Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity

Fujimoto, Akihiro; Furuta, Mayuko; Shiraishi, Yuichi; Gotoh, Kunihito; Kawakami, Yoshiiku; Arihiro, Koji; Nakamura, Tõru; Ueno, Masaki; Ariizumi, Shun Ichi; Hà, Nguyễn Hải; Shigemizu, Daichi; Abe, Tetsuo; Boroevich, Keith A.; Nakano, Kaoru; Sasaki, Aya; Kitada, Rina; Maejima, Kazihiro; Yamamoto, Yujiro; Tanaka, Hiroko; Shibuya, Tetsuo; Shibata, Tatsuhiro; Ojima, Hidenori; Shimada, Kazuaki; Hayami, Shinya; Shigekawa, Yoshinobu; Aikata, Hiroshi; Ohdan, Hideki; Marubashi, Shigeru; Yamada, Terumasa; Kubo, Michiaki; Hirano, Satoshi; Ishikawa, Osamu; Yamamoto, Masakazu; Yamaue, Hiroki; Chayama, Kazuaki; Miyano, Satoru; Tsunoda, Tatsuhiko; Nakagawa, Hidewaki

doi:10.1038/ncomms7120

Cited by 182 publications

(167 citation statements)

References 49 publications

Supporting

Mentioning

161

Contrasting

Order By: Relevance

“…It is reported that LAMA1 is associated with cancer pathways, such as integrin signaling and cell adhesion in NSCLC (39). In addition, PCLO promoted cell invasion in liver cancer cell lines (40). These four genes might be associated with the etiology of LCNEC; however, confirmation in large studies is needed, and functional experiments on these genes are required to clarify their biological role.…”

Section: Discussionmentioning

confidence: 99%

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung

Miyoshi

Umemura

Matsumura

et al. 2017

Clinical Cancer Research

143

View full text Add to dashboard Cite

Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations.Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases).Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P ¼ 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%).Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/ mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung

Miyoshi

Umemura

Matsumura

et al. 2017

Clinical Cancer Research

143

View full text Add to dashboard Cite

show abstract

“…Before the implementation of next-generation sequencing technologies, our knowledge of the role of mutations in iCCA was limited, encompassing recurrent activating mutations in KRAS (19%), low frequency mutations in BRAF (5%), and EGFR (3%), and widely varying reports of loss-offunction mutations in the tumor suppressor TP53 (16%, range 1%-38%; Tables 1 and 2; refs. 31,[50][51][52][53][54][55][56][57][58][59][60][61][62][63][64]. While KRAS and TP53 mutations are relatively common in all CCA, mutations in IDH1/2 and BRAF are considerably more prevalent in iCCA (Table 1).…”

Section: Molecular Pathogenesismentioning

confidence: 99%

Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma

Moeini

Sia

Bardeesy

et al. 2016

Clinical Cancer Research

193

176

View full text Add to dashboard Cite

Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous hepatobiliary neoplasm with poor prognosis and limited therapeutic options. The incidence of this neoplasm is growing globally. One third of iCCA tumors are amenable to surgical resection, but most cases are diagnosed at advanced stages with chemotherapy as the only established standard of practice. No molecular therapies are currently available for the treatment of this neoplasm. The poor understanding of the biology of iCCA and the lack of known oncogenic addiction loops has hindered the development of effective targeted therapies. Studies with sophisticated animal models defined IDH mutation as the first gatekeeper in the carcinogenic process and led to the discovery of striking alternative cellular origins. RNA-and exome-sequencing technologies revealed the presence of recurrent novel fusion events (FGFR2 and ROS1 fusions) and somatic mutations in metabolic (IDH1/2) and chromatinremodeling genes (ARID1A, BAP1). These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA. More than 100 clinical trials testing molecular therapies alone or in combination with chemotherapy including iCCA patients have not reported conclusive clinical benefits. Recent discoveries have shown that up to 70% of iCCA patients harbor potential actionable alterations that are amenable to therapeutic targeting in early clinical trials. Thus, the first biomarkerdriven trials are currently underway.

show abstract

“…The genomic heterogeneity of CCA (TABLE 1) is not only related to the diverse anatomical location of the tumour (that is, intrahepatic, perihilar or distal) but also to the various risk factors and associated pathologies 29,[67][68][69][70][71][72][73][74][75] . The most prevalent genetic alterations identified in CCA affect key networks such as DNA repair (TP53) 72,73,75 , the WNT-CTNNB1 pathway 67 , tyrosine kinase signalling (KRAS, BRAF, SMAD4 and FGFR2) 29,68,70,[73][74][75] , protein tyrosine phosphatase (PTPN3) 71 , epigenetic (IDH1 and IDH2) 69,70,72,74,75 and chromatin-remodelling factors (histone-lysine N-methyltransferase 2C, also known as MLL3) 73 , including the SWI/SNF complex (ARID1A, PBRM1 and BAP1) 69,70,72,75 and deregulated Notch signalling, which is a key component in cholangiocyte differentiation and biliary duct development.…”

Section: Genomic Heterogeneitymentioning

confidence: 99%

“…The most prevalent genetic alterations identified in CCA affect key networks such as DNA repair (TP53) 72,73,75 , the WNT-CTNNB1 pathway 67 , tyrosine kinase signalling (KRAS, BRAF, SMAD4 and FGFR2) 29,68,70,[73][74][75] , protein tyrosine phosphatase (PTPN3) 71 , epigenetic (IDH1 and IDH2) 69,70,72,74,75 and chromatin-remodelling factors (histone-lysine N-methyltransferase 2C, also known as MLL3) 73 , including the SWI/SNF complex (ARID1A, PBRM1 and BAP1) 69,70,72,75 and deregulated Notch signalling, which is a key component in cholangiocyte differentiation and biliary duct development. Recurrent genetic variants have also been identified in the promoter of the human telomerase reverse transcriptase (TERT) 70 , which for CCA is found to be associated with chronic hepatitis 70 . Thus, all these alterations summarize some of the genome defects and pathways involved in CCA development, and represent potential candidates for personalized targeted cancer therapy.…”

Section: Genomic Heterogeneitymentioning

confidence: 99%