best strategies to target these tumor types.

8    Rizvi, S., and G. J. Gores. Pathogenesis, diagnosis, and management of cholangiocarcinoma. (2013). Gastroenterology. 145: 1215-29. pdf 3979. IDH 1, IDH2 mutation in Figure 2 very good!! 印了 但沒空念    Cholangiocarcinomas (CCAs) are hepatobiliary cancers with features of cholangiocyte differentiation; they can be classified anatomically as intrahepatic CCA (iCCA), perihilar CCA (pCCA), or distal CCA. These subtypes differ not only in their anatomic location, but in epidemiology, origin, etiology, pathogenesis, and treatment. The incidence and mortality of iCCA has been increasing over the past 3 decades, and only a low percentage of patients survive until 5 years after diagnosis. Geographic variations in the incidence of CCA are related to variations in risk factors. Changes in oncogene and inflammatory signaling pathways, as well as genetic and epigenetic alterations and chromosome aberrations, have been shown to contribute to the development of CCA. Furthermore, CCAs are surrounded by a dense stroma that contains many cancer-associated fibroblasts, which promotes their progression. We have gained a better understanding of the imaging characteristics of iCCAs and have developed advanced cytologic techniques to detect pCCAs. Patients with iCCAs usually are treated surgically, whereas liver transplantation after neoadjuvant chemoradiation is an option for a subset of patients with pCCAs. We review recent developments in our understanding of the epidemiology and pathogenesis of CCA, along with advances in classification, diagnosis, and treatment.

9    Subbiah, I. M., V. Subbiah, A. M. Tsimberidou, A. Naing, A. O. Kaseb, M. Javle, S. Fu, D. S. Hong, S. Piha-Paul, J. J. Wheler, K. R. Hess, F. Janku, G. S. Falchook, R. A. Wolff, and R. Kurzrock. Targeted Therapy of Advanced Gallbladder Cancer and Cholangiocarcinoma with Aggressive Biology: Eliciting Early Response Signals from Phase 1 trials. (2013). Oncotarget. 4: 153-62. pdf not yet. cholangioncarcinoma and gallbaldder carcinoma clinical trial    PURPOSE: Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few therapeutic options for relapsed disease. METHODS: Given the overall poor prognosis in this population and the availability of novel targeted therapies, we systematically analyzed the characteristics and outcomes for GC and CC patients treated on phase I trials with an emphasis on targeted agents and locoregional therapies. RESULTS: Of 40 treated patients (GC=6; CC=34; median age, 60 years), 8 (20%) had stable disease (SD) > 6 months, 3 (8%) partial response (PR), on protocols with hepatic arterial drug infusion and anti-angiogenic, anti-HER-2/neu or novel MAPK/ERK kinase (MEK) inhibitors. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0), 3.0 months (95% CI 2.3, 4.6), and 3.0 months (95% CI 2.4, 3.9) for their first-, second-, and last-line FDA-approved therapy. In univariate analysis, >3 metastatic sites, elevated alanine aminotransferase (ALT) (>56IU/L), serum creatinine (>1.6mg/dL), and CA19-9 (>35U/mL) were associated with a shorter PFS. Mutational analysis revealed mutation in the KRAS oncogene in 2 of 11 patients (18%). The SD >6 months/PR rate of 28% was seen with hepatic arterial infusion of oxaliplatin, and inhibitors of angiogenesis, HER-2/neu or MEK. CONCLUSIONS: The PFS in phase I trials was similar to that of the first, second, and last-line therapy (P=0.95, 0.98, 0.76, respectively) with FDA-approved agents given in the advanced setting, emphasizing a role for targeted agents in a clinical trials setting as potentially valuable therapeutic options for these patients.

