Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26–2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81–6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.Breast cancer is the most common cancer affecting women worldwide. It is also the principal cause of death from cancer among women globally, accounting for 14% of all cancer deaths (1). The etiology of breast cancer is multifactorial, and the risk depends on various factors like age, family history, and reproductive, hormonal, or dietary factors. The majority of breast cancers are sporadic, but approximately 15% of cases show familial aggregation (2, 3). Since the identification of the first breast and ovarian cancer susceptibility genes breast cancer 1 and 2 (BRCA1 and BRCA2, respectively) by linkage analysis and positional cloning, several breast cancer susceptibility genes and alleles with different levels of risk and prevalence in the population have been recognized. BRCA1 and BRCA2 mutation carriers have more than 10-fold increased risk of breast cancer compared with women in the general population, and mutations in TP53, PTEN, STK11, and CDH1 have also been associated with a high lifetime risk of breast cancer in the context of rare inherited cancer syndromes (4). In addition, rare variants in genes such as checkpoint kinase 2 (CHEK2), ataxia telangiectasia mutated (ATM), and BRCA1 interacting helicase BRIP1, that confer a two- to fourfold increased risk, and in partner and localizer of BRCA2 (PALB2), with even higher risk estimates, have been found with candidate gene approaches (5, 6), and an increasing number of common low-risk loci with modest odds ratios (ORs; as much as 1.26-fold increased risk for heterozygous carriers) have been identified by genome-wide association studies (7).However, the major portion of hereditary breast cancer still remains unexplained, and many susceptibility loci are yet to be found. Exome sequencing combined with genotyping of the identified variants in case-control analysis is an effective method to recognize novel risk alleles, based on the assumption that disease-causing variants are rare and often accumulate in the protein-coding areas of the genome (8–10).Since the discovery that proteins encoded by the BRCA1 and BRCA2 breast/ovarian cancer susceptibility genes are directly involved in homologous recombination repair of DNA double-strand breaks, it has been evident that other genes involved in DNA repair are attractive breast cancer susceptibility candidates (4). Biallelic mutations in ATM gene cause rare ataxia telangiectasia disease and are associated with an increased risk for breast cancer as a result of improper DNA damage response (11). Fanconi anemia (FA) is a rare genetic disorder caused by biallelic mutations in FA genes that also participate in DNA repair. At least 15 FA genes have been identified (12). Patients with heterozygous mutations in certain FA genes have an elevated risk for various cancers, and monoallelic mutations in at least four of these genes [BRCA2, BRIP1, PALB2, and RAD51 paralog C (RAD51C)] are associated with an increased risk of breast or ovarian cancer (12, 13). Recurrent founder mutations in several cancer susceptibility genes, including the BRCA2, PALB2, and RAD51C FA genes, have been identified in the Finnish population (14–16). The PALB2 and RAD51C founder mutations have been detected at 2% frequency in Finnish breast or ovarian cancer families (15–17), whereas, in other populations, mutations in these genes are rare and often unique for each family. Founder effects in the isolated populations such as Finland or Iceland may enrich certain mutations and thus explain a significant proportion of all mutations in certain genes (18, 19). This provides an advantage in the search for novel susceptibility genes and alleles.In this study, we used exome sequencing to uncover previously unidentified recurrent breast or ovarian cancer predisposing variants in the Finnish population with a focus on DNA repair genes. Selected variants were further genotyped in a large case-control sample set. Our investigation revealed an association of a nonsense mutation (rs147021911) in an FA complementation gene, FANCM, with breast cancer, especially with triple-negative (TN) breast cancer (TNBC).     

Does outdoor air pollution induce new cases of asthma? Biological plausibility and evidence; a review

It is widely accepted that air pollution can exacerbate asthma in those who already have the condition. What is less clear is whether air pollution can contribute to the initiation of new cases of asthma. Mechanistic evidence from toxicological studies, together with recent information on genes that predispose towards the development of asthma, suggests that this is biologically plausible, particularly in the light of the current understanding of asthma as a complex disease with a variety of phenotypes. The epidemiological evidence for associations between ambient levels of air pollutants and asthma prevalence at a whole community level is unconvincing; meta-analysis confirms a lack of association. In contrast, a meta-analysis of cohort studies found an association between asthma incidence and within-community variations in air pollution (largely traffic dominated). Similarly, a systematic review suggests an association of asthma prevalence with exposure to traffic, although only in those living very close to heavily trafficked roads carrying a lot of trucks. Based on this evidence, the U.K.'s Committee on the Medical Effects of Air Pollutants recently concluded that, overall, the evidence is consistent with the possibility that outdoor air pollution might play a role in causing asthma in susceptible individuals living very close to busy roads carrying a lot of truck traffic. Nonetheless, the effect on public health is unlikely to be large: air pollutants are likely to make only a small contribution, compared with other factors, in the development of asthma, and in only a small proportion of the population.     

