bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3387: Mutational analysis in metastatic melanoma to the breast and ovary: correlation with clinic-pathological and immunohistochemical findings
Authors: Giubellino Alessio , Moreno Vanessa , Naizhen Xu , Xi Liqiang , Raffeld Mark , Merino Maria 
Published: July 2017

Abstract
Metastatic malignant melanoma or stage IV melanoma is the most deadly skin cancer, claiming an estimated 10,000 deaths every year. The occurrence of metastatic malignant melanoma to the breast and ovary is uncommon, and can represent a challenge for the diagnosis and clinical management. We investigated and correlated the morphologic, immunohistochemical and molecular aspects of these tumors.
Morphologic analysis of the cases revealed a predominance of epithelioid pattern, and few of these were associated with more spindle cell areas. Most of the tumor cells aberrantly expressed high levels of PD-L1, especially in the metastatic melanoma to the breast. Other relevant melanoma targets for immunotherapy were also explored by immunohistochemistry. Of note, most of the metastatic tumors were negative for NY-ESO.
The mutational analysis of these metastatic lesions, using next generation sequencing for the detection of cancer gene mutations including rare mutations at low frequency, found an heterogeneous mutational landscape, reinforcing the importance of personalized treatments. Mutations in RAS gene family members in these metastatic tumors were the most frequent in our samples, followed by CDKN2A and CTNNB1 mutations. Other less frequent mutations were also detected, including ATM and KIT. Interestingly, one rapidly progressive melanoma metastatic to the breast in a young patient had areas of spindle cell morphology and no common melanoma gene mutations.
Overall, our cases illustrate the pathologic and molecular variability of metastatic malignant melanoma to uncommon organs of involvement, such as breast and ovary, and provide novel insights into their diagnostic and clinical management algorithm.
Note: This abstract was not presented at the meeting.
Citation Format: Alessio Giubellino, Vanessa Moreno, Xu Naizhen, Liqiang Xi, Mark Raffeld, Maria Merino. Mutational analysis in metastatic melanoma to the breast and ovary: correlation with clinic-pathological and immunohistochemical findings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3387. doi:10.1158/1538-7445.AM2017-3387
Abstract 3389: Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma
Authors: Liang Winnie S. , Hendricks William , Kiefer Jeffrey , Schmidt Jessica , Sekar Shobana , Carpten John , Craig David W. , Adkins Jonathan , Cuyugan Lori , Manojlovic Zarko , Halperin Rebecca F. , Helland Adrienne , Nasser Sara , Legendre Christophe , Hurley Laurence H. , Sivaprakasam Karthigayini , Johnson Douglas B. , Crandall Holly , Busam Klaus J. , Zismann Victoria , Luca Valerie De , Lee Jeeyun , Sekulic Aleksandar , Ariyan Charlotte E. , Sosman Jeffrey , Trent Jeffrey 
Published: July 2017

Abstract
Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. Contrasting with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis, and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.
Citation Format: Winnie S. Liang, William Hendricks, Jeffrey Kiefer, Jessica Schmidt, Shobana Sekar, John Carpten, David W. Craig, Jonathan Adkins, Lori Cuyugan, Zarko Manojlovic, Rebecca F. Halperin, Adrienne Helland, Sara Nasser, Christophe Legendre, Laurence H. Hurley, Karthigayini Sivaprakasam, Douglas B. Johnson, Holly Crandall, Klaus J. Busam, Victoria Zismann, Valerie De Luca, Jeeyun Lee, Aleksandar Sekulic, Charlotte E. Ariyan, Jeffrey Sosman, Jeffrey Trent. Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3389. doi:10.1158/1538-7445.AM2017-3389
Abstract 3391: Next generation sequencing paves the way for personalized medicine in pheochromocytoma and paraganglioma patients and their families
Authors: Gieldon Laura , Richter Susan , Rump Andreas , Hackmann Karl , Tzschach Andreas , Eisenhofer Graeme , Pęczkowska Mariola , Prejbisz Aleksander , Schröck Evelin , Klink Barbara 
Published: July 2017

