Germline pathogenic variants in the MRE11, RAD50, and NBN (MRN) genes in cancer predisposition: A systematic review and meta-analysis.

The MRE11, RAD50, and NBN genes encode the MRN complex sensing DNA breaks and directing their repair. While carriers of biallelic germline pathogenic variants (gPV) develop rare chromosomal instability syndromes, the cancer risk in heterozygotes remains controversial. We performed a systematic review and meta-analysis of 53 studies in patients with different cancer diagnoses to better understand the cancer risk. We found an increased risk (odds ratio, 95% confidence interval) for gPV carriers in NBN for melanoma (7.14; 3.30-15.43), pancreatic cancer (4.03; 2.14-7.58), hematological tumors (3.42; 1.14-10.22), and prostate cancer (2.44, 1.84-3.24), but a low risk for breast cancer (1.29; 1.00-1.66) and an insignificant risk for ovarian cancer (1.53; 0.76-3.09). We found no increased breast cancer risk in carriers of gPV in RAD50 (0.93; 0.74-1.16; except of c.687del carriers) and MRE11 (0.87; 0.66-1.13). The secondary burden analysis compared the frequencies of gPV in MRN genes in patients from 150 studies with those in the gnomAD database. In NBN gPV carriers, this analysis additionally showed a high risk for brain tumors (5.06; 2.39-9.52), a low risk for colorectal (1.64; 1.26-2.10) and hepatobiliary (2.16; 1.02-4.06) cancers, and no risk for endometrial, and gastric cancer. The secondary burden analysis showed also a moderate risk for ovarian cancer (3.00; 1.27-6.08) in MRE11 gPV carriers, and no risk for ovarian and hepatobiliary cancers in RAD50 gPV carriers. These findings provide a robust clinical evidence of cancer risks to guide personalized clinical management in heterozygous carriers of gPV in the MRE11, RAD50, and NBN genes.

Population-specific validation and comparison of the performance of 77- and 313-variant polygenic risk scores for breast cancer risk prediction.

BACKGROUND: The polygenic risk score (PRS) allows the quantification of the polygenic effect of many low-penetrance alleles on the risk of breast cancer (BC). This study aimed to evaluate the performance of two sets comprising 77 or 313 low-penetrance loci (PRS77 and PRS313) in patients with BC in the Czech population. METHODS: In a retrospective case-control study, variants were genotyped from both the PRS77 and PRS313 sets in 1329 patients with BC and 1324 noncancer controls, all women without germline pathogenic variants in BC predisposition genes. Odds ratios (ORs) were calculated according to the categorical PRS in individual deciles. Weighted Cox regression analysis was used to estimate the hazard ratio (HR) per standard deviation (SD) increase in PRS. RESULTS: The distributions of standardized PRSs in patients and controls were significantly different (p < 2.2 × 10-16) with both sets. PRS313 outperformed PRS77 in categorical and continuous PRS analyses. For patients in the highest 2.5% of PRS313, the risk reached an OR of 3.05 (95% CI, 1.66-5.89; p = 1.76 × 10-4). The continuous risk was estimated as an HRper SD of 1.64 (95% CI, 1.49-1.81; p < 2.0 × 10-16), which resulted in an absolute risk of 21.03% at age 80 years for individuals in the 95th percentile of PRS313. Discordant categorization into PRS deciles was observed in 248 individuals (9.3%). CONCLUSIONS: Both PRS77 and PRS313 are able to stratify individuals according to their BC risk in the Czech population. PRS313 shows better discriminatory ability. The results support the potential clinical utility of using PRS313 in individualized BC risk prediction.

A comprehensive analysis of germline predisposition to early-onset ovarian cancer.