10    Sia, D., V. Tovar, A. Moeini, and J. M. Llovet. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. (2013). Oncogene. 32: 4861-70. pdf 3807. in BB2014Mar. Must Read. cholangiocarcinoma related.     Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with very poor prognosis. Genome-wide, high-throughput technologies have made major advances in understanding the molecular basis of this disease, although important mechanisms are still unclear. Recent data have revealed specific genetic mutations (for example, KRAS, IDH1 and IDH2), epigenetic silencing, aberrant signaling pathway activation (for example, interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), tyrosine kinase receptor-related pathways) and molecular subclasses with unique alterations (for example, proliferation and inflammation subclasses). In addition, some ICCs share common genomic traits with hepatocellular carcinoma. All this information provides the basis to explore novel targeted therapies. Currently, surgery at early stage is the only effective therapy. At more advanced stages, chemotherapy regimens are emerging (that is, cisplatin plus gemcitabine), along with molecular targeted agents tested in several ongoing clinical trials. Nonetheless, a first-line conclusive treatment remains an unmet need. Similarly, there are no studies assessing tumor response related with genetic alterations. This review explores the recent advancements in the knowledge of the molecular alterations underlying ICC and the future prospects in terms of therapeutic strategies leading towards a more personalized treatment of this neoplasm.

11    Razumilava, N., and G. J. Gores. Cholangiocarcinoma. (2014). Lancet. 383: 2168-79. pdf 3982    Cholangiocarcinoma represents a diverse group of epithelial cancers united by late diagnosis and poor outcomes. Specific diagnostic and therapeutic approaches are undertaken for cholangiocarcinomas of different anatomical locations (intrahepatic, perihilar, and distal). Mixed hepatocellular cholangiocarcinomas have emerged as a distinct subtype of primary liver cancer. Clinicians need to be aware of intrahepatic cholangiocarcinomas arising in cirrhosis and properly assess liver masses in this setting for cholangiocarcinoma. Management of biliary obstruction is obligatory in perihilar cholangiocarcinoma, and advanced cytological tests such as fluorescence in-situ hybridisation for aneusomy are helpful in the diagnosis. Liver transplantation is a curative option for selected patients with perihilar but not with intrahepatic or distal cholangiocarcinoma. International efforts of clinicians and scientists are helping to identify the genetic drivers of cholangiocarcinoma progression, which will unveil early diagnostic markers and direct development of individualised therapies.

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1    Wu, Y. M., F. Su, S. Kalyana-Sundaram, N. Khazanov, B. Ateeq, X. Cao, R. J. Lonigro, P. Vats, R. Wang, S. F. Lin, A. J. Cheng, L. P. Kunju, J. Siddiqui, S. A. Tomlins, P. Wyngaard, S. Sadis, S. Roychowdhury, M. H. Hussain, F. Y. Feng, M. M. Zalupski, M. Talpaz, K. J. Pienta, D. R. Rhodes, D. R. Robinson, and A. M. Chinnaiyan. Identification of targetable FGFR gene fusions in diverse cancers. (2013). Cancer discovery. 3: 636-47. pdf 3670. in BB2013June, 2013-06. FGFR Gene fusion. HNSCC.    Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2, including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Because of the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts, which incorporate transcriptome analysis for gene fusions, are poised to identify rare, targetable FGFR fusions across diverse cancer types.

2    Arai, Y., Y. Totoki, F. Hosoda, T. Shirota, N. Hama, H. Nakamura, H. Ojima, K. Furuta, K. Shimada, T. Okusaka, A. Kosuge, and T. Shibata. FGFR2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. (2013). Hepatology. pdf 3923.  FGFR2. Gene Fusion. Hepatology. 2013 Oct 9. doi: 10.1002/hep.26890.    Cholangiocarcinoma is an intractable cancer, with limited therapeutic options, in which the molecular mechanisms underlying tumor development remain poorly understood. Identification of novel driver oncogene and applying to targeted therapies for molecularly defined cancers might lead to improvements in outcomes 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 9 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 FGFR kinase inhibitors, BGJ398 and PD173074 effectively suppressed transformation. CONCLUSIONS: 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.

