Biallelic mutations in the base excision DNA repair gene MUTYH predispose to colorectal cancer (CRC). Evidence that monoallelic mutations also confer an elevated CRC risk is controversial. Precise ...quantification of the CRC risk and the phenotype associated with MUTYH mutations is relevant to the counseling, surveillance, and clinical management of at-risk individuals.
We analyzed a population-based series of 9,268 patients with CRC and 5,064 controls for the Y179C and G396D MUTYH mutations. We related genotypes to phenotype and calculated genotype-specific CRC risks.
Overall, biallelic mutation status conferred a 28-fold increase in CRC risk (95% CI,17.66 to 44.06); this accounted for 0.3% of CRCs in the cohort. Genotype relative risks of CRC were strongly age dependent, but penetrance was incomplete at age 60 years. CRC that developed in the context of biallelic mutations were microsatellite stable. Biallelic mutation carriers were more likely to have proximal CRC (P = 4.0 x 10(-4)) and synchronous polyps (P = 5.7 x 10(-9)) than noncarriers. The performance characteristics of clinicopathologic criteria for the identification of biallelic mutations are poor. Monoallelic mutation was not associated with an increased CRC risk (odds ratio, 1.07; 95% CI, 0.87 to 1.31).
The high risk and the propensity for proximal disease associated with biallielic MUTYH mutation justify colonoscopic surveillance. Although mutation screening should be directed to patients with APC-negative polyposis and early-onset proximal MSS CRC in whom detection rates will be highest, the expanded phenotype associated with MUTYH mutation needs to be recognized. There is no evidence than monoallelic mutation status per se is clinically important.
Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL ...susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10(-9)), 4q26 (rs6858698, P = 3.07 × 10(-9)), 6q25.2 (IPCEF1, rs2236256, P = 1.50 × 10(-10)) and 7q31.33 (POT1, rs17246404, P = 3.40 × 10(-8)). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 × 10(-7)) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 × 10(-10)) and 8q22.3 (rs2511714, P = 2.90 × 10(-9)). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two ...case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P
c = 7.72 × 10−8 and 2.09 × 10−8, respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk.
Genomewide association studies have identified 10 low-penetrance loci that confer modestly increased risk for colorectal cancer (CRC). Although they underlie a significant proportion of CRC in the ...general population, their impact on the familial risk for CRC has yet to be formally enumerated. The aim of this study was to examine the combined contribution of the 10 variants, rs6983267, rs4779584, rs4939827, rs16892766, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, on familial CRC.
The population-based series of CRC samples included in this study consisted of 97 familial cases and 691 sporadic cases. Genotypes in the 10 loci and clinical data, including family history of cancer verified from the Finnish Cancer Registry, were available. The overall number of risk alleles (0-20) was determined, and its association with familial CRC was analyzed. Excess familial risk was estimated using cancer incidence data from the first-degree relatives of the cases.
A linear association between the number of risk alleles and familial CRC was observed (P = 0.006). With each risk-allele addition, the odds of having an affected first-degree relative increased by 1.16 (95% confidence interval, 1.04-1.30). The 10 low-penetrance loci collectively explain approximately 9% of the variance in familial risk for CRC.
This study provides evidence to support the previous indirect estimations that these low-penetrance variants account for a relatively small proportion of the familial aggregation of CRC.
Our results emphasize the need to characterize the remaining molecular basis of familial CRC, which should eventually yield in individualized targeting of preventive interventions.
The usefulness of opportunistic arrhythmia screening strategies, using an electrocardiogram (ECG) or other methods for random "snapshot" assessments is limited by the unexpected and occasional nature ...of arrhythmias, leading to a high rate of missed diagnosis. We have previously validated a cardiac monitoring system for AF detection pairing simple consumer-grade Bluetooth low-energy (BLE) heart rate (HR) sensors with a smartphone application (RITMIA™, Heart Sentinel srl, Italy). In the current study, we test a significant upgrade to the above-mentioned system, thanks to the technical capability of new HR sensors to run algorithms on the sensor itself and to acquire, and store on-board, single-lead ECG strips. We have reprogrammed an HR monitor intended for sports use (Movensense HR+) to run our proprietary RITMIA algorithm code in real-time, based on RR analysis, so that if any type of arrhythmia is detected, it triggers a brief retrospective recording of a single-lead ECG, providing tracings of the specific arrhythmia for later consultation. We report the initial data on the behavior, feasibility, and high diagnostic accuracy of this ultra-low weight customized device for standalone automatic arrhythmia detection and ECG recording, when several types of arrhythmias were simulated under different baseline conditions. Conclusions: The customized device was capable of detecting all types of simulated arrhythmias and correctly triggered a visually interpretable ECG tracing. Future human studies are needed to address real-life accuracy of this device.
