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Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment1. The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic therapy2. Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded by ERBB2)-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery3 were then correlated with multi-omic features in these diagnostic biopsies. Here we show that response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.
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Neoplasias de la Mama , Ecosistema , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Femenino , Genómica , Humanos , Aprendizaje Automático , Terapia Neoadyuvante , Microambiente TumoralRESUMEN
BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.
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Población Negra , Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Femenino , Humanos , Población Negra/genética , Neoplasias de la Mama/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido SimpleRESUMEN
The high-grade serous ovarian cancer (HGSOC) risk locus at chromosome 1p34.3 resides within a frequently amplified genomic region signifying the presence of an oncogene. Here, we integrate in silico variant-to-function analysis with functional studies to characterize the oncogenic potential of candidate genes in the 1p34.3 locus. Fine mapping of genome-wide association statistics identified candidate causal SNPs local to H3K27ac-demarcated enhancer regions that exhibit allele-specific binding for CTCF in HGSOC and normal fallopian tube secretory epithelium cells (FTSECs). SNP risk associations colocalized with eQTL for six genes (DNALI1, GNL2, RSPO1, SNIP1, MEAF6, and LINC01137) that are more highly expressed in carriers of the risk allele, and three (DNALI1, GNL2, and RSPO1) were upregulated in HGSOC compared to normal ovarian surface epithelium cells and/or FTSECs. Increased expression of GNL2 and MEAF6 was associated with shorter survival in HGSOC with 1p34.3 amplifications. Despite its activation of ß-catenin signaling, RSPO1 overexpression exerted no effects on proliferation or colony formation in our study of ovarian cancer and FTSECs. Instead, GNL2, MEAF6, and SNIP1 silencing impaired in vitro ovarian cancer cell growth. Additionally, GNL2 silencing diminished xenograft tumor formation, whereas overexpression stimulated proliferation and colony formation in FTSECs. GNL2 influences 60S ribosomal subunit maturation and global protein synthesis in ovarian cancer and FTSECs, providing a potential mechanism of how GNL2 upregulation might promote ovarian cancer development and mediate genetic susceptibility of HGSOC.
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Cromosomas Humanos Par 1 , Cistadenocarcinoma Seroso/genética , Proteínas de Unión al GTP/genética , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/genética , Sitios de Carácter Cuantitativo , Alelos , Empalme Alternativo , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Secuenciación de Inmunoprecipitación de Cromatina , Cistadenocarcinoma Seroso/patología , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Elementos de Facilitación Genéticos , Femenino , Proteínas de Unión al GTP/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Xenoinjertos , Humanos , Ratones , Clasificación del Tumor , Oportunidad Relativa , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Polimorfismo de Nucleótido Simple , Pronóstico , Transcriptoma , Población BlancaRESUMEN
Rare pathogenic variants in known breast cancer-susceptibility genes and known common susceptibility variants do not fully explain the familial aggregation of breast cancer. To investigate plausible genetic models for the residual familial aggregation, we studied 17,425 families ascertained through population-based probands, 86% of whom were screened for pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM, and TP53 via gene-panel sequencing. We conducted complex segregation analyses and fitted genetic models in which breast cancer incidence depended on the effects of known susceptibility genes and other unidentified major genes and a normally distributed polygenic component. The proportion of familial variance explained by the six genes was 46% at age 20-29 years and decreased steadily with age thereafter. After allowing for these genes, the best fitting model for the residual familial variance included a recessive risk component with a combined genotype frequency of 1.7% (95% CI: 0.3%-5.4%) and a penetrance to age 80 years of 69% (95% CI: 38%-95%) for homozygotes, which may reflect the combined effects of multiple variants acting in a recessive manner, and a polygenic variance of 1.27 (95% CI: 0.94%-1.65), which did not vary with age. The proportion of the residual familial variance explained by the recessive risk component was 40% at age 20-29 years and decreased with age thereafter. The model predicted age-specific familial relative risks consistent with those observed by large epidemiological studies. The findings have implications for strategies to identify new breast cancer-susceptibility genes and improve disease-risk prediction, especially at a young age.
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Adulto , Anciano de 80 o más Años , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Femenino , Humanos , Herencia Multifactorial/genética , Penetrancia , Adulto JovenRESUMEN
By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.
