Capacidad predictiva del modelo BCRAPro frente al profesional de enfermería en la selección de candidatos a estudio genético de cáncer de mama u ovario hereditario

Objetivo: Comparar la capacidad predictiva del modelo predictivo BRCAPro y de los profesionales de enfermería con distintos niveles de formación/experiencia en la identificación de familias susceptibles de ser estudiadas genéticamente dada su historia personal y familiar de cáncer de mama. Método: Estudio descriptivo en el que 2 enfermeras con diferente grado de formación en consejo genético han estimado la probabilidad de ser portador de mutación en los genes BRCA1/BRCA2 de 157 familias. Se calculó la sensibilidad, especificidad, valor predictivo positivo (VPP) y valor predictivo negativo (VPN) de ambas enfermeras y del BRCAPro. Resultados: La enfermera con menor experiencia demostró mayor especificidad (N2:0,84) frente a la enfermera con mayor experiencia (N1:0,23) o a BRCAPro (0,47). La sensibilidad de las profesionales de enfermería fue de 0,95 (N1) y del 0,28 (N2), mientras que la de BRCAPro fue del 0,74. El VPP fue similar en las tres situaciones. El VPN de la enfermera con mayor experiencia (0,93) fue superior al de BRCAPro (0,85) y la enfermera con menor experiencia (0,72). Conclusiones: La experiencia clínica aporta una alta sensibilidad pero a costa de una pérdida significativa de especificidad. El modelo de predicción BRCAPro obtiene valores intermedios entre ambas enfermeras, por lo que podría ser una herramienta que ayudase a mejorar aquellos valores en los que se obtiene menor puntuación, es decir, la especificidad y VPP para enfermeras con mayor experiencia y la sensibilidad y VPN para aquellas con menor experiencia

Correction: Dueñas et al. Assessing effectiveness of colonic and gynecological risk reducing surgery in Lynch syndrome individuals. Cancers 2020, 12, 3419.

In the original article, there was a mistake in Figure 3 as published [1]. The image presented corresponded to endometrial cancer-specific mortality cumulative incidence, instead of the figure referred to in the title (all-cause mortality cumulative incidence)

Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients

Fanconi anemia (FA) is caused by biallelic mutations in FA genes. Monoallelic mutations in five of these genes (BRCA1, BRCA2, PALB2, BRIP1 and RAD51C) increase the susceptibility to breast/ovarian cancer and are used in clinical diagnostics as bona-fide hereditary cancer genes. Increasing evidence suggests that monoallelic mutations in other FA genes could predispose to tumor development, especially breast cancer. The objective of this study is to assess the mutational spectrum of 14 additional FA genes (FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANCP, FANCQ, FANCR and FANCU) in a cohort of hereditary cancer patients, to compare with local cancer-free controls as well as GnomAD. A total of 1021 hereditary cancer patients and 194 controls were analyzed using our next generation custom sequencing panel. We identified 35 pathogenic variants in eight genes. A significant association with the risk of breast cancer/breast and ovarian cancer was found for carriers of FANCA mutations (odds ratio (OR) = 3.14 95% confidence interval (CI) 1.4-6.17, p = 0.003). Two patients with early-onset cancer showed a pathogenic FA variant in addition to another germline mutation, suggesting a modifier role for FA variants. Our results encourage a comprehensive analysis of FA genes in larger studies to better assess their role in cancer risk

Highly sensitive microsatellite instability and immunohistochemistry assessment in endometrial aspirates as a tool for cancer risk individualization in Lynch syndrome

Women with Lynch syndrome (LS) are at increased risk of endometrial cancer (EC), among other tumors, and are characterized by mismatch repair (MMR) deficiency and microsatellite instability (MSI). While risk-reducing gynecologic surgeries effectively decrease EC incidence, doubts arise regarding the appropriate timing of the surgery. We explored the usefulness of highly sensitive MSI (hs-MSI) assessment in endometrial aspirates for individualizing gynecologic surveillance in LS carriers. Ninety-three women with LS, 25 sporadic EC patients (9 MMR-proficient and 16 MMR-deficient), and 30 women with benign gynecologic disease were included in this study. hs-MSI was assessed in prospectively collected endometrial aspirates in 67 LS carriers, EC cases, and controls. MMR, PTEN, ARID1A, and PAX2 protein expression patterns were evaluated in the LS samples. Follow-up aspirates from 8 LS carriers were also analyzed. Elevated hs-MSI scores were detected in all aspirates from MMR-deficient EC cases (3 LS and 16 sporadic) and negative in aspirates from controls and MMR-proficient EC cases. Positive hs-MSI scores were also detected in all 4 LS aspirates reported as complex hyperplasia. High hs-MSI was also present in 10 of 49 aspirates (20%) from LS carriers presenting a morphologically normal endometrium, where MMR protein expression loss was detected in 69% of the samples. Interestingly, the hs-MSI score was positively correlated with MMR-deficient gland density and the presence of MMR-deficient clusters, colocalizing PTEN and ARID1A expression loss. High hs-MSI scores and clonality were evidenced in 2 samples collected up to 4 months before EC diagnosis; hs-MSI scores increased over time in 5 LS carriers, whereas they decreased in a patient with endometrial hyperplasia after progestin therapy. In LS carriers, elevated hs-MSI scores were detected in aspirates from premalignant and malignant lesions and normal endometrium, correlating with MMR protein loss. hs-MSI assessment and MMR immunohistochemistry may help individualize EC risk assessment in women with LS

Decapping Protein Edc4 Regulates Dna Repair And Phenocopies Brca1

BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency

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

Biological basis of extensive pleiotropy between blood traits and cancer risk

Background: The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. Methods: Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. Results: The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. Conclusions: This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk

Capacidad predictiva del modelo BCRAPro frente al profesional de enfermería en la selección de candidatos a estudio genético de cáncer de mama u ovario hereditario

Objetivo: Comparar la capacidad predictiva del modelo predictivo BRCAPro y de los profesionales de enfermería con distintos niveles de formación/experiencia en la identificación de familias susceptibles de ser estudiadas genéticamente dada su historia personal y familiar de cáncer de mama. Método: Estudio descriptivo en el que 2 enfermeras con diferente grado de formación en consejo genético han estimado la probabilidad de ser portador de mutación en los genes BRCA1/BRCA2 de 157 familias. Se calculó la sensibilidad, especificidad, valor predictivo positivo (VPP) y valor predictivo negativo (VPN) de ambas enfermeras y del BRCAPro. Resultados: La enfermera con menor experiencia demostró mayor especificidad (N2:0,84) frente a la enfermera con mayor experiencia (N1:0,23) o a BRCAPro (0,47). La sensibilidad de las profesionales de enfermería fue de 0,95 (N1) y del 0,28 (N2), mientras que la de BRCAPro fue del 0,74. El VPP fue similar en las tres situaciones. El VPN de la enfermera con mayor experiencia (0,93) fue superior al de BRCAPro (0,85) y la enfermera con menor experiencia (0,72). Conclusiones: La experiencia clínica aporta una alta sensibilidad pero a costa de una pérdida significativa de especificidad. El modelo de predicción BRCAPro obtiene valores intermedios entre ambas enfermeras, por lo que podría ser una herramienta que ayudase a mejorar aquellos valores en los que se obtiene menor puntuación, es decir, la especificidad y VPP para enfermeras con mayor experiencia y la sensibilidad y VPN para aquellas con menor experiencia