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1.
Am J Hum Genet ; 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39096911

RESUMEN

Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.

2.
Nature ; 596(7872): 393-397, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34349265

RESUMEN

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.


Asunto(s)
Envejecimiento/genética , Ovario/metabolismo , Adulto , Alelos , Animales , Huesos/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Quinasa de Punto de Control 2/genética , Diabetes Mellitus Tipo 2 , Dieta , Europa (Continente)/etnología , Asia Oriental/etnología , Femenino , Fertilidad/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Envejecimiento Saludable/genética , Humanos , Longevidad/genética , Menopausia/genética , Menopausia Prematura/genética , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Insuficiencia Ovárica Primaria/genética , Útero
3.
Am J Hum Genet ; 110(3): 475-486, 2023 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-36827971

RESUMEN

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.


Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/genética , Genes BRCA2 , Mutación de Línea Germinal , Células Germinativas , Predisposición Genética a la Enfermedad
4.
Am J Hum Genet ; 108(7): 1190-1203, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34146516

RESUMEN

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).


Asunto(s)
Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Anotación de Secuencia Molecular , Regiones Promotoras Genéticas , Neoplasias de la Mama/genética , Sistemas CRISPR-Cas , Línea Celular , Mapeo Cromosómico , Cromosomas Humanos Par 2 , Femenino , Estudios de Asociación Genética , Variación Genética , Humanos , Factores de Riesgo , Eliminación de Secuencia
5.
Breast Cancer Res Treat ; 206(2): 295-305, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38653906

RESUMEN

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.


Asunto(s)
Índice de Masa Corporal , Densidad de la Mama , Neoplasias de la Mama , Estudio de Asociación del Genoma Completo , Hormonas Esteroides Gonadales , Análisis de la Aleatorización Mendeliana , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico por imagen , Hormonas Esteroides Gonadales/sangre , Globulina de Unión a Hormona Sexual/análisis , Globulina de Unión a Hormona Sexual/metabolismo , Globulina de Unión a Hormona Sexual/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Mamografía , Estradiol/sangre , Testosterona/sangre , Fenotipo
6.
J Med Genet ; 60(12): 1186-1197, 2023 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-37451831

RESUMEN

BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Estudio de Asociación del Genoma Completo , Judíos/genética , Israel/epidemiología , Predisposición Genética a la Enfermedad , Factores de Riesgo , Herencia Multifactorial/genética , Factores de Transcripción
7.
Hum Mutat ; 20232023.
Artículo en Inglés | MEDLINE | ID: mdl-38725546

RESUMEN

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.


Asunto(s)
Proteína BRCA1 , Proteína BRCA2 , Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Humanos , Estudios de Casos y Controles , Proteína BRCA2/genética , Femenino , Proteína BRCA1/genética , Neoplasias de la Mama/genética , Funciones de Verosimilitud , Variación Genética , Penetrancia , Pruebas Genéticas/métodos
8.
Breast Cancer Res ; 25(1): 93, 2023 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-37559094

RESUMEN

BACKGROUND: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. METHODS: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. RESULTS: Assuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). CONCLUSIONS: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.


Asunto(s)
Neoplasias de la Mama , Interacción Gen-Ambiente , Adulto , Femenino , Humanos , Predisposición Genética a la Enfermedad , Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Teorema de Bayes , Estudio de Asociación del Genoma Completo , Factores de Riesgo , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles
9.
Breast Cancer Res ; 25(1): 72, 2023 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-37340476

RESUMEN

INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.


Asunto(s)
Neoplasias de la Mama , Genes BRCA2 , Adulto , Femenino , Humanos , Índice de Masa Corporal , Proteína BRCA1/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteína BRCA2/genética , Riesgo , Estudios Retrospectivos , Aumento de Peso/genética , Heterocigoto , Predisposición Genética a la Enfermedad
10.
Br J Cancer ; 128(10): 1941-1954, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36959380

RESUMEN

BACKGROUND: Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults. METHODS: To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines. RESULTS: Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability. CONCLUSION: These studies of the genomic, transcriptomic and chemical biology landscape represent a resource 'atlas' for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCS is found.