3    Ross, J. S., K. Wang, L. Gay, R. Al-Rohil, J. V. Rand, D. M. Jones, H. J. Lee, C. E. Sheehan, G. A. Otto, G. Palmer, R. Yelensky, D. Lipson, D. Morosini, M. Hawryluk, D. V. Catenacci, V. A. Miller, C. Churi, S. Ali, and P. J. Stephens. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. (2014). Oncologist. 19: 235-42. pdf 4001, FGFR2 fusion, cholangiocarcinoma not read yet! IHC    Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence. Relapsed ICC has a poor prognosis, and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies. We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy. Methods. DNA sequencing of hybridization-captured libraries was performed for 3,320 exons of 182 cancer-related genes and 36 introns of 14 genes frequently rearranged in cancer. Sample DNA was isolated from 40 mum of 28 formalin-fixed paraffin-embedded ICC specimens and sequenced to high coverage. Results. The most commonly observed alterations were within ARID1A (36%), IDH1/2 (36%), and TP53 (36%) as well as amplification of MCL1 (21%). Twenty cases (71%) harbored at least one potentially actionable alteration, including FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2A (7%), CDK6 (7%), ERBB3 (7%), MET (7%), NRAS (7%), BRCA1 (4%), BRCA2 (4%), NF1 (4%), PIK3CA (4%), PTCH1 (4%), and TSC1 (4%). Four (14%) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 (FGFR2-KIAA1598, FGFR2-BICC1, FGFR2-TACC3, and RABGAP1L-NTRK1). Conclusion. Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients.

4    Borad, M. J., M. D. Champion, J. B. Egan, W. S. Liang, R. Fonseca, A. H. Bryce, A. E. McCullough, M. T. Barrett, K. Hunt, M. D. Patel, S. W. Young, J. M. Collins, A. C. Silva, R. M. Condjella, M. Block, R. R. McWilliams, K. N. Lazaridis, E. W. Klee, K. C. Bible, P. Harris, G. R. Oliver, J. D. Bhavsar, A. A. Nair, S. Middha, Y. Asmann, J. P. Kocher, K. Schahl, B. R. Kipp, E. G. Barr Fritcher, A. Baker, J. Aldrich, A. Kurdoglu, T. Izatt, A. Christoforides, I. Cherni, S. Nasser, R. Reiman, L. Phillips, J. McDonald, J. Adkins, S. D. Mastrian, P. Placek, A. T. Watanabe, J. Lobello, H. Han, D. Von Hoff, D. W. Craig, A. K. Stewart, and J. D. Carpten. (Mayo Clinic Cancer Center, Arizon and Mayo Clinic, Minnesota) Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. (2014). PLoS Genet. 10: e1004135. pdf 4118.    Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50 approximately 350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50 approximately 8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.

5    Graham, R. P., E. G. Barr Fritcher, E. Pestova, J. Schulz, L. A. Sitailo, G. Vasmatzis, S. J. Murphy, R. R. McWilliams, S. N. Hart, K. C. Halling, L. R. Roberts, G. J. Gores, F. J. Couch, L. Zhang, M. J. Borad, and B. R. Kipp. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. (2014). Human pathology. 45: 1630-8. pdf 4119.    Patients with cholangiocarcinoma often present with locally advanced or metastatic disease. There is a need for effective therapeutic strategies for advanced stage cholangiocarcinoma. Recently, FGFR2 translocations have been identified as a potential target for tyrosine kinase inhibitor therapies. This study evaluated 152 cholangiocarcinomas and 4 intraductal papillary biliary neoplasms of the bile duct for presence of FGFR2 translocations by fluorescence in situ hybridization and characterized the clinicopathologic features of cases with FGFR2 translocations. Thirteen (10 women, 3 men; 8%) of 156 biliary tumors harbored FGFR2 translocations, including 12 intrahepatic cholangiocarcinomas (12/96; 13%) and 1 intraductal papillary neoplasm of the bile duct. Histologically, cholangiocarcinomas with FGFR2 translocations displayed prominent intraductal growth (62%) or anastomosing tubular glands with desmoplasia (38%). Immunohistochemically, the tumors with FGFR2 translocations frequently showed weak and patchy expression of CK19 (77%). Markers of the stem cell phenotype in cholangiocarcinoma, HepPar1 and CK20, were negative in all cases. The median cancer-specific survival for patients whose tumors harbored FGFR2 translocations was 123 months compared to 37 months for cases without FGFR2 translocations (P = .039). This study also assessed 100 cholangiocarcinomas for ERBB2 amplification and ROS1 translocations. Of the cases tested, 3% and 1% were positive for ERBB2 amplification and ROS1 translocation, respectively. These results confirm that FGFR2, ERRB2, and ROS1 alterations are potential therapeutic targets for intrahepatic cholangiocarcinoma.