The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling ...in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene.
Abstract
Background
PAOLA1 is a phase III study assessing olaparib maintenance therapy in advanced high-grade ovarian carcinoma patients responding to first-line platinum-taxane–based chemotherapy ...plus bevacizumab as standard of care. Randomization was stratified by treatment outcome and tumor BRCA1/2 status (tBRCA) at screening.
Methods
tBRCA was tested on formalin-fixed, paraffin-embedded tumor blocks on 5 French platforms using 2 next-generation sequencing methods based either on hybrid capture or amplicon technology. One of the exploratory objectives was to assess the concordance between germline (gBRCA) and tBRCA testing in French patients. gBRCA testing was performed on blood samples on the same platforms.
Results
From May 2015 to July 2017, tBRCA tests were performed for 1176 screened patients. Only 52 (4.4%) tumor samples were noncontributive. The median interval between reception of the tumor sample and availability of the tBRCA status result was 37 days (range = 8-260). A pathogenic variant was reported in 27.1% tumor samples (319 of 1176 screened patients). tBRCA and gBRCA testing were performed for 451 French patients with negative results for both tests in 306 patients (67.8%) and positive results for both tests in 85 patients (18.8%). Only 1 large genomic rearrangement of BRCA1 was detected, exclusively in the blood sample. Interestingly, tBRCA testing revealed 6.4% of pathogenic variant (29 of 451) not detected by gBRCA testing.
Conclusions
tBRCA testing is an appropriate tool with an acceptable turnaround time for clinical practice and a low failure rate, ensuring reliable identification of patients likely to benefit from poly(ADP-ribose) polymerase inhibitor therapy.
Synthetic petrochemical-based polymers have had a tremendous industrial impact since the 1940s. Dechy-Cabaret et al focus on the different approaches reported in the literature for the controlled ...ring-opening polymerization of lactide and glycolide until 2003.
Somatic/germline
mutations (m)/(likely) pathogenic variants (PV) (
/
) remain the best predictive biomarker for PARP inhibitor efficacy. As >95% of high-grade serous ovarian cancers (HGSOC) have a ...somatic
, combined tumor-based
(
) and
mutation testing (
) may improve the quality of results in somatic
identification and interpretation of the 'second hit' event, i.e., loss of heterozygosity (LOH). A total of 237 patients with HGSOC underwent
testing. The ratio of allelic fractions (AFs) for
was calculated to estimate the proportion of cells carrying
and to infer LOH. Among the 142/237
results, 16.2% demonstrated a pathogenic/deleterious variant (DEL)
. Among the 195 contributive tumor samples, 43 DEL of
(22.1%) were identified (23
and 20
with LOH identified in 37/41 conclusive samples. The median AF of
was 0.52 (0.01-0.93), confirming huge variability in tumor cellularity. Initially, three samples were considered as wild type with <10% cellularity. However, additional testing detected a very low AF (<0.05) in both
and
, thus reidentifying them as
. Combined
testing is rapid, sensitive, and identifies somatic and germline
AF
is essential for interpreting
in low-cellularity samples and provides indirect evidence for LOH as the 'second hit' of
-related tumorigenesis.
For the first time, the application of microreactors as a tool for acquiring kinetic data on a photochemical reaction is demonstrated. For illustration, a T‐photochromic system is considered. By ...using modeling tools and carrying out specific experiments in a spiral‐shaped microreactor irradiated by an ultraviolet/light‐emitting diode (UV‐LED) array, the two kinetic parameters of the reaction, namely, quantum yield and rate of thermal back reaction, are determined. Once these parameters are known, the photochromic reaction is performed in two other microreactors in order to investigate a wider range of operating conditions. It is observed that a critical residence time exists beyond which the conversion into the open form decreases due to a decomposition reaction. The value of the critical residence depends on the microreactor type, which can be predicted by applying the model developed.
Promising perspectives are presented the first time for the application of microreactors as a means for investigating photochemical reaction kinetics. A T‐photochromic system is considered as an example. Its kinetic parameters are determined by modeling tools and specific experiments in a spiral‐shaped microreactor irradiated by a UV/light‐emitting diode array.
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•The need for chemical engineering to address some issues in flow photochemistry is highlighted.•Modeling is a powerful tool to identify the parameters influencing a photochemical ...reaction.•Strategies for photochemical process intensification are presented
The present paper aims to illustrate that chemical engineering enables to address some of the current challenges and issues in continuous-flow photochemistry. For that, some common limitations encountered in industrial photochemistry are firstly highlighted and a general overview on flow photochemistry equipment is presented. The main challenges linked to photochemical (micro)reactor engineering are subsequently stated. By considering only the case of a purely direct photochemical reactions A→Bhυ in homogenous medium, the key factors to consider when implementing such photochemical reactions in microstructured technologies are outlined. Their influence on the outputs (conversion, productivity, photonic efficiency) of this simple type of photochemical reaction is then discussed. The significance of chemical engineering frameworks is finally demonstrated using several examples concerning the understanding of the coupling between the different phenomena involved, the predictions of the performances obtained, the acquisition of kinetics data and the elaboration of strategies for photochemical process intensification and smart scale-up. In the future, the challenge will be to integrate the complexity of photochemistry (e.g. heterogeneous phase reactions) into the present modelling tools so as to enlarge the spectrum of strategies devoted to photochemical process intensification.
Introduction Microsatellite instability (MSI) is a genetic marker that is useful in the detection and treatment of Lynch syndrome (Sd). Although conventional techniques such as immunohistochemistry ...(IHC) and polymerase chain reaction (PCR) are the standards for MSI detection, the advent of next-generation sequencing (NGS) has offered new possibilities, especially with circulating DNA. Case report We present the case of a 26-year-old patient with Lynch Sd and a BRAF -mutated metastatic colon cancer. The discordant MSI results between the conventional methods and NGS posed challenges in making treatment decisions. Subsequent NGS analysis revealed a high MSI status, leading to participation in an immunotherapy trial, with remarkable clinical response. Conclusion This case emphasizes the importance of comprehensive molecular profiling and strong interdisciplinary collaborations, especially in cases with ambiguous MSI results.
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