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Neoplasias de la Mama , Estudio de Asociación del Genoma Completo , Femenino , Humanos , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Transcriptoma/genética , Neoplasias de la Mama/genética , Estudios de Casos y ControlesRESUMEN
The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis1-6. It is therefore essential to identify patients who have a high risk of late relapse7-9. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns10,11; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression12,13). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47-62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials.
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Neoplasias de la Mama/clasificación , Neoplasias de la Mama/genética , Recurrencia Local de Neoplasia/clasificación , Recurrencia Local de Neoplasia/genética , Receptores de Estrógenos/genética , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Femenino , Humanos , Modelos Biológicos , Metástasis de la Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Especificidad de Órganos , Pronóstico , Receptor ErbB-2/deficiencia , Receptor ErbB-2/genética , Receptores de Estrógenos/análisis , Receptores de Estrógenos/deficiencia , Factores de Tiempo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Common genetic variation throughout the genome together with rare coding variants identified to date explain about a half of the inherited genetic component of epithelial ovarian cancer risk. It is likely that rare variation in the non-coding genome will explain some of the unexplained heritability, but identifying such variants is challenging. The primary problem is lack of statistical power to identifying individual risk variants by association as power is a function of sample size, effect size and allele frequency. Power can be increased by using burden tests which test for association of carriers of any variant in a specified genomic region. This has the effect of increasing the putative effect allele frequency. PAX8 is a transcription factor that plays a critical role in tumour progression, migration and invasion. Furthermore, regulatory elements proximal to target genes of PAX8 are enriched for common ovarian cancer risk variants. We hypothesised that rare variation in PAX8 binding sites are also associated with ovarian cancer risk, but unlikely to be associated with risk of breast, colorectal or endometrial cancer. We have used publicly available, whole-genome sequencing data from the UK 100,000 Genomes Project to evaluate the burden of rare variation in PAX8 binding sites across the genome. Data were available for 522 ovarian cancers, 2,984 breast cancers, 2,696 colorectal cancers, 836 endometrial cancers and 2253 non-cancer controls. Active binding sites were defined using data from multiple PAX8 and H3K27 ChIPseq experiments. We found no association between the burden of rare variation in PAX8 binding sites (defined in several ways) and risk of ovarian, breast or endometrial cancer. An apparent association with colorectal cancer was likely to be a technical artefact as a similar association was also detected for rare variation in random regions of the genome. Despite the null result this study provides a proof-of -principle for using burden testing to identify rare, non-coding germline genetic variation associated with disease. Larger sample sizes available from large-scale sequencing projects together with improved understanding of the function of the non-coding genome will increase the potential of similar studies in the future.
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BACKGROUND: Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander (NHPI) women. METHODS: Participants included 1734 Asian (785 cases, 949 controls), 266 NHPI (99 cases, 167 controls), 1149 Hispanic (505 cases, 644 controls), and 24,189 White (9,981 cases, 14,208 controls) women from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations by race and ethnicity. RESULTS: Heterogeneity in EOC risk associations by race and ethnicity (p ≤ 0.02) was observed for oral contraceptive (OC) use, parity, tubal ligation and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in NHPI and Asian women. The inverse association for tubal ligation with risk was most pronounced for NHPI participants (OR=0.25, 95% CI 0.13-0.48), versus Asian and White participants, respectively (OR=0.68, 95% CI 0.51-0.90; OR=0.78, 95% CI 0.73-0.85). CONCLUSIONS: Differences in EOC risk factor associations were observed across racial and ethnic groups, which could in part be due to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies.
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Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for the prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual-level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined (1) the PRSs built in the AA training dataset and (2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odds ratio per standard deviation of the joint PRS in the validation set was 1.34 [95% confidence interval (CI): 1.27-1.42] with the area under receiver operating characteristic curve (AUC) of 0.581. Compared with women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared with existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.