Polypropylene meshes coated with a polysaccharide based bioadhesive for intra-abdominal mesh fixation in a rabbit model

Background

In this study, we evaluate a new bioadhesive for intra-abdominal onlay mesh fixation of a polypropylene–polyvinylchloride graft.

Methods

Three pieces of a commercially available polypropylene/polyvinylfluoride mesh, each 3 × 3 cm in size, and three pieces of the same mesh coated with a polysaccharide bioadhesive were fixated to the surface of the anterior abdominal wall of 30 New Zealand white rabbits. The fixation was performed either by using four transabdominal Prolene^® 4/0 sutures, four spiral tacks (Protack 5 mm Tyco), or cyanoacrylate glue (Glubran^® GEM, Viareggio, Italy). Each mesh position and the according kind of fixation were randomized before implantation. The animals were sacrificed 12 weeks postoperatively. After determining the extent of intra-abdominal adhesions, the meshes were excised en bloc with the anterior abdominal wall for tensile strength measurements and histological analysis.

Results

All meshes coated with the bioadhesive adhered to the intact peritoneum without extra fixation. Irrespective of the fixation technique coated meshes led to more and stronger adhesions. Mesh shrinkage by scarring was increased in coated meshes fixed with glue and low in uncoated meshes fixed with tacks. Testing the tensile strength, coated meshes fixed with transfascial sutures achieved the best results (16.14 ± 6.1 N), whereas coated meshes fixed with glue showed the lowest strength (10.39 ± 4.81 N). The foreign body reaction was considerably more distinctive using coated mesh. The mesh ingrowth was not influenced by this reaction.

Conclusions

All meshes coated with the new bioadhesive were self-adhesive in that way; they stayed in position when attached to the peritoneum. Although this may facilitate intra-operative mesh fixation, the bioadhesive displayed several disadvantages, such as stronger adhesions and an increased shrinkage of the implant. The tensile strength was not influenced by the use of the bioadhesive. At present, we see no major advantage for polysaccharide bioadhesive applied in this study.     

Cerebrospinal fluid biomarkers in Alzheimer’s disease, vascular dementia and ischemic stroke patients: a critical analysis

Vascular factors are thought to contribute to the development of disease pathology in neurodegenerative dementia such as Alzheimer’s disease (AD). Another entity, called vascular dementia (VaD), comprises a less defined group of dementia patients having various vascular diseases that especially emerge in the elderly population and require valid options for examination and differential diagnosis. In the context of a retrospective study, we analyzed the cerebrospinal fluid (CSF) biomarkers t-tau, p-tau and Aß42 of a total of 131 patients with AD (n = 47), mild cognitive impairment (MCI) (n = 22), VaD (n = 44) and stroke (n = 18). We found a remarkable alteration in CSF biomarker profile in AD, VaD and in acute ischemic events. CSF profile in AD patients was altered in a very similar way as in stroke patients, without statistical differences. In stroke, increase depend largely on size and duration after the initial event. Total tau levels were useful to differ between VaD and stroke. Aß42 decreased in a similar way in AD, VaD and stroke and had a trend to lower levels in MCI but not in controls.     

