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Background: PETCAM was a randomized trial evaluating the effect of PET-CT compared to conventional imaging (control) on the surgical management of patients with resectable ...colorectal cancer liver metastases (CRLM). It concluded that PET-CT did not result in frequent change in surgical management (8·0%, 21/263) with only 2·7% (7/263) avoidance of liver resections. In this study we conducted a cost analysis of these two arms up to one year following randomization. Methods: Health care utilization was collected for all study participants. Unit costs for hospitalization, physician services, chemotherapy and outpatient radiological and endoscopic procedures were obtained from administrative databases. Cost analysis was undertaken from the perspective of a third-party payer (i.e., Ministry of Health). Mean cost with its 95% credible interval was estimated using a Bayesian approach. Results: The estimated mean cost per patient in the PET-CT arm was CAN $45,454 (min-max: 1,340-181,420) and in the control arm, CAN $40,859 (min-max: 279-293,558), with a net difference of CAN $4,327, 95% credible interval -2,207 to 10,614. The primary cost driver was cost of hospitalization for liver surgery (+ $2,997 CAN for the PET-CT arm), mainly due to a longer length of hospital stay for the PET-CT arm compared to control (median 7 days vs. 6 days, P= 0·034) and a higher rate of postoperative complications (52/255, 20% vs. 13/128, 10%, P = 0·014). Baseline characteristics were similar between groups, including a similar number of liver segments involved with cancer, number of segments resected and type of liver resection performed. Conclusions: PET-CT does not appear to provide a significant clinical benefit in the surgical management of patients with resectable CRLM and it is not cost saving compared to control.
Summary
We conducted gene–smoking interaction analysis in GWAS data of pancreati cancer. We found a possible interaction of axon guidance pathway genes with smoking in modifying the risk of ...pancreatic cancer. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer.
Cigarette smoking is the best established modifiable risk factor for pancreatic cancer. Genetic factors that underlie smoking-related pancreatic cancer have previously not been examined at the genome-wide level. Taking advantage of the existing Genome-wide association study (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study in 2028 cases and 2109 controls to examine gene–smoking interactions at pathway/gene/single nucleotide polymorphism (SNP) level. Using the likelihood ratio test nested in logistic regression models and ingenuity pathway analysis (IPA), we examined 172 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, 3 manually curated gene sets, 3 nicotine dependency gene ontology pathways, 17 912 genes and 468 114 SNPs. None of the individual pathway/gene/SNP showed significant interaction with smoking after adjusting for multiple comparisons. Six KEGG pathways showed nominal interactions (P < 0.05) with smoking, and the top two are the pancreatic secretion and salivary secretion pathways (major contributing genes: RAB8A, PLCB and CTRB1). Nine genes, i.e. ZBED2, EXO1, PSG2, SLC36A1, CLSTN1, MTHFSD, FAT2, IL10RB and ATXN2 had P
interaction < 0.0005. Five intergenic region SNPs and two SNPs of the EVC and KCNIP4 genes had P
interaction < 0.00003. In IPA analysis of genes with nominal interactions with smoking, axonal guidance signaling
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P
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12
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7
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and α-adrenergic signaling
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52
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5
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genes were significantly overrepresented canonical pathways. Genes contributing to the axon guidance signaling pathway included the SLIT/ROBO signaling genes that were frequently altered in pancreatic cancer. These observations need to be confirmed in additional data set. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer.