Abstract
More than 35% of pheochromocytomas and paragangliomas (PPGL) are thought to occur due to an underlying genetic predisposition. 18 susceptibility genes have been identified for PPGL, which explain app. 30% of familial cases. Further PPGL predisposition genes, however, remain to be discovered. In addition, identification of biomarkers for malignancy also remains a current challenge since histologic assessment does not suffice discrimination of malignant PPGLs. Personalized screening protocols, risk stratification measures and surveillance guidelines are needed for PPGL patients and their family members at risk.
We performed panel sequencing for 94 tumor predisposition syndrome (TPS) genes and identified 12 pathogenic germline mutations in 60 PPGL patients. Two of these patients were identified with NF1-mutations although they did not meet the diagnostic criteria for Neurofibromatosis. Thus, TPS gene panel sequencing proved superior to routine Sanger sequencing since mutations were identified in genes that would have routinely been excluded from analysis.
Combining results of immunohistochemistry as well as biochemical profiling by measuring Krebs-cycle metabolites and genetic analyses of tumors we were able to reclassify variants of uncertain significance (VUS) as either pathogenic mutations or polymorphisms in several patients.
Three incidentally found pathogenic mutations in CHEK2 and MSH2 prompted further analyses such as testing for microsatellite instability in order to evaluate possible effects on PPGL development.
For patients in whom no underlying mutation could be detected we performed custom candidate gene panel sequencing of tumor derived-DNA. Whole exome sequencing (WES) was carried out in 15 cases highly suspicious for a genetic background in order to identify new candidate predisposition genes that will further be evaluated in the patient cohort and in functional studies.
We will also present guidelines for diagnostics, surveillance and prevention of PPGL for patients and their family members.
Citation Format: Laura Gieldon, Susan Richter, Andreas Rump, Karl Hackmann, Andreas Tzschach, Graeme Eisenhofer, Mariola Pęczkowska, Aleksander Prejbisz, Evelin Schröck, Barbara Klink. Next generation sequencing paves the way for personalized medicine in pheochromocytoma and paraganglioma patients and their families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3391. doi:10.1158/1538-7445.AM2017-3391
Abstract 3395: Alternative splicing of the MEAF6 gene promotes neuroendocrine prostate cancer development
Authors: Lee Ahn R. , Li Yinan , Xie Ning , Collins Colin C. , Dong Xuesen 
Published: July 2017

Abstract
In response to the selection pressures exerted by potent androgen receptor (AR) pathway inhibitors (ARPI), adenocarcinoma prostate cancer (PCa) cells can undergo an adaptive process of cellular phenotype reprogramming termed neuroendocrine trans-differentiation. With this AR-bypass mechanism of survival emerges a lethal treatment-resistant PCa subtype called treatment-induced neuroendocrine PCa (t-NEPC). t-NEPC is becoming a major clinical issue as it is estimated to affect &gt;25% of advanced-stage PCa patients with the level of incidences predicted to rise as a result of the extensive applications of ARPI in the clinic. This underscores the gravity of our aims to delineate the molecular underpinnings of t-NEPC to inform future therapies that prevent or mitigate t-NEPC development.
In this study, we have identified a splice variant of the MYST/Esa1-associated factor 6 (MEAF6) gene, MEAF6-1, that is highly expressed in t-NEPC tumor biopsies as well as neuroendocrine cell lines of prostate and lung cancers. We show that the neuronal RNA splicing factor, SRRM4, stimulates MEAF6-1 splicing. Enhanced MEAF6-1 expression in prostate adenocarcinoma cell lines does not induce neuroendocrine trans-differentiation of these cells. Rather, it stimulates cell proliferation, anchorage-independent cell growth, invasion, and xenograft tumor growth. Gene microarray identified that these MEAF6-1 actions are in part mediated by the ID1 and ID3 genes. These findings suggest that the MEAF6-1 variant does not induce neuroendocrine differentiation of prostate cancer cells, but facilitates t-NEPC progression through accelerating proliferation of cells that have acquired neuroendocrine phenotypes.
Citation Format: Ahn R. Lee, Yinan Li, Ning Xie, Colin C. Collins, Xuesen Dong. Alternative splicing of the MEAF6 gene promotes neuroendocrine prostate cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3395. doi:10.1158/1538-7445.AM2017-3395
Abstract 340: SRMS regulates normal and oncogenic KIT signaling
Authors: Nagaraj Sachin Raj M , Kazi Julhash U. , Rönnstrand Lars 
Published: July 2017