The subset of ovarian cancer (OC) diagnosed ≤ 30yo represents a distinct subgroup exhibiting disparities from late-onset OC in many aspects, including indefinite germline cancer predisposition. We performed DNA/RNA-WES with HLA-typing, PRS assessment and survival analysis in 123 early-onset OC-patients compared to histology/stage-matched late-onset and unselected OC-patients, and population-matched controls. Only 6/123(4.9%) early-onset OC-patients carried a germline pathogenic variant (GPV) in high-penetrance OC-predisposition genes. Nevertheless, our comprehensive germline analysis of early-onset OC-patients revealed two divergent trajectories of potential germline susceptibility. Firstly, overrepresentation analysis highlighted a connection to breast cancer (BC) that was supported by the CHEK2 GPV enrichment in early-onset OC(p = 1.2 × 10-4), and the presumably BC-specific PRS313, which successfully stratified early-onset OC-patients from controls(p = 0.03). The second avenue pointed towards the impaired immune response, indicated by LY75-CD302 GPV(p = 8.3 × 10-4) and diminished HLA diversity compared with controls(p = 3 × 10-7). Furthermore, we found a significantly higher overall GPV burden in early-onset OC-patients compared to controls(p = 3.8 × 10-4). The genetic predisposition to early-onset OC appears to be a heterogeneous and complex process that goes beyond the traditional Mendelian monogenic understanding of hereditary cancer predisposition, with a significant role of the immune system. We speculate that rather a cumulative overall GPV burden than specific GPV may potentially increase OC risk, concomitantly with reduced HLA diversity.

A comprehensive study evaluating germline FANCG variants in predisposition to breast and ovarian cancer.

BACKGROUND: Monoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear. METHODS: Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk. RESULTS: The frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss-of-heterozygosity of the wild-type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations. CONCLUSION: Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.

A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition.

Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37). The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors. Based on these observations, we classified this variant as likely pathogenic.

Impact of platinum group elements on the soil invertebrate Folsomia candida.

OBJECTIVES: Trace concentrations of the platinum group elements (PGE; Pt, Pd and Rh) are nowadays an irreplaceable part of environmental analysis and assessment. These rare elements are used as effective substances in automotive catalysts to reduce pollution by emissions originating from fuel combustion. Due to their harmful potential, it is necessary to monitor their content and behaviour in different samples. Effect assessment using ecotoxicological bioassays with organisms at different trophic levels can provide valuable pieces of information on the risk of chemical substances in the ecosystem. DESIGN: The experiments were carried out as described in the OECD Guideline 232 [CSN ISO 11267 - Soil quality - Inhibition of reproduction of Collembola (Folsomia candida) by soil pollutants]. The reproductive effects of palladium (PdCl2) and rhodium (RhCl3) were examined. Concentrations of PGE tested were as follows: 5, 10, 25, 50 and 100 µmol.L-1. The EC50 (medium effective concentration) was determined after 28 days of exposure. Inhibition of reproduction of PGE-exposed collembolans was compared against controls. RESULTS: Values of 28dEC50 of PdCl2 and RhCl3 amounted to 21.0 µmol.L-1 and 266.22 µmol.L-1, respectively. We can confirm that the relative order of toxicities is Pd (II) > Pt(IV) >> Rh(III). CONCLUSION: To the best of our knowledge, this is the first study to use Folsomia candida as an indicator species to assess the risk of soil contamination by palladium and rhodium. However, more toxicity data for various species are needed to evaluate the environmental risks of PGEs in soils.

Oral enzyme combination with bromelain, trypsin and the flavonoid rutoside reduces systemic inflammation and pain when used pre- and post-operatively in elective total hip replacement: a randomized exploratory placebo-controlled trial.