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273
Background: Substantial progress has been made in the understanding of the genomic landscape of PDAC, but the clinical utility of these data remains uncertain. Methods: As part of ...the BC Cancer Personalized Oncogenomics (POG) and PanGen studies, whole genome analysis and transcriptome sequencing were performed on fresh biopsy and blood sample from 47 mPDAC patients. Genomic findings informed therapy choices including potential eligibility for the CCTG PM.1 molecular basket trial. Results: Cohort consists of 53% male, average age 57.8, 34/47 had ≥2 lines of treatment. 37/47 biopsies were from liver and 26/47 were collected pre-treatment. 8/47 (17%) patients had aberrations with strong evidence of clinical actionability. These include 2 germline BRCA2, 1 germline BRCA1, 1 somatic XRCC2 homozygous deletion with strong COSMIC signature 3, all predictive of platinum sensitivity. Patients with XRCC2 deletion and BRCA1 had over 2 years on FOLFIRINOX. Fusions affecting the NRG1 gene were identified in 3 patients, all with KRAS wildtype tumours, which may confer ERRB inhibitor sensitivity. 1/3 NRG1 fusion patients had thus far been treated with the ERBB inhibitor afatinib, with reduction of CA19-9 from >120,000 to 7246 and dramatic response noted on PET CT imaging one month post treatment. One patient had mismatch repair deficiency, and a high mutational burden, suggestive of immune checkpoint inhibitor sensitivity. In total 85% (40/47) sequenced mPDAC patients had potentially actionable mutations which includes CCTG PM.1 trial eligibility: 24/47 with cell cycle dysregulation (CDK4/6 inhibitor arm), 4/47 with high homologous recombination defects (PARP inhibitor arm), 1/47 ERBB2 amplification (anti-HER2 arm), 2/47 high expression of FGFR1 (Sunitinib arm) and 1/47 with high FLT4 and IGF1R expression (Axitinib arm). Conclusions: More routine use of comprehensive genomic analysis should be considered in mPDAC given finding of high degree of actionability. Importantly, a significant proportion (17%) had findings with strong evidence of clinical impact.(NCT02155621, NCT02869802, NCT03297606)
Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian ...randomization (MR) to identify possible new aspirin targets that decrease CRC risk.
Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (
= 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (
= 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).
Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively).
MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis.
Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.
ABSTRACT
Mismatch repair (MMR) gene sequence variants of uncertain clinical significance are often identified in suspected Lynch syndrome families, and this constitutes a challenge for both ...researchers and clinicians. Multifactorial likelihood model approaches provide a quantitative measure of MMR variant pathogenicity, but first require input of likelihood ratios (LRs) for different MMR variation‐associated characteristics from appropriate, well‐characterized reference datasets. Microsatellite instability (MSI) and somatic BRAF tumor data for unselected colorectal cancer probands of known pathogenic variant status were used to derive LRs for tumor characteristics using the Colon Cancer Family Registry (CFR) resource. These tumor LRs were combined with variant segregation within families, and estimates of prior probability of pathogenicity based on sequence conservation and position, to analyze 44 unclassified variants identified initially in Australasian Colon CFR families. In addition, in vitro splicing analyses were conducted on the subset of variants based on bioinformatic splicing predictions. The LR in favor of pathogenicity was estimated to be ∼12‐fold for a colorectal tumor with a BRAF mutation‐negative MSI‐H phenotype. For 31 of the 44 variants, the posterior probabilities of pathogenicity were such that altered clinical management would be indicated. Our findings provide a working multifactorial likelihood model for classification that carefully considers mode of ascertainment for gene testing.
Keywords: pancreatic cancer, patient-derived organoids, transcriptomic signatures, PASS-01 Background: Patients with advanced pancreatic ductal adenocarcinoma (PDAC) continue to have a dire prognosis ...and only a minority of patients is fit enough to receive second-line treatment. Secondary and exploratory objectives include determine the objective response rate, duration of response and overall survival associated with mFFX or GA, whether the chemotherapy sensitivity signature predictions correlate with responders, if PDO transcriptomic profiles parallel those obtained from patient samples, whether GATA6 expression can serve as a biomarker of response 4, the use of serial cell free circulating tumor DNA and circulating tumour cell analysis to identify emerging or de novo resistance and evaluate biomarkers of immune-oncologic sensitivity. At progression, as per RECIST 1.1 criteria, chemotherapy sensitivity signatures (RNA) and/or PDO pharmacotyping and WGS data will be used where possible to guide second-line therapy in an effort to continually provide the most active therapeutic regimens to each patient.
Telomeres cap chromosome ends, protecting them from degradation, double‐strand breaks, and end‐to‐end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an ...RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset‐based meta‐analyses of 204,993 directly‐measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene‐level p value cutoffs ≤3.08 × 10−5). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere‐related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.
What's new?
Variants in several telomere‐related genes have been linked to cancer risk. Here the authors systematically searched for associations between >200,000 variants in 22 of these gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk utilizing a novel ASSociation analysis based on SubSET (ASSET) meta‐analytic approach. They identified several independent variants with a complex association pattern across cancer types, providing the basis for new mechanistic studies into the role of telomere structure and maintenance in cancer.
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