Abstract
SRMS (Src-related tyrosine kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites) belongs to a family of non-receptor tyrosine kinases, which harbours a Src homology 3 and a Src homology 2, as well as a protein kinase domain. SRMS was first identified in a screen for the genes that regulate the growth and differentiation of neuroepithelial cells. SRMS, however, is an understudied member of this family. The present study was undertaken in order to explore the role of SRMS in signaling downstream of KIT. The receptor tyrosine kinase KIT, also known as the stem cell factor receptor, plays a key role in several developmental processes and have been implicated in many human cancers such as gastrointestinal stromal tumors, acute myeloid leukemia and testicular carcinoma. To understand the role of SRMS in KIT signaling, we generated Ba/F3 cell lines overexpressing KIT and SRMS. We observed that SRMS regulates normal and oncogenic KIT signaling differentially with respect to cell proliferation and apoptosis. SRMS association triggers KIT ubiquitination which in turn downregulates the receptor. Further, expression of SRMS downregulates wild-type KIT-mediated phosphorylation of AKT, ERK1/2, p38. Taken together the data demonstrates that SRMS regulates both normal KIT and an oncogenic mutant of KIT, and have differential impact on receptor downstream signaling.
Citation Format: Sachin Raj M Nagaraj, Julhash U. Kazi, Lars Rönnstrand. SRMS regulates normal and oncogenic KIT signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 340. doi:10.1158/1538-7445.AM2017-340
Abstract 3410: Phenotypic characterization of allelic variation within the HEAT repeats of the mechanistic target of rapamycin
Authors: Wiley Patricia A. , Gary Joy , Phyo Zaw , Zhang Shuling , Sciorillo Amanda , Fraizer Dorian 
Published: July 2017

Abstract
The mammalian target of rapamycin (mTOR), a protein in the phosphoinositide 3-kinase (PI3K) pathway important to cell cycle regulation, is frequently activated in cancer. This signaling pathway regulates cell growth and metabolism, and when dysregulated in cancer, it contributes to tumor angiogenesis and growth. mTOR contains two distinct complexes, MTORC1, and MTORC2. MTORC1 plays a role in biosynthesis, while MTORC2 helps with cellular metabolism. It has been shown that mTOR knockout models are embryonically lethal to mice. However, lower levels of functional mTOR have been shown to be beneficial and slow cancer progression. Allelic variation occurs within inbred strains of mice, including BALB/c mice. One allelic variant in mTOR, R628C, which contributes to tumor susceptibility has been identified in BALB/c mice. This single amino acid change occurs in the HEAT repeats of mTOR. HEAT repeats have been shown to facilitate binding partner interactions, dimerization, and localization. Studies on mutations found within the HEAT repeats in several proteins have altered protein function and emphasize the structural importance of HEAT repeats. The goal of this study is to further elucidate the functional significance of HEAT repeats in TOR function and how allelic variation in the HEAT repeats may contribute to tumor susceptibility. Characterization of this allelic variant has shown stress inputs, such as irradiation, lead to a more severe phenotype and reduced mTORC1/2 signaling. Subsequent in vitro studies using a tetracycline inducible expression system (T-RExTM) have shown differential binding to mTORC1/2 complex partners in cells expressing the Balb/c allele. Additional studies are being performed to assess other complex binding partners, dimerization state and localization of the allelic variant. Our findings will model mTOR signaling activation mechanisms in humans to aid in development of new cancer treatments.
Note: This abstract was not presented at the meeting.
Citation Format: Patricia A. Wiley, Joy Gary, Zaw Phyo, Shuling Zhang, Amanda Sciorillo, Dorian Fraizer. Phenotypic characterization of allelic variation within the HEAT repeats of the mechanistic target of rapamycin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3410. doi:10.1158/1538-7445.AM2017-3410
Abstract 3415: RNF43 somatic mutations in endometrioid ovarian cancers occur in the setting of synchronous endometrioid endometrial cancers
Authors: Levine Defne L. , Dao Fanny , Olvera Narciso , LaVigne Katherine , Solit David B. , Jelinic Petar 
Published: July 2017

