ResearchPad - tumor-markers-and-signatures https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Circulating ensembles of tumor‐associated cells: A redoubtable new systemic hallmark of cancer]]> https://www.researchpad.co/article/elastic_article_6994 What's new?

Circulating Ensembles of Tumor Associated Cells (C‐ETACs) comprised of tumor emboli, immune cells, and fibroblasts pose well‐recognized risks of thrombosis and aggressive metastasis. However, the detection and characterization of C‐ETACs have been impaired by methodological difficulties. Here, the authors have developed a label‐free non‐mechanical process that permits enrichment of viable apoptosis‐resistant C‐ETACs from peripheral blood. They show that heterotypic C‐ETACs are not merely incidental findings in cancer but rather a systemic manifestation of malignancy. C‐ETACs are present in a significant proportion of all solid organ malignancies and are rare in asymptomatic individuals. Monitoring of C‐ETACs could help inform cancer management.

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<![CDATA[A novel circulating tumor cell subpopulation for treatment monitoring and molecular characterization in biliary tract cancer]]> https://www.researchpad.co/article/elastic_article_6983 What's new?

Late diagnosis of advanced biliary tract cancer (BTC) limits tissue biopsy for molecular analyses, resulting in missed opportunities for personalized therapy. Meanwhile, circulating tumor cells (CTCs) are promising tissue surrogates, but current CTC‐based methods detect only a fraction of BTC patients. Here, using unbiased CTC‐enrichment, coupled with identification and recovery of single cells, the authors identify a novel CTC subpopulation detectable in all BTC patient samples prior to treatment. The presence of even a single epithelial CTC was associated with reduced disease‐specific survival. This novel approach to CTC detection could be useful for treatment‐response monitoring and molecular characterization in BTC.

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<![CDATA[Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma]]> https://www.researchpad.co/article/N8ece76b8-405c-46e4-a63f-98999632661a

Molecular changes occurring during invasion and clinical progression of cancer are difficult to study longitudinally in patient‐derived material. A unique feature of urothelial bladder cancer (UBC) is that patients frequently develop multiple nonmuscle invasive tumors, some of which may eventually progress to invade the muscle of the bladder wall. Here, we use a cohort of 73 patients that experienced a total of 357 UBC diagnoses to study the stability or change in detected molecular alterations during cancer progression. The tumors were subtyped by gene expression profiling and analyzed for hotspot mutations in FGFR3, PIK3CA and TERT, the most frequent early driver mutations in this tumor type. TP53 alterations, frequent in advanced UBC, were inferred from p53 staining pattern, and potential genomic alterations were inferred by gene expression patterns at regions harboring frequent copy number alterations. We show that early driver mutations were largely preserved in UBC recurrences. Changes in FGFR3, PIK3CA or TERT mutation status were not linked to changes in molecular subtype and aggressive behavior. Instead, changes into a more aggressive molecular subtype seem to be associated with p53 alterations. We analyze changes in gene expression from primary tumors, to recurrences and progression tumors, and identify two modes of progression: Patients for whom progression is preceded by or coincides with a radical subtype shift, and patients who progress without any systematic molecular changes. For the latter group of patients, progression may be either stochastic or depending on factors already present at primary tumor initiation.

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<![CDATA[Approaches to triage optimization in HPV primary screening: Extended genotyping and p16/Ki‐67 dual‐stained cytology—Retrospective insights from ATHENA]]> https://www.researchpad.co/article/Nb7600f63-2a5a-41e4-ae18-a4c51b827e86

The objective of our study was to assess the performance of different triage strategies for high‐risk human papillomavirus (hrHPV)‐positive results utilizing either extended genotyping or a p16/Ki‐67 dual‐stained cytology (DS) approach, with or without partial genotyping. A subset of women with hrHPV infections participating in the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study were analyzed to determine the number of cervical intraepithelial neoplasia grade 3 or worse (≥CIN3) cases detected, and the absolute risk for ≥CIN3 of each genotype. A clinical utility table was constructed to compare the impact of different triage strategies. In all, 2,339 women with single‐genotype hrHPV infections were identified. Among these were 171 ≥CIN3 cases. The U.S. Food and Drug Administration (FDA)‐approved algorithm (HPV16/18 positive, or 12‐other hrHPV positive and Pap positive, i.e., ≥ atypical squamous cells of undetermined significance) for primary HPV screening detected 132/171 (77.2%) ≥CIN3 cases and required 964 colposcopies (colposcopies per ≥CIN3 ratio: 7.3). An approach that uses DS instead of cytology in the FDA‐approved algorithm detected 147/171 (86.0%) ≥CIN3 cases, requiring 1,012 colposcopies (ratio: 6.9). Utilizing DS for triage of all hrHPV‐positive women identified 126/171 (73.7%) ≥CIN3 cases, requiring 640 colposcopies (ratio: 5.1). A strategy that detected HPV16/18/31/33/35+ captured 130/171 (76.0%) ≥CIN3 cases, requiring 1,025 colposcopies (ratio: 7.9). Inclusion of additional genotypes resulted in greater disease detection at the expense of higher colposcopy ratios. Substituting cytology with a DS triage approach improved disease detection and the colposcopy detection rate. Further reduction of colposcopy rates can be achieved by using DS without partial genotyping. Extended genotyping strategies can identify a comparable number of cases but requires an increased number of colposcopies.

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<![CDATA[Characterization of transcriptomic signature of primary prostate cancer analogous to prostatic small cell neuroendocrine carcinoma]]> https://www.researchpad.co/article/N326f3554-900f-4a84-8ff9-47ca8e58001b

Prostatic small cell neuroendocrine carcinoma (SC/NE) is well studied in metastatic castration‐resistant prostate cancer; however, it is not well characterized in the primary setting. Herein, we used gene expression profiling of SC/NE prostate cancer (PCa) to develop a 212 gene signature to identify treatment‐naïve primary prostatic tumors that are molecularly analogous to SC/NE (SC/NE‐like PCa). The 212 gene signature was tested in several cohorts confirming similar molecular profile between prostatic SC/NE and small cell lung carcinoma. The signature was then translated into a genomic score (SCGScore) using modularized logistic regression modeling and validated in four independent cohorts achieving an average AUC >0.95. The signature was evaluated in more than 25,000 primary adenocarcinomas to characterize the biology, prognosis and potential therapeutic response of predicted SC/NE‐like tumors. Assessing SCGScore in a prospective cohort of 17,967 RP and 6,697 biopsy treatment‐naïve primary tumors from the Decipher Genomic Resource Information Database registry, approximately 1% of the patients were found to have a SC/NE‐like transcriptional profile, whereas 0.5 and 3% of GG1 and GG5 patients respectively showed to be SC/NE‐like. More than 80% of these patients are genomically high‐risk based on Decipher score. Interrogating in vitro drug sensitivity analyses, SC/NE‐like prostatic tumors showed higher response to PARP and HDAC inhibitors.

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<![CDATA[KRAS driven expression signature has prognostic power superior to mutation status in non‐small cell lung cancer]]> https://www.researchpad.co/article/5b36bba4463d7e5cdec78da1

KRAS is the most frequently mutated oncogene in non‐small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer.

We divided NSCLC patients with mutation and RNA‐seq data into KRAS mutated and wild type groups. Mann‐Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a “transcriptomic fingerprint” of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using univariate and multivariate Cox regression analysis.

Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3 and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p < 0.01). The KRAS signature also remained significant (p < 0.01) in a multivariate analysis including age, gender, smoking history and tumor stage.

We generated a “surrogate signature” of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself.

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