Reduced brain corticotropin‐releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats

The brain corticotropin‐releasing factor (CRF) system triggers a variety of neuroendocrine and behavioural responses to stress. Whether maternal behaviour and emotionality in lactation are modulated by CRF has rarely been investigated. In the present study, we measured CRF mRNA expression within the parvocellular part of the paraventricular nucleus in virgin and lactating Wistar rats bred for high (HAB) and low (LAB) anxiety‐related behaviour or non‐selected for anxiety (NAB). Further, we intracerebroventricularly infused synthetic CRF or the CRF receptor (CRF‐R) antagonist D‐Phe to manipulate CRF‐R1/2 non‐specifically in lactating HAB, LAB, and NAB dams, and monitored maternal care, maternal motivation, maternal aggression, and anxiety. The CRF mRNA expression in the parvocellular part of the paraventricular nucleus was higher in HAB vs. LAB rats independent of reproductive status. The lactation‐specific decrease of CRF mRNA was confirmed in LAB and NAB dams but was absent in HAB dams. Intracerebroventricular CRF decreased maternal care under basal conditions in the home cage in all breeding lines and reduced attack behaviour in HAB and LAB dams during maternal defence. In contrast, D‐Phe rescued maternal care after exposure to maternal defence in the home cage without influencing maternal aggression. Furthermore, D‐Phe decreased and CRF tended to increase anxiety in HAB/NAB and LAB dams, respectively, suggesting an anxiogenic effect of CRF in lactating females. In conclusion, low CRF‐R activation during lactation is an essential prerequisite for the adequate occurrence of maternal behaviour.     

The relationship between negative trauma-related cognitions and psychosocial functioning in veterans with posttraumatic stress disorder and alcohol use disorder

Abstract

Background: The comorbidity of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is highly prevalent and associated with especially poor psychosocial functioning. Negative trauma-related cognitions are theoretically proposed to be associated with poor psychosocial functioning in PTSD, but few studies have examined the association between negative trauma-related cognitions and psychosocial functioning in PTSD/AUD. Evaluating this association may provide evidence of a potential treatment target for improving psychosocial functioning in PTSD/AUD. We hypothesized that negative trauma-related cognitions, including cognitions about the self, world, and self-blame, would be independently associated with poor psychosocial functioning in the following domains: vitality, psychosocial well-being, role limitations due to emotional distress, and social functioning. Methods: We examined the relationship between negative trauma-related cognitions and psychosocial functioning in 145 treatment-seeking veterans with PTSD/AUD using multiple linear regression analyses while controlling for PTSD and alcohol abuse and dependence severity. Results: Our hypotheses were partially supported. We found that negative trauma-related cognitions were uniquely associated with greater psychosocial functional impairment, independent of PTSD and alcohol abuse and dependence severity. Specifically, negative trauma-related cognitions about the self were associated with greater psychosocial functional impairment across all domains, cognitions about the world were associated with worse social functioning and psychological well-being, and self-blame was associated with impaired psychological well-being. Conclusions: Given that improvements in negative trauma-related cognitions are a mechanism of trauma-focused treatment, future studies should examine whether changes in negative trauma-related cognitions through trauma-focused treatment are associated with improved psychosocial functioning.     

Decline of Systolic and Diastolic 2D Strain Rate During Follow-Up of HLHS Patients After Fontan Palliation

Accurate assessment of ventricular function is particularly important in children with hypoplastic left heart syndrome (HLHS) after completion of the total cavopulmonary connection (TCPC). For this purpose, two-dimensional speckle tracking (2DST) is a promising technique as it does not depend on the angle of insonation or the geometry of the ventricle. The objective of this study was to assess changes in systolic and diastolic right ventricular (RV) function within a 5-year follow-up period of HLHS patients after TCPC using conventional and 2DST echocardiography. RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), E/A, E/e′ and 2DST parameters [global longitudinal peak systolic strain (GS) and strain rate (GSRs), global strain rate in early (GSRe) and late (GSRa) diastole] of 40 HLHS patients were compared at 1.6 and at 5.1 years after TCPC. RVFAC, E/A, E/e′ and GS did not change, whereas TAPSE (13.7 ± 3.2 vs. 10.5 ± 2.4 mm/m², p < 0.001), GSRs (?1.56 ± 0.28 vs. ?1.35 ± 0.31 1/s, p < 0.001), GSRe (2.22 ± 0.49 vs. 1.96 ± 0.44 1/s, p = 0.004) and GSRa (1.19 ± 0.39 vs. 0.92 ± 0.39 1/s, p < 0.001) decreased significantly. Systolic and diastolic RV function parameters of HLHS patients decreased from 1.6 to 5.1 years after TCPC in our patients. Changes in global strain rate parameters may be signaling early RV dysfunction that is not detectable by traditional echocardiography. Further study is needed to verify this and to determine whether these changes are clinically relevant.