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e14755
Background: Rare cancers lack standard or investigational therapeutic options. Next-generation sequencing (NGS) has provided new insight into personalized medicine. We sought to ...catalog genetic alterations detected from tissue NGS in rare cancers and to assess their clinical utility. Methods: This was a single-center series with patients (pts) who had been referred to the National Cancer Center Hospital (Tokyo, Japan). Patients with a metastatic/unresectable disease who underwent comprehensive genomic profiling of their tumor for the purpose of precision treatment were first identified (approved by the NCCH institutional review board). Among them, pts diagnosed as rare cancers, defined as an incidence of < 6/100,000 pts/year, were included in this study. Prospectively consentedpts had tissue NGS testing (NCC Oncopanel) for point mutations, select indels, copy number amplifications, fusions. Alterations were assessed for incidence according to cancer type, functional impact, therapeutic implications. Results: Between July 2013 to April 2016, 289 pts were enrolled. 217 pts with sufficient tissue sample succeeded in sequencing. 78% (169/217) had a least one alteration most likely pathogenic. Most common alterations were TP53, PIK3CA, BRCA2, KRAS, MYC, ERBB2, RB1, CCND1, and ARID1A. 114/289 pts (39%) were classified as rare cancers: gynecological cancers (44 pts), cholangiocarcinoma (20), sarcomas (16), NET (9), thymic carc. (6), mesothelioma (3), CUP (2), urachal carc. (2), GIST (1), thyroid carc. (1), other super-rare cancers (10). 86 pts succeeded in sequencing; 72 % (62/86) had a variant most likely pathogenic. Most common alterations were TP53, KRAS, BRCA2, FBXW7, NF1, PIK3CA, ALK, BRCA1, and CCND1. 23 pts (27%) of rare cancer pts received a targeted drug of which 9 (10%) were “matched” to a detected alteration. Response rate to the “matched” therapy was CR/PR/SD/PD = 0/1/5/3 (ORR 11%). Conclusions: Genomic alterations were equally detected in rare cancers as well as common cancers, however showed different alteration profiles. Rare cancer pts receiving “matched” therapy and the response rate to those remain low, suggesting a need for a more efficient treatment development platform. Clinical trial information: UMIN000011141.
Pancreatic ductal adenocarcinoma (PDA) is associated with very poor prognoses. Therefore, new therapies and preclinical models are urgently needed. In the present study, we sought to develop more ...realistic experimental models for use in PDA research.
We developed patient-derived xenografts (PDXs), established PDX-derived cell lines (PDCLs), and generated cell line-derived xenografts (CDXs), which we integrated to create 13 matched "trios" - i.e., patient-derived tumor models of PDA. We then compared and contrasted histological and molecular alterations between these three model systems.
Orthotopic implantation (OI) of the PDCLs resulted in tumorigenesis and metastases to the liver and peritoneum. Morphological comparisons of OI-CDXs and OI-PDXs with passaged tumors revealed that the histopathological features of the original tumor were maintained in both models. Molecular alterations in PDX tumors (including those to KRAS, TP53, SMAD4, and CDKN2A) were similar to those in the respective PDCLs and CDX tumors. When gene expression levels in the PDCLs, ectopic tumors, and OI tumors were compared, the distant metastasis-promoting gene CXCR4 was specifically upregulated in OI tumors, whose immunohistochemical profiles suggested epithelial-mesenchymal transition and adeno-squamous trans-differentiation.
These patient-derived tumor models provide useful tools for monitoring responses to antineoplastic agents and for studying PDA biology.
Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are closely related tumors commonly characterized by
MDM2/CDK4
gene amplification, and lack clinically effective ...treatment options when inoperable. To identify novel therapeutic targets, we performed targeted genomic sequencing analysis of 19 WDLPS and 37 DDLPS tumor samples using a panel of 104 cancer-related genes (NCC oncopanel v3) developed specifically for genomic testing to select suitable molecular targeted therapies. The results of this analysis indicated that these sarcomas had very few gene mutations and a high frequency of amplifications of not only
MDM2
and
CDK4
but also other genes. Potential driver mutations were found in only six (11%) samples; however, gene amplification events (other than
MDM2
and
CDK4
amplification) were identified in 30 (54%) samples. Receptor tyrosine kinase (RTK) genes in particular were amplified in 18 (32%) samples. In addition, growth of a WDLPS cell line with
IGF1R
amplification was suppressed by simultaneous inhibition of CDK4 and IGF1R, using palbociclib and NVP-AEW541, respectively. Combination therapy with CDK4 and RTK inhibitors may be an effective therapeutic option for WDLPS/DDLPS patients with RTK gene amplification.
Oral conditions are relatively common in patients with inflammatory bowel disease (IBD). However, the contribution of oral maladies to gut inflammation remains unexplored. Here, we investigated the ...effect of periodontitis on disease phenotypes of patients with IBD. In all, 60 patients with IBD (42 with ulcerative colitis UC and 18 with Crohn's disease CD) and 45 healthy controls (HCs) without IBD were recruited for this clinical investigation. The effects of incipient periodontitis on the oral and gut microbiome as well as IBD characteristics were examined. In addition, patients were prospectively monitored for up to 12 months after enrollment. We found that, in both patients with UC and those with CD, the gut microbiome was significantly more similar to the oral microbiome than in HCs, suggesting that ectopic gut colonization by oral bacteria is increased in patients with IBD. Incipient periodontitis did not further enhance gut colonization by oral bacteria. The presence of incipient periodontitis did not significantly affect the clinical outcomes of patients with UC and CD. However, the short CD activity index increased in patients with CD with incipient periodontitis but declined or was unchanged during the study period in patients without periodontitis. Thus, early periodontitis may associate with worse clinically symptoms in some patients with CD.