Abstract
Introduction: Somatic frameshift mutations in RNF43 have previously been filtered out in cancer genome sequencing projects given that they occur in homopolymer tracts and resemble polymerase slippage errors. Two RNF43 hotspot mutations have been identified and validated in endometrioid endometrial cancer (EEC) and appear to negatively regulate Wnt signaling. These frameshift mutations occur at codons R117 and G659. Due to shared clinical and morphologic features of EEC and endometrioid ovarian cancer (EmOC), we determined the frequency of RNF43 somatic mutations in EmOC.
Methods: We reviewed the clinical and pathologic features of EmOC samples diagnosed from 2006 to 2015, retrieved from laboratory databases and institutional archives. DNA was extracted from formalin-fixed, paraffin-embedded tumor samples using standard protocols. Sanger and next-generation sequencing (NGS) were used to screen for hotspot mutations at codons R117 and G659 with custom designed primers. NGS at each hotspot was covered with a minimum sequencing depth of 400X.
Results: Forty-seven EmOC patients with available tumor specimens were identified and included in the analysis. The median age at diagnosis was 55 years old (range 34-84). The majority of patients had FIGO stage I or stage II disease (n=38, 81%). Thirteen (28%) patients had synchronous endometrial endometrioid or mixed histology tumors. Two (4.3%) RNF43 somatic mutations at codon G659 were identified in both Sanger and NGS from the EmOC tumor specimens. No mutations at codon R117 were identified. The allele fractions of the G659 mutations were 4.3% and 2.8% seen in 33 and 18 reads with a coverage of 775X and 646X, respectively. A review of pathology reports indicated that both mutated samples had synchronous EECs. These two mutated samples represent 15.4% of cases diagnosed with synchronous EmOC and EEC in this cohort.
Conclusions: RNF43 somatic mutations are uncommon in EmOCs and associated with synchronous EECs. Recent massively parallel sequencing data suggests that EmOCs in the setting of synchronous EECs are clonally related and disseminated cells are related to nearby anatomic structures. Our data supports that RNF43 somatic mutations in EmOC are clonally expanded from EECs likely through trans-tubal migration.
Citation Format: Defne L. Levine, Fanny Dao, Narciso Olvera, Katherine LaVigne, David B. Solit, Petar Jelinic. RNF43 somatic mutations in endometrioid ovarian cancers occur in the setting of synchronous endometrioid endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3415. doi:10.1158/1538-7445.AM2017-3415
Abstract 3416: Clarifying the biological significance of the CHK2 K373E somatic mutation discovered in The Cancer Genome Atlas database
Authors: Higashiguchi Masayoshi , Nagatomo Izumi , Kijima Takashi , Morimura Osamu , Miyake Kotaro , Minami Toshiyuki , Koyama Shohei , Hirata Haruhiko , Iwahori Kota , Takimoto Takayuki , Takeda Yoshito , Kida Hiroshi , Kumanogoh Atsushi 
Published: July 2017

