The wide spectrum of POT1 gene mutations correlates with multiple cancer types.

The POT1 protein forms part of the shelterin complex, which binds and protects telomeres. Germline mutations in the POT1 gene have recently been shown to be involved in tumors in different tissues such as familial colorectal, glioma and melanoma tumors, which demonstrate the importance of this gene. Recently, we uncovered a mutation in the POT1 gene (p.R117C) as causative of cardiac angiosarcomas in families with multiple tumors. Our in silico studies predicted that the POT1 p.R117C protein had lost the ability to interact with TPP1 and ssDNA. In vitro studies corroborated this prediction, and showed that this lack of function leads to abnormally long telomeres with increased fragility. In order to better understand the spectrum of mutations in the POT1 gene and its relation with tumorigenesis, we extended the study to families with multiple tumors (with and without angiosarcomas) and sporadic angiosarcomas and cardiac sarcomas. We found four new mutations that were not described previously and another patient carrying the previously described p.R117C mutation. In silico studies predicted that these new mutations were damaging in the same manner as previously described for the POT1 p.R117C mutation. These mutations were present in both, families and sporadic cases with angiosarcomas and sarcomas, although the major part was involved in families with AS and in cardiac tumors. The wide spectrum of mutations in the POT1 gene leading to different tumorigenesis processes demonstrates the general importance of this gene.pre-print252 K

The benefit of adding polygenic risk scores, lifestyle factors, and breast density to family history and genetic status for breast cancer risk and surveillance classification of unaffected women from germline CHEK2 c.1100delC families

To determine the changes in surveillance category by adding a polygenic risk score based on 311 breast cancer (BC)-associated variants (PRS311), questionnaire-based risk factors and breast density on personalized BC risk in unaffected women from Dutch CHEK2 c.1100delC families. In total, 117 unaffected women (58 heterozygotes and 59 non-carriers) from CHEK2 families were included. Blood-derived DNA samples were genotyped with the GSAMDv3-array to determine PRS311. Lifetime BC risk was calculated in CanRisk, which uses data from the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Women, were categorized into three surveillance groups. The surveillance advice was reclassified in 37.9 % of heterozygotes and 32.2 % of non-carriers after adding PRS311. Including questionnaire-based risk factors resulted in an additional change in 20.0 % of heterozygotes and 13.2 % of non-carriers; and a subanalysis showed that adding breast density on top shifted another 17.9 % of heterozygotes and 33.3 % of non-carriers. Overall, the majority of heterozygotes were reclassified to a less intensive surveillance, while non-carriers would require intensified surveillance. The addition of PRS311, questionnaire-based risk factors and breast density to family history resulted in a more personalized BC surveillance advice in CHEK2-families, which may lead to more efficient use of surveillance.</p

Validity and Reliability of the Decision Regret Scale in Cancer Patients Receiving Adjuvant Chemotherapy

OBJECTIVES: Decisional regret is an indicator of satisfaction with the treatment decision and can help to identify those patients who need more support and evaluate the efficacy of decision support interventions. The objectives of this study are, 1) to evaluate the psychometric properties of the Decision Regret Scale and 2) to analyze the moderating effect of psychological distress on functional status and regret in patients with cancer following adjuvancy. METHODS: A prospective, multicenter cohort of 403 patients who completed the Decision Regret Scale (DRS), Health-Related Quality of Life (EORTC QLQ-C30), and Brief Symptom Inventory (BSI). The evaluation was conducted six months after receiving adjuvant treatment in patients with resected cancer. RESULTS: After treatment, most participants (51.9%) experienced no decision regret; 33.7% felt mild regret, and 14.4% exhibited high levels of regret. The Spanish version of the DRS demonstrated satisfactory properties: it had a strong, clear unidimensional factorial structure with substantial loadings. Decisional regret was related with lower scores on functional, symptom, and quality of life scales, and higher levels of psychological distress (all P = 0.001). Psychological distress was found to have a moderating effect on the relationship between functional state and decision regret. CONCLUSIONS: The Spanish version of the DRS is a reliable, valid tool to evaluate regret and post-decisional quality in clinical practice and further highlights the potential clinical implications of psychological distress for the relation between physical status and regret

Circulating microRNAs in Early Breast Cancer Patients and Its Association With Lymph Node Metastases

MicroRNAs have emerged as important regulators of the metastatic process. In addition, circulating miRNAs appear to be surprisingly stable in peripheral blood making them ideal noninvasive biomarkers for disease diagnosis. Here, we performed a proof-of-principle study to investigate the expression profile of circulating miRNAs and their association with the metastatic lymph node status in early breast cancer patients. Sentinel lymph node status was detected by one-step nucleic acid (OSNA) analysis. We performed RNA-sequencing in 16 plasma samples and validated the results by qPCR. Gene Ontology term enrichment and KEGG pathway analyses were carried out using DAVID tools. We found16 differentially expressed miRNAs (q < 0.01) in patients with positive SLNs. Fourteen miRNAs were down-regulated (miR-339-5p, miR-133a-3p, miR-326, miR-331-3p, miR-369-3p, miR-328-3p, miR-26a-3p, miR-139-3p, miR-493-3p, miR-664a-5p, miR-146a-5p, miR-323b-3p, miR-1307-3p and miR-423-3p) and 2 were up-regulated (miR-101-3pand miR-144-3p). Hierarchical clustering using differentially expressed miRNAs clearly distinguished patients according to their lymph node status. Gene ontology analysis showed a significant enrichment of biological processes associated with the regulation of the epithelial mesenchymal transition, cell proliferation and transcriptional regulation. Our results suggest the potential role of several circulating miRNAs as surrogate markers of lymph node metastases in early breast cancer patients. Further validation in a larger cohort of patients will be necessary to confirm our results