Asunto(s)
Sarcoma de Células Claras , Niño , Adolescente , Adulto Joven , Humanos , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/metabolismo , Sarcoma de Células Claras/patología , Transcriptoma , Genómica , Secuencia de Bases , ARN , Proteínas de Fusión Oncogénica/genética
11.
Br J Cancer ; 128(12): 2283-2294, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37076566

RESUMEN

BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). RESULTS: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. CONCLUSIONS: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.


Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Humanos , Femenino , Virulencia , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ováricas/genética , Predisposición Genética a la Enfermedad
12.
Am J Hum Genet ; 107(5): 837-848, 2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33022221

RESUMEN

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.


Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Herencia Multifactorial , Neoplasias Primarias Secundarias/genética , Adulto , Anciano , Pueblo Asiatico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/etnología , Neoplasias de la Mama/terapia , Estudios de Cohortes , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/etnología , Neoplasias Primarias Secundarias/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Medición de Riesgo , Población Blanca
13.
Eur J Epidemiol ; 38(10): 1053-1068, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37789226

RESUMEN

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation.


Asunto(s)
Neoplasias de la Mama , Melatonina , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/epidemiología , Melatonina/genética , Melatonina/metabolismo , Teorema de Bayes , Polimorfismo de Nucleótido Simple , Modelos Logísticos , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad
14.
Breast Cancer Res ; 24(1): 2, 2022 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-34983606

RESUMEN

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.


Asunto(s)
Neoplasias de la Mama , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Riesgo
15.
Am J Hum Genet ; 104(1): 21-34, 2019 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-30554720

RESUMEN

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.


Asunto(s)
Neoplasias de la Mama/clasificación , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Herencia Multifactorial/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/prevención & control , Femenino , Humanos , Anamnesis , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Receptores de Estrógenos/metabolismo , Reproducibilidad de los Resultados , Medición de Riesgo
16.
Breast Cancer Res Treat ; 194(3): 673-682, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35780210

RESUMEN

PURPOSE: The American Cancer Society (ACS) published an updated Guideline for Cancer Prevention (ACS Guideline) in 2020. Research suggests that adherence to the 2012 ACS Guideline might lower breast cancer risk, but there is limited evidence that this applies to women at increased familial and genetic risk of breast cancer. METHODS: Using the Breast Cancer Family Registry (BCFR), a cohort enriched for increased familial and genetic risk of breast cancer, we examined adherence to three 2020 ACS Guideline recommendations (weight management (body mass index), physical activity, and alcohol consumption) with breast cancer risk in 9615 women. We used Cox proportional hazard regression modeling to calculate hazard ratios (HRs) and 95% confidence intervals (CI) overall and stratified by BRCA1 and BRCA2 pathogenic variant status, family history of breast cancer, menopausal status, and estrogen receptor-positive (ER +) breast cancer. RESULTS: We observed 618 incident invasive or in situ breast cancers over a median 12.9 years. Compared with being adherent to none (n = 55 cancers), being adherent to any ACS recommendation (n = 563 cancers) was associated with a 27% lower breast cancer risk (HR = 0.73, 95% CI: 0.55-0.97). This was evident for women with a first-degree family history of breast cancer (HR = 0.68, 95% CI: 0.50-0.93), women without BRCA1 or BRCA2 pathogenic variants (HR = 0.71, 95% CI: 0.53-0.95), postmenopausal women (HR = 0.63, 95% CI: 0.44-0.89), and for risk of ER+ breast cancer (HR = 0.63, 95% CI: 0.40-0.98). DISCUSSION: Adherence to the 2020 ACS Guideline recommendations for BMI, physical activity, and alcohol consumption could reduce breast cancer risk for postmenopausal women and women at increased familial risk.


Asunto(s)
Neoplasias de la Mama , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , American Cancer Society , Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Ejercicio Físico , Femenino , Humanos , Sistema de Registros , Factores de Riesgo , Estados Unidos/epidemiología
17.
Genet Med ; 24(1): 119-129, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34906479

RESUMEN

PURPOSE: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. METHODS: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. RESULTS: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. CONCLUSION: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.


Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Mutación de Línea Germinal/genética , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/genética
18.
J Pediatr ; 251: 113-119.e7, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35777474

RESUMEN

OBJECTIVE: To evaluate the risks, benefits, and utility of testing for adult-onset hereditary breast and ovarian cancer (HBOC) in adolescents and young adults. STUDY DESIGN: We evaluated interest in genetic testing of adolescents for adult-onset HBOC genes through semistructured interviews with mothers and adolescents who had previously participated in breast cancer research or had pursued (mothers) clinical testing for HBOC. RESULTS: The majority of mothers (73%) and daughters (75%) were interested in the daughter having genetic testing and were motivated by the future medical utility and current social utility of relieving anxiety and allowing them to prepare. Mothers and daughters both reported that approximately 3 years in the future was the best time to test the daughter regardless of the current age of the daughter. Overall, both mothers and daughters expressed the importance of the involvement of the mother to provide educational and emotional support but ultimately it was the daughter's decision to test. Balancing the independence and maturity of the daughter while reinforcing communication and support within the dyad was a prominent theme throughout the interviews. CONCLUSIONS: There is interest among some high-risk adolescents and young adults to engage in genetic counseling and undergo testing. Providing pretest and posttest genetic counseling, assessing preferences for parent involvement, and offering psychosocial support may be important if genetic testing for HBOC is offered to adolescents and young adults before age 25 years.


Asunto(s)
Neoplasias de la Mama , Madres , Adulto Joven , Femenino , Adolescente , Humanos , Adulto , Asesoramiento Genético , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/psicología , Núcleo Familiar , Pruebas Genéticas
19.
J Genet Couns ; 31(6): 1249-1260, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35794807

RESUMEN

Indications for genetic testing for inherited cancer syndromes are expanding both in the academic and the community setting. However, only a fraction of individuals who are candidates for testing pursue this option. Therefore, it is important to understand those factors that impact the uptake of genetic testing in individuals affected and unaffected with cancer. A successful translation of genomic risk stratification into clinical care will require that providers of this information are aware of the attitudes, perceived risks and benefits, and concerns of individuals who will be considering testing. The purpose of this study was to assess beliefs, attitudes and preferences for genetic risk information, by personal characteristics of women affected and unaffected by breast cancer enrolled in the Breast Cancer Family Registry Cohort. Data for this analysis came from eight survey questions, which asked participants (N = 9,048, 100% female) about their opinions regarding genetic information. Women reported that conveying the accuracy of the test was important and were interested in information related to personal level of risk, finding out about diseases that could be treated, and information that could be helpful to their families. Young women were most interested in how their own health needs might be impacted by genetic test results, while older women were more interested in how genetic information would benefit other members of the family. Interest in how the genetic test was performed was highest among Asian and Hispanic women. Women affected with breast cancer were more likely to report feeling sad about possibly passing down a breast cancer gene, while unaffected women were more uncertain about their future risk of cancer. The variety of informational needs identified has implications for how genetic counselors can tailor communication to individuals considering genetic testing.


Asunto(s)
Neoplasias de la Mama , Asesoramiento Genético , Femenino , Humanos , Anciano , Masculino , Asesoramiento Genético/psicología , Pruebas Genéticas , Neoplasias de la Mama/genética , Neoplasias de la Mama/psicología , Familia/psicología , Comunicación , Predisposición Genética a la Enfermedad
20.
Br J Sports Med ; 56(20): 1157-1170, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36328784

RESUMEN

OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.


Asunto(s)
Neoplasias de la Mama , Ejercicio Físico , Conducta Sedentaria , Femenino , Humanos , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Factores de Riesgo
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