Dataset Information

Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable ?-catenin Overexpression and a ?-catenin Mutation.

ABSTRACT: Objective ?Sinonasal teratocarcinosarcomas are rare, aggressive tumors of the skull base. Treatment options are limited and outcomes are poor. Little is known in regard to the genetic factors regulating these tumors. Characterization of actionable molecular alterations in these tumors could provide potentially successful therapeutic options. Methods ?We performed targeted exome sequencing on an index sinonasal teratocarcinosarcoma specimen to identify potential driver mutations. We performed immunohistochemical stains for ?-catenin on paraffin-embedded tissue on the index tumor and a subsequent teratocarcinosarcoma. Online databases of cancer mutations (Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas) were accessed. Results ?We identified an activating p.S45F mutation in ?-catenin in our index sinonasal teratocarcinosarcoma. This mutation results in constitutive signaling in the Wnt/?-catenin pathway. We confirmed ?-catenin overexpression and nuclear localization via immunohistochemistry in the index tumor and a second patient. The p.S45F activating mutation was found in a variety of solid tumors, and accounts for 3.3 to 10.4% of all known ?-catenin mutations. Conclusion ?We identified a potential driver mutation in ?-catenin in a sinonasal teratocarcinosarcoma, resulting in ?-catenin overexpression. These findings suggest a role for the Wnt/?-catenin pathway in sinonasal teratocarcinosarcoma tumorigenesis and a role for anti-?-catenin targeted therapy.

SUBMITTER: Birkeland AC

PROVIDER: S-EPMC5515660 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable β-catenin Overexpression and a β-catenin Mutation.

Birkeland Andrew C AC Burgin Sarah J SJ Yanik Megan M Scott Megan V MV Bradford Carol R CR McHugh Jonathan B JB McLean Scott A SA Sullivan Stephen E SE Nor Jacques E JE McKean Erin L EL Brenner J Chad JC

Journal of neurological surgery. Part B, Skull base 20170327 4

<b>Objective</b> Sinonasal teratocarcinosarcomas are rare, aggressive tumors of the skull base. Treatment options are limited and outcomes are poor. Little is known in regard to the genetic factors regulating these tumors. Characterization of actionable molecular alterations in these tumors could provide potentially successful therapeutic options. <b>Methods</b> We performed targeted exome sequencing on an index sinonasal teratocarcinosarcoma specimen to identify potential driver mutations. We ...[more]

PMID: 28725522

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Project description:BACKGROUND:Comprehensive mutational profiling data now available on all major cancers have led to proposals of novel molecular tumor classifications that modify or replace the established organ- and tissue-based tumor typing. The rationale behind such molecular reclassifications is that genetic alterations underlying cancer pathology predict response to therapy and may therefore offer a more precise view on cancer than histology. The use of individual actionable mutations to select cancers for treatment across histotypes is already being tested in the so-called basket trials with variable success rates. Here, we present a computational approach that facilitates the systematic analysis of the histological context dependency of mutational effects by integrating genomic and proteomic tumor profiles across cancers. METHODS:To determine effects of oncogenic mutations on protein profiles, we used the energy distance, which compares the Euclidean distances of protein profiles in tumors with an oncogenic mutation (inner distance) to that in tumors without the mutation (outer distance) and performed Monte Carlo simulations for the significance analysis. Finally, the proteins were ranked by their contribution to profile differences to identify proteins characteristic of oncogenic mutation effects across cancers. RESULTS:We apply our approach to four current proposals of molecular tumor classifications and major therapeutically relevant actionable genes. All 12 actionable genes evaluated show effects on the protein level in the corresponding tumor type and showed additional mutation-related protein profiles in 21 tumor types. Moreover, our analysis identifies consistent cross-cancer effects for 4 genes (FGFR1, ERRB2, IDH1, KRAS/NRAS) in 14 tumor types. We further use cell line drug response data to validate our findings. CONCLUSIONS:This computational approach can be used to identify mutational signatures that have protein-level effects and can therefore contribute to preclinical in silico tests of the efficacy of molecular classifications as well as the druggability of individual mutations. It thus supports the identification of novel targeted therapies effective across cancers and guides efficient basket trial designs.

Project description:Biliary tract cancer (BTC) represents a heterogeneous disease with dismal outcome. Herein, we examined genotype and angiogenesis features in BTC. We applied genotyping (Sanger, qPCR, 101-gene panel NGS), mRNA relative quantification methods, and β-catenin immunohistochemistry in 84 FFPE BTC (55 gallbladder [GBC], 14 intrahepatic [ICC], 15 extrahepatic [ECC] carcinomas). We identified 541 mutations in 68 (81%) tumors. Top mutated genes were CTNNB1 (36%); PTEN (33%); TP53 (31%); PIK3R1 (29%); PIK3CA (13%); BRCA2 and KRAS (12%); BRCA1 (11%). Six GBCs were hypermutated [hm] displaying a distinct mutational pattern. Mutations in TP53 and PI3K, Wnt and RAS components were prevalent among non-hypermutated tumors. All hmGBCs carried mutations in BRCA2 and other homologous recombination repair (HRR) genes, in PD1, but not in CTNNB1 and KRAS. None of the pathogenic BRCA2 p.D2723G and BRCA1 p.Q563* and c.5266dupC was present at frequencies expected for germline mutations. We observed copy gains (>6 copies) in EGFR (9% of informative tumors), PRKAR1A (7%), PIK3CA (6%), ERBB2 (5%) and MET (4%). TP53 mutations were prevalent in GBC (P<0.001) and PRKAR1A copy gains in ICC (P=0.007). PTEN was frequently co-mutated with CTNNB1 (P<0.001). Unrelated to CTNNB1 mutations, nuclear β-catenin was detected in 45% of tumors, among them in 5/6 hmGBC. We observed strong mRNA expression correlation of the two neuropilins (NRP1 and NRP2) with each other (Spearman's rho 0.59) and with the endothelin receptor (NRP2 rho 0.66; NRP2 rho 0.51), and between VEGFA and its receptors (FLT1 rho 0.49; KDR rho 0.45). All PIK3CA mutated tumors expressed endothelin 1 mRNA (P=0.010). Most tumors expressing nuclear β-catenin were negative for VEGFC (P=0.009) and FLT4 (P=0.002) mRNA expression. In conclusion, we confirmed the presence of known genomic aberrations in BTC and different genotypes between BTC subsets. Novel findings are the coexistence of PI3K and WNT pathway gene alterations in BTC, their association with angiogenesis, and the hypermutated GBCs with HRR gene mutations, all of which may be considered for new treatment options in this difficult to treat disease.

Dataset Information

Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable ?-catenin Overexpression and a ?-catenin Mutation.

Publications

Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable β-catenin Overexpression and a β-catenin Mutation.

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