ETV5 i RUNX1, nous factors de transcripció implicats en la invasió miometrial del carcinoma endometrial

Actualment, en càncer d'endometri, està àmpliament acceptat el model dualístic que, atenent a bases morfològiques, diferencia tumors de tipus i o endometrioides dels de tipus ii o no endometrioides. La genètica molecular ha aportat dades que donen suport a aquest model dualístic de la tumorigènesi endometrial i algunes claus per a poder especular sobre la seqüència temporal de les alteracions moleculars que defineixen les rutes tumorigèniques. En els càncers endometrials endometrioides, o de tipus i, es coneixen alteracions majors, com poden ser el silenciament del gen PTEN, la inestabilitat de microsatèll. its associada a defectes en els gens reparadors de DNA, o mutacions al gen K-ras. Aquestes alteracions defineixen la progressió de l'endometri normal cap a la hiperplàsia i posteriorment cap al carcinoma. Recentment, l'ús de la tecnologia de microxips de cDNA per a identificar les diferències en els patrons d'expressió gènica entre els diferents tipus histològics de càncer d'endometri han permès la identificació de gens expressats diferencialment que podrien ajudar-nos a entendre les diferències en la biologia i el pronòstic clínic dels diferents histiotips tumorals. En el nostre laboratori hem aïllat i caracteritzat dos nous factors de transcripció, ETV5 i RUNX1, que estan associats amb els passos inicials de la infiltració miometrial en el càncer d'endometri endometrioide. Aquests estudis, i els d'altres gens implicats en el control de la mitosi com a mecanisme major de carcinogènesi en els càncers d'endometri no endometrioides, representen exemples de la utilitat dels estudis genètics amplis per a comprendre el procés de tumorigènesi i les rutes implicades en la patogènesi molecular del càncer d'endometri.A dualistic model, which has been established on a morphological basis and that differentiates type i endometrioid from type ii non-endometrioid endometrial cancer, is widely accepted. Molecular genetics have provided us with data supporting the dualistic model of endometrial tumorigenesis and with some clues to speculate about the sequence of the molecular alterations defining the tumorigenesis pathways. In type i endometrioid endometrial cancer, PTEN gene silencing, microsatellite instability associated with defects in DNA mismatch repair genes, or mutations in the K-ras gene are the known major alterations defining the progression from normal endometrium to hyperplasia and then on to carcinoma. Recently, cDNA microarray technology for identifying the differences in gene expression patterns between the histological types of endometrial cancer have permitted the identification of differentially expressed genes that could help us to understand differences in the biology and the clinical outcome between histiotypes. In our laboratory, we have recently isolated and characterized two new transcription factors, ETV5 and RUNX1, which expression appears to be associated with initial steps of myometrial infiltration in endometrioid endometrial carcinoma. These studies, as well as those on other genes involved in the mitotic checkpoint as a major mechanism of carcinogenesis in non-endometrioid endometrial cancer, represent examples of how useful large genetic screenings can be for understanding the tumorigenesis process and the future directions in the molecular pathogenesis of endometrial cancer

POT1 and Damage Response Malfunction Trigger Acquisition of Somatic Activating Mutations in the VEGF Pathway in Cardiac Angiosarcomas

Background: Mutations in the POT1 gene explain abnormally long telomeres and multiple tumors including cardiac angiosarcomas (CAS). However, the link between long telomeres and tumorigenesis is poorly understood. Methods and Results: Here, we have studied the somatic landscape of 3 different angiosarcoma patients with mutations in the POT1 gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the POT1 gene has been studied. Patients with CAS and nonfunctional POT1 did not repress ATR (ataxia telangiectasia RAD3-related)-dependent DNA damage signaling and showed a constitutive increase of cell cycle arrest and somatic activating mutations in the VEGF (vascular endothelial growth factor)/angiogenesis pathway (KDR gene). The same observation was made in POT1 mutation carriers with tumors different from CAS and also in CAS patients without mutations in the POT1 gene but with mutations in other genes involved in DNA damage signaling. Conclusions: Inhibition of POT1 function and damage-response malfunction activated DNA damage signaling and increased cell cycle arrest as well as interfered with apoptosis, which would permit acquisition of somatic mutations in the VEGF/angiogenesis pathway that drives tumor formation. Therapies based on the inhibition of damage signaling in asymptomatic carriers may diminish defects on cell cycle arrest and thus prevent the apoptosis deregulation that leads to the acquisition of driver mutations

DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p&lt;0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7×10-3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8×10-3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied

Mammographic density and breast cancer in women from high risk families

Introduction: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. Methods: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. Results: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. Conclusions: Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization

Simple Summary Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancer (RCC), with no data on its prevalence worldwide. No genotype-phenotype associations have been described. The aim of our study was to describe the genotypic and phenotypic features of the largest series of patients with HLRCC from Spain reported to date. Of 27 FH germline pathogenic variants, 12 were not previously reported in databases. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants. The frequency of RCCs (10.9%) was lower than those reported in the previously published series. Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys