Identification and Validation of a Biomarker Signature in Patients With Resectable Pancreatic Cancer via Genome-Wide Screening for Functional Genetic Variants

Dimitrakopoulos, Christos; Vrugt, Bart; Flury, Renata; Schraml, Peter; Knippschild, Uwe; Wild, Peter J.; Hoerstrup, Simon P.; Henne‐Bruns, Doris; Wuerl, Peter; Graf, Rolf; Breitenstein, Stefan; Bond, Gareth L.; Beerenwinkel, Niko; Grochola, Lukasz F.

doi:10.1001/jamasurg.2019.0484

Cited by 32 publications

(27 citation statements)

References 52 publications

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“…A recent study of 195 patients in the European cohort with pancreatic ductal adenocarcinoma indicated singlenucleotide polymorphisms (SNP) in YKL39 that was associated with tumor-associated survival after pancreatic resection. Individuals who were homozygous for the minor A allele of SNP rs684559 (YKL-39) had an increased risk for tumorassociated death compared with patients with at least 1 G allele of rs684559 (protective phenotype) (114). Our recent study for the first time demonstrated the prognostic role of YKL-39 in cancer metastasis in breast cancer patients after neoadjuvant therapy (33).…”

Section: Chemotherapy Tams and Chitinase-like Proteinsmentioning

confidence: 90%

YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer

2020

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YKL-39 belongs to the evolutionarily conserved family of Glyco_18-containing proteins composed of chitinases and chitinase-like proteins. Chitinase-like proteins (CLPs) are secreted lectins that lack hydrolytic activity due to the amino acid substitutions in their catalytic domain and combine the functions of cytokines and growth factors. One of the major cellular sources that produce CLPs in various pathologies, including cancer, are macrophages. Monocytes recruited to the tumor site and programmed by tumor cells differentiate into tumor-associated macrophages (TAMs), which are the primary source of pro-angiogenic factors. Tumor angiogenesis is a crucial process for supplying rapidly growing tumors with essential nutrients and oxygen. We recently determined that YKL-39 is produced by tumor-associated macrophages in breast cancer. YKL-39 acts as a strong chemotactic factor for monocytes and stimulates angiogenesis. Chemotherapy is a common strategy to reduce tumor size and aggressiveness before surgical intervention, but chemoresistance, resulting in the relapse of tumors, is a common clinical problem that is critical for survival in cancer patients. Accumulating evidence indicates that TAMs are essential regulators of chemoresistance. We have recently found that elevated levels of YKL-39 expression are indicative of the efficiency of the metastatic process in patients who undergo neoadjuvant chemotherapy. We suggest YKL-39 as a new target for anti-angiogenic therapy that can be combined with neoadjuvant chemotherapy to reduce chemoresistance and inhibit metastasis in breast cancer patients.

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Section: Chemotherapy Tams and Chitinase-like Proteinsmentioning

confidence: 90%

YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer

2020

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“…On the other hand, the lack of information on risk stratification brings the merits of limitations for clinicians to conduct individualized treatment strategies. Recently, several gene expression biomarker signatures that based on gene expression profiling (GEP) and whole genome methylation profiling have been build and used to predict the prognosis of human cancer [13][14][15][16], but none gene signatures have been utilized for PTCLs patients.…”

Section: To Date the Most Widely Used Model For Evaluating The Prognmentioning

confidence: 99%

Prognostic and predictive value of a mRNA signature in peripheral T-cell lymphomas: a mRNA expression analysis

Kuang

Xie

et al. 2020

Preprint

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Background: Current international prognostic index is widely questioned on the risk stratification of peripheral T-cell lymphoma and do not accurately predict the outcome for patients. We postulated that multiple mRNAs could combined into a single model to improve risk stratification and to guide Clinicians implementing personalized therapeutic regimen for these patients. Methods: The gene expression profiles with clinical characteristics were selected and downloaded from the Gene Expression Omnibus (GEO) database. weighted gene co-expression network analysis (WGCNA) was used to screening genes in selected module which most closely related to PTCLs. Then build a gene classifier using a Lasso Cox Regression model and validated the prognostic accuracy of this mRNA signature in an internal validation cohort. Finally, a prognostic nomogram was constructed and performance was assessed by calibration plot and the concordance index (C-index). Results: 799 WGCNA-selected mRNAs in black module were identified and a mRNA signature which based on DOCK2, GSTM1, H2AFY, KCNAB2, LAPTM5 and SYK for PTCLs was developed. Significantly statistical difference can be seen in overall survival of PTCLs between low risk group and high risk group(training set :hazard ratio [HR] 4.3, 95% CI 2.4–7.4, p<0·0001; internal testing set :hazard ratio [HR] 2.4, 95% CI 1.2–4.8, p<0·01).Multivariate regression demonstrated that the signature was an independently prognostic factor contrast to age and gender. Furthermore, receiver operating characteristic analysis indicated that this signature exhibited excellent diagnostic efficiency for overall survival. Moreover, the nomogram which combined the six-genes risk signature and multiple clinical factors suggesting that predicted survival probability agreed well with the actual survival probability. Conclusions: The signature is a reliable prognostic tool for patients with PTCLs and it has the potential for clinicians to implement personalized therapeutic regimen for patients with stage PTCLs.

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“…For this study, we selected 25 SNPs reported to be associated with PA susceptibility in previously studies [22][23][24][25][26][27] to look for in the Brazilian population: rs11655237, rs2736098, rs351365, rs3790844, rs1486134, rs16986825, rs9581943, rs35226131, rs1561927, rs9854771, rs73328514, rs7310409, rs1517037, rs2853677, rs2941471, rs6971499, rs10991043, rs4016812, rs13303010, rs9543325, rs4795218, rs7190458, rs10094872, rs684559 and rs353630.…”

Section: Snp Selectionmentioning

confidence: 99%

Susceptibility Loci for Pancreatic Cancer in the Brazilian Population

Aoki

Stein

Oliveira

et al. 2020

Preprint

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Background: Pancreatic adenocarcinoma (PA) is a very aggressive cancer and has one of the poorest prognoses. Usually the diagnosis is late and resistant to conventional treatment. Environmental and genetic factors contribute to the etiology, such as tobacco and alcohol consumption, chronic pancreatitis, diabetes and obesity. Somatic mutation in pancreatic cancer cells are known and SNP profile by GWAS could access novel genetic risk factors for this disease in different population context. Here we describe a SNP panel for Brazilian pancreatic cancer, together with clinical and epidemiological data. Methods: 78 pancreatic adenocarcinoma and 256 non-pancreatic cancer subjects had 25 somatic SNP genotyped by real-time PCR. Unconditional logistic regression methods were used to assess the main effects on PA risk, using allelic, co-dominant and dominant inheritance models. Results: 9 SNPs were nominally associated with pancreatic adenocarcinoma risk, with 5 of the minor allele conferring protective effect while 4 related as risk factor. In epidemiological and clinical data, tobacco, diabetes and pancreatitis history were significant related to pancreatic adenocarcinoma risk. Conclusion: We could assess for the first time some SNPs related with PA in Brazilian populations, a result that could be used for genetic screening in risk population such as familial pancreatic cancer, smokers, alcohol users and diabetes patients.

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Identification and Validation of a Biomarker Signature in Patients With Resectable Pancreatic Cancer via Genome-Wide Screening for Functional Genetic Variants

Cited by 32 publications

References 52 publications

YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer

YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer

Prognostic and predictive value of a mRNA signature in peripheral T-cell lymphomas: a mRNA expression analysis

Susceptibility Loci for Pancreatic Cancer in the Brazilian Population

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