Background: Early mobilization after total hip replacement (THR) is key for fast recovery but is often limited by pain. Oral enzyme combinations (OECs) have demonstrated anti-inflammatory and pain-relieving effects. Objectives and design: This prospective, randomized, double-blind, placebo-controlled exploratory trial evaluated the effects of pre- and post-operative use of OEC (90 mg bromelain, 48 mg trypsin, 100 mg rutoside) following elective THR, on post-operative recovery. Methods: Candidates for primary elective cementless THR owing to osteoarthritis were eligible for participation [age ⩾50 years, body mass index 25-35 kg/m2, C-reactive protein (CRP) ⩽6 mg/L]. Following randomization to OEC or placebo, intervention started pre-operatively and continued onwards until day 42. Main outcomes included post-operative CRP levels (days 1-7), self-reported hip pain at rest (by 0-10 cm visual analogue scale on post-operative days 1-42), post-operative analgesic use [by cumulative analgesic consumption score (CACS) days 7-42], tolerability and adverse events. Results: Patients (N = 34) were recruited from a tertiary orthopaedic hospital in the Czech Republic, of whom 33 completed the study (OEC/placebo: n = 15/18). Baseline characteristics across the groups were comparable. Compared with placebo, the OEC group had numerically lower CRP levels on post-operative days 1-7, including peak level [mean (standard deviation) OEC versus placebo: 81.4 (28.3) versus 106.7 (63.3) mg/L], which translated into a significant 32% lower CRP area under the curve (p = 0.034). The OEC group reported significantly less pain during post-operative days 1-7 versus placebo (analysis of variance treatment × visit [F(4) = 3.989]; p = 0.005). Analgesic use was numerically reduced as assessed through an accumulated CACS. No deleterious effects on haemorheological parameters were observed in either group. Conclusions: Pre- and post-operative use of OEC significantly reduced CRP levels and patient self-reported pain. OEC may be an efficacious and safe treatment option to facilitate post-operative recovery following THR. Trial registration: EudraCT number 2016-003078-41.

Impact of platinum on the soil invertebrate Folsomia candida.

OBJECTIVES: Regarding the environmental pollution, platinum group elements (PGE) are in the centre of interest of current research. These rare elements are used as effective substances in automotive catalysts to reduce pollution by emissions originating from fuel combustion. Due to their harmful potential, it is necessary to monitor their content and behaviour in different samples. Comprehensive studies on PGE behaviour and effects are still lacking. Their distribution in the food chain and data on bioaccumulation has not been described so far. METHODS: We focused on reproductive effects of platinum (PtCl4), in particular. Our study is based on a collembolan laboratory breed, test optimalization and validation according to the OECD 232 standards [CSN ISO 11267 - Soil quality - Inhibition of reproduction of Collembola (Folsomia candida) by soil pollutants]. The concentrations of PtCl4 tested were as follows: 5, 10, 25, 50 and 100 µM. The EC50 was determined after 28 days of testing. RESULTS: The results were evaluated using the inhibition of reproduction compared with controls. The EC50 was determined after the 28-day test. The value of 28dEC50 of the boric acid test was estimated at 120 mg/kg and the measured 28dEC50 of PtCl4 was 200.4 µM. CONCLUSION: The presented data can be considered as a step forward in the assessment of the potential risk of platinum in the terrestrial environment. However, more toxicity data for various species are needed to evaluate the environmental risk of platinum in soils.

Comparison of the effect of platinum on producers in aquatic environment.

OBJECTIVES: An enhanced worldwide application of platinum group elements (PGE), in particular platinum, has been observed during recent decades. An increased concentration of PGE was determined in collected samples of great amount of aqueous ecosystems.The aim was to compare phytotoxic effect of platinum (PtCl4) by performing two different bioassays on green algae Pseudokirchneriella subcapitata and macrophyte duckweed, Lemna minor. MEDTHODS: The algal experiment (Pseudokichneriella subcapitata) followed OECD 201, the concentration row for PtCl4 was: 0.05; 0.01; 0.25; 0.5; 1 µM. The duckweed (Lemna minor) experiment was conducted according to OECD 221, employed PtCl4 concentrations were: 5; 10; 25; 50; 100 µM. Plants were cultivated as a microbiotest, using micro-volumes. RESULTS: The results of the algal test showed significant growth inhibition of the final biomass. The values of 72hEC5(µ), 72hEC10(µ), 72hEC20(µ) counted on a basis of average specific growth rate (µ) were 0.31 µM, 0.58 µM and 1.12 µM of PtCl4, respectively. The values, obtained on a basis of the area under the growth curves (A), were 0.04 µM (72hEC5(A)), 0.24 µM (72hEC10(A)) and 0.64 µM (72hEC20(A)). The experiment with duckweed showed 50% of growth inhibition and the values of 168hEC50(µ) were 19.55 µM and 168hEC50(A) 13.63 µM of PtCl4. CONCLUSION: The fronds of duckweed showed strong adverse effect of platinum influence (chlorosis, necrosis). The algal test and the estimation of 72hEC5(A) appears to be the most sensitive.