Abstract
Identification of somatic mutations that contribute to cancer development leads not only to more precise understanding of cancer pathogenesis, but also development of novel molecular targeted therapies. Analyses of cancer genomes using high-throughput sequencing technology are currently conducted as international collaborative research projects, and the results of those analyses are deposited in public databases, allowing everyone in the world to access to these data.
To identify a somatic mutation that plays an important role in cancer pathogenesis, we counted the occurrences of each somatic mutation found in the TCGA lung adenocarcinoma dataset and became interested in the CHK2 K373E mutation (c1117A&gt;G), which was present in 31 of 542 patients. The K373E mutation impaired CHK2 autophosphorylation at Thr383 and Ser516. In vitro kinase assay revealed that the K373E mutation markedly attenuates CHK2 kinase activity. Growth curves showed that wild-type CHK2 substantially suppressed cell proliferation, but this effect was lost in the K373E mutant in HCT-15 harboring tetracycline-inducible CHK2. Clonogenic assays revealed that wild-type CHK2 promoted survival after ionizing radiation and this pro-survival function was impaired in K373E CHK2. The results of western blotting and RT-PCR suggested that the p53-independent induction of p21 by CHK2 might underlie these effects.
Therefore, we identified a somatic mutation that contributes to cancer pathogenesis, using information in a public database. This kind of attempt is expected to lead to discovering new 'driver' mutations in the future.
Citation Format: Masayoshi Higashiguchi, Izumi Nagatomo, Takashi Kijima, Osamu Morimura, Kotaro Miyake, Toshiyuki Minami, Shohei Koyama, Haruhiko Hirata, Kota Iwahori, Takayuki Takimoto, Yoshito Takeda, Hiroshi Kida, Atsushi Kumanogoh. Clarifying the biological significance of the CHK2 K373E somatic mutation discovered in The Cancer Genome Atlas database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3416. doi:10.1158/1538-7445.AM2017-3416
Abstract 3418: Additional mutation in PTPN11 gene promotes tumorigenesis of the NF1 gene mutated cells
Authors: Arima Yoshimi , Harigai Ritsuko , Sato Ryo , Takenouchi Toshiki , Kosaki Kenjiro , Saya Hideyuki 
Published: July 2017

Abstract
The NF1 tumor suppressor gene encodes neurofibromin and is a functional Ras GTPase-activating protein (RasGAP) involved in negatively regulating the Ras signal by accelerating the conversion of activated Ras-GTP to inactive Ras-GDP. NF1 gene germline mutations cause Neurofibromatosis type 1 (NF1, von Recklinghausen disease). We hypothesized that additional genetic alterations promote the malignancy of NF1-associated tumors. To test our hypothesis, we inoculated a GFP-labeled human NF1-deficient cell line, sNF96.2-GFP, which has a frame-shift mutation (c.3683delC, p.Asn1229MetfsTer11) in the NF1 gene, into the renal sub-capsules of immunodeficient mice. A subclonal cell line, the A-1 cell, was established from the developed tumor. We found that A-1 cells show much higher tumorigenic activity and phosphorylation status of MEK and Akt than the parental sNF96.2-GFP cells. We analyzed the genomic DNA of both the sNF96.2 and the A-1 cells by using the next-generation sequencing and our medical exome panel of 4813 genes, which are known to be responsible for most human genetic disorders. We identified 18 heterozygous variants within coding regions of 17 genes that were present in the A-1 cells, but not in the original sNF96.2 cells. We found a single base substitution (c.1508G&gt;T, p.Gly503Val) in the PTPN11 gene, which encodes the tyrosine phosphatese SHP-2, and is associated with the regulation of the Ras signaling pathway. It is critical to note that constitutional gain-of-function mutations in the PTPN11 gene cause Noonan Syndrome in humans due to activation of the Ras pathway. To determine the role of PTPN11 mutation in NF1-associated tumors, we established a cell line overexpressing PTPN11mut in sNF96.2-GFP cells. We inoculated parental cells and PTPN11mut cells into the subcutaneous of nude mice, and we found that PTPN11mut cells show much higher tumorigenic activity than the parental sNF96.2-GFP cells. Our data suggests that this additional gene mutation in PTPN11 promotes the malignant characteristics of NF1-associated tumors.
Citation Format: Yoshimi Arima, Ritsuko Harigai, Ryo Sato, Toshiki Takenouchi, Kenjiro Kosaki, Hideyuki Saya. Additional mutation in PTPN11 gene promotes tumorigenesis of the NF1 gene mutated cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3418. doi:10.1158/1538-7445.AM2017-3418