There is variability in the outcome of patients with chronic lymphocytic leukemia with apparently the same stage of disease. Identifying genetic variants that influence patients' outcome and response ...to treatment may provide important insights into the biology of the disease.
We investigated the possibility that genetic variation influences outcome by conducting a genome-wide analysis of 346,831 single nucleotide polymorphisms in 356 patients entered into a phase III trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Genotypes were linked to individual patients' outcome data and response to chemotherapy. The association between genotype and progression-free survival was assessed by Cox regression analysis adjusting for treatment and clinicopathology.
The strongest associations were shown for rs1949733 (ACOX3; P=8.22x10-7), rs1342899 (P=7.72×10(-7)) and rs11158493 (PPP2R5E; P=8.50×10(-7)). In addition, the 52 single nucleotide polymorphisms associated at P<10(-4) included rs438034 (CENPF; P=4.86×10(-6)), previously correlated with cancer progression, and rs2255235 (B2M; P=3.10×10(-5)) and rs2064501 (IL22RA2; P=4.81×10(-5)) which map to B-cell genes.
Our findings provide evidence that genetic variation is a determinant of progression-free survival of patients with chronic lymphocytic leukemia. Specific associations warrant further analyses.
From Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo, Università di Pavia, Pavia, Italy (FL, MZ, MEB); Clinica Pediatrica, Università di Bologna, Ospedale SantOrsola Malpighi, ...Bologna, Italy (AP); Dipartimento di Ematologia e Oncologia Pediatrica, Istituto Giannina Gaslini, Genova, Italy (GM); Clinica Pediatrica, Università di Milano-Bicocca, Ospedale Nuovo San Gerardo, Monza, Italy (DL); Divisione di Ematologia, Ospedale di Pescara, Pescara, Italy (PDB); Clinica Pediatrica, Università di Brescia, Spedali Civili, Brescia, Italy (FP); Clinica Pediatrica, Ospedale Infantile Regina Margherita, Torino, Italy (FF); Clinica Pediatrica, I° Policlinico, IIa Università di Napoli, Napoli, Italy (BN); Clinica Pediatrica, Università di Padova, Padova, Italy (CM)
Correspondence: Franco Locatelli, Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo e Università di Pavia. E-mail: f.locatelli{at}smatteo.pv.it
Background and Objectives: Hematopoietic stem cell transplantation (HSCT) still represents the only treatment potentially able to prevent/rescue the development of marrow failure and myeloid malignancies in patients with Fanconi anemia (FA). While in the past HSCT from an HLA-identical sibling was proven to cure many patients, a higher incidence of treatment failure has been reported in recipients of an unrelated donor (UD) or HLA-partially matched related allograft.
Design and Methods: We analyzed the outcome of 64 FA patients (age range, 2–20 years) who underwent HSCT between January 1989 and December 2005. Patients were transplanted from either an HLA-identical sibling (n=31), an UD (n=26), or an HLA-partially matched relative (n=7). T-cell depletion of the graft was performed in patients transplanted from an HLA-disparate relative.
Results: The 8-year estimate of overall survival (OS) for the whole cohort was 67%; it was 87%, 40% and 69% when the donor was an HLA-identical sibling, an UD and a mismatched relative, respectively ( p <0.01). The outcome of recipients of grafts from an UD improved over time, the probability of survival being 10% and 72% for patients transplanted before and after 1998, respectively ( p <0.05). The OS probability of children who did or did not receive fludarabine in preparation for the allograft was 86% and 59%, respectively ( p <0.05).
Interpretation and Conclusions: These data, useful for counselling, provide support to the concept that a relevant proportion of FA patients undergoing HSCT can now be successfully cured, even in the absence of an HLA-identical sibling, especially if the conditioning regimen includes fludarabine.
Key words: Fanconi anemia, unrelated donor, fludarabine, hematopoietic stem cell transplantation.
Abstract The plasminogen pathway plays an important role in the behavior of many tumors including lung cancer. Hence genetic variants encoding plasminogen activator (PLAU), plasminogen receptor ...(PLAUR), plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) may contribute to lung cancer prognosis. To investigate this proposition we genotyped PAI-1 A15T, PLAU L141P, PLAUR L317P and PAI-2 S413C variants in 698 patients with lung cancer, 522 with non-small cell (NSCLC) and 176 with small cell lung cancer (SCLC). PAI-1 A15T was significantly associated with overall survival (OS), with carriers of variant alleles having a worse prognosis (hazard ratio (HR) = 1.14; 95% confidence interval CI: 1.03–1.26). An association was also detected between OS in NSCLC and carrier status for PAI-2 413C (HR = 1.13; 95% CI: 1.01–1.24). These common genetic variants identified warrant further evaluation as promising prognostic markers of patient outcome.
We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of ...genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10−16). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.
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