The majority of gastrointestinal stromal tumors (GIST) can be cured by surgery alone, but relapse occurs in 20% to 40% of cases. GISTs are considered to invariably arise through gain of function KIT ...or PDGFA mutation of the interstitial cells of Cajal (ICC). However, the genetic basis of the malignant progression of GISTs are poorly understood.
The expression levels of 54,613 probe sets in 32 surgical samples of untreated GISTs of the stomach and small intestine were analyzed with oligonucleotide microarrays. The representative GeneChip data were validated by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry.
Unbiased hierarchical clustering consistently separated the 32 cases of GIST into two major classes according to tumor site. The two major classes were further separated into novel subclasses, which were significantly correlated with various pathological prognostic parameters, the frequency of metastasis (P < .05), and clinical outcome. Immunohistochemical analysis of 152 independent patients with gastric GISTs revealed that the expression of dipeptidyl peptidase IV (T-cell activation antigen CD26) protein was significantly associated with poorer overall and disease-free survival (P < .00001).
CD26 appears to be a reliable biomarker of malignant GISTs of the stomach. The postoperative recurrence rate of CD26-negative cases was as low as 2.0% (two of 102). Therefore, postoperative follow-up of such patients might be made less intensive. CD26 may play an important role in the malignant progression of gastric GISTs and serve as a therapeutic target.
Advanced cancer genomics technologies are now being employed in clinical sequencing, where next-generation sequencers are used to simultaneously identify multiple types of DNA alterations for ...prescription of molecularly targeted drugs. However, no computational tool is available to accurately detect DNA alterations in formalin-fixed paraffin-embedded (FFPE) samples commonly used in hospitals. Here, we developed a computational tool tailored to the detection of single nucleotide variations, indels, fusions, and copy number alterations in FFPE samples. Elaborated multilayer noise filters reduced the inherent noise while maintaining high sensitivity, as evaluated in tumor-unmatched normal samples using orthogonal technologies. This tool, cisCall, should facilitate clinical sequencing in everyday diagnostics. It is available at https://www.ciscall.org .
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The febrile response is a complex physiological reaction to disease, including a cytokine-mediated increase in body temperature and the activation of inflammatory systems. Fever has beneficial roles ...in terms of disease prognosis, partly by suppressing the expression of inflammatory cytokines. However, the molecular mechanisms underlining the fever-mediated suppression of inflammatory gene expression have not been clarified. In this study, we showed that heat shock suppresses LPS-induced expression of IL-6, a major pyrogenic cytokine, in mouse embryonic fibroblasts and macrophages. Heat shock transcription factor 1 (HSF1) activated by heat shock induced the expression of activating transcription factor (ATF) 3, a negative regulator of IL-6, and ATF3 was necessary for heat-mediated suppression of IL-6, indicating a fever-mediated feedback loop consisting of HSF1 and ATF3. A comprehensive analysis of inflammatory gene expression revealed that heat pretreatment suppresses LPS-induced expression of most genes (86%), in part (67%) via ATF3. When HSF1-null and ATF3-null mice were injected with LPS, they expressed much higher levels of IL-6 than wild-type mice, resulting in an exaggerated febrile response. These results demonstrate a novel inhibitory pathway for inflammatory cytokines.
In lung cancer progression, p53 mutations are more often observed in invasive tumors than in noninvasive tumors, suggesting that p53 is involved in tumor invasion and metastasis. To understand the ...nature of p53 function as a tumor suppressor, it is crucial to elucidate the detailed mechanism of the alteration in epithelial cells that follow oncogenic KRAS activation and p53 inactivation. Here, we report that KRAS activation induces epithelial-mesenchymal transition and that p53 inactivation is required for cell motility and invasiveness. Furthermore, TSPAN2, a transmembrane protein, is responsible for cell motility and invasiveness elicited by p53 inactivation. TSPAN2 is highly expressed in p53-mutated lung cancer cells, and high expression of TSPAN2 is associated with the poor prognosis of lung adenocarinomas. TSPAN2 knockdown suppresses metastasis to the lungs and liver, enabling prolonged survival. TSPAN2 enhances cell motility and invasiveness by assisting CD44 in scavenging intracellular reactive oxygen species.
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•KRAS activation is linked to EMT in small airway epithelial cells•p53 inactivation, but not KRAS activation, enhances cell invasion and motility•TSPAN2 is identified as a factor responsible for invasion, motility, and metastasis•TSPAN2 assists a ROS-scavenging function of CD44 to promote cell invasion
Enari and colleagues investigate the detailed mechanism of epithelial cell alteration during lung cancer progression. They show that KRAS activation induces epithelial-mesenchymal transition and that p53 inactivation is required for cell motility and invasiveness. They find that TSPAN2 is responsible for the cell motility and invasiveness elicited by p53 inactivation and that TSPAN2 scavenges intracellular reactive oxygen species in collaboration with CD44. These data suggest that TSPAN2 may be a potential target for lung cancer therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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