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Neoplasias de la Mama , Estudio de Asociación del Genoma Completo , Neoplasias de la Mama/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Herencia Multifactorial/genética , Receptores de Estrógenos/genética , Factores de RiesgoRESUMEN
BACKGROUND: Genetic, lifestyle, reproductive, and anthropometric factors are associated with the risk of developing breast cancer. However, it is not yet known whether polygenic risk score (PRS) and absolute risk based on a combination of risk factors are associated with the risk of progression of breast cancer. This study aims to estimate the distribution of sojourn time (pre-clinical screen-detectable period) and mammographic sensitivity by absolute breast cancer risk derived from polygenic proï¬le and the other risk factors. METHODS: The authors used data from a population-based case-control study. Six categories of 10-year absolute risk based on different combinations of risk factors were derived using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm. Women were classiï¬ed into low, medium, and high-risk groups. The authors constructed a continuous-time multistate model. To calculate the sojourn time, they simulated the trajectories of subjects through the disease states. RESULTS: There was little diï¬erence in sojourn time with a large overlap in the 95% conï¬dence interval (CI) between the risk groups across the six risk categories and PRS studied. However, the age of entry into the screen-detectable state varied by risk category, with the mean age of entry of 53.4 years (95% CI, 52.2-54.1) and 57.0 years (95% CI, 55.1-57.7) in the high-risk and low-risk women, respectively. CONCLUSION: In risk-stratiï¬ed breast screening, the age at the start of screening, but not necessarily the frequency of screening, should be tailored to a woman's risk level. The optimal risk-stratiï¬ed screening strategy that would improve the beneï¬t-to-harm balance and the cost-eï¬ectiveness of the screening programs needs to be studied.
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Neoplasias de la Mama , Femenino , Humanos , Persona de Mediana Edad , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/diagnóstico , Puntuación de Riesgo Genético , Estudios de Casos y Controles , Edad de Inicio , Factores de Riesgo , Medición de Riesgo , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing. METHODS: We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia. RESULTS: WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03-1.39) and in women (1.15, 1.06-1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03-1.57; and 1.40, 1.10-1.77, respectively), and with colon cancer in women (1.20, 1.07-1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women. CONCLUSIONS: This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI.
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Índice de Masa Corporal , Neoplasias Colorrectales , Análisis de la Aleatorización Mendeliana , Relación Cintura-Cadera , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Masculino , Femenino , Factores de Riesgo , Circunferencia de la CinturaRESUMEN
OBJECTIVE: This study aimed to provide an up-to-date systematic review of "the long-term outcomes of bilateral salpingo-oophorectomy at the time of hysterectomy" and perform a meta-analysis for the reported associations. DATA SOURCES: Our study updated a previous systematic review by searching the literature using PubMed, Web of Science, and Embase for publications between January 2015 and August 2022. STUDY ELIGIBILITY CRITERIA: Our study included studies of women who had a hysterectomy with bilateral salpingo-oophorectomy vs women who had a hysterectomy with ovarian conservation or no surgery. METHODS: The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations. Adjusted hazard ratios were extracted and combined to obtain fixed effect estimates. RESULTS: Compared with hysterectomy or no surgery, hysterectomy with bilateral salpingo-oophorectomy in young women was associated with decreased risk of breast cancer (hazard ratio, 0.78; 95% confidence interval, 0.73-0.84) but with an increased risk of colorectal cancer (hazard ratio, 1.27; 95% confidence interval, 1.10-1.47). In addition, it was associated with an increased risk of total cardiovascular diseases, coronary heart disease, and stroke with hazard ratios of 1.18 (95% confidence interval, 1.11-1.25), 1.17 (95% confidence interval, 1.10-1.25), and 1.20 (95% confidence interval, 1.10-1.31), respectively. Compared with no surgery, hysterectomy with bilateral salpingo-oophorectomy before the age of 50 years was associated with an increased risk of hyperlipidemia (hazard ratio, 1.44; 95% confidence interval, 1.25-1.65), diabetes mellitus (hazard ratio, 1.16; 95% confidence interval, 1.09-1.24), hypertension (hazard ratio, 1.13; 95% confidence interval, 1.06-1.20), dementia (hazard ratio, 1.70; 95% confidence interval, 1.07-2.69), and depression (hazard ratio, 1.39; 95% confidence interval, 1.22-1.60). The evidence on the association with all-cause mortality in young women showed substantial heterogeneity between the studies (I2=85%; P<.01). CONCLUSION: Hysterectomy with bilateral salpingo-oophorectomy was associated with multiple long-term outcomes. The benefits of the addition of bilateral salpingo-oophorectomy to hysterectomy should be balanced against the risks.
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Enfermedades Cardiovasculares , Diabetes Mellitus , Femenino , Humanos , Persona de Mediana Edad , Salpingooforectomía , Ovariectomía , Histerectomía/efectos adversosRESUMEN
OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.
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Neoplasias , Medicina Estatal , Humanos , Reparación de la Incompatibilidad de ADN/genética , Laboratorios , GenómicaRESUMEN
AIMS/HYPOTHESIS: Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk. METHODS: We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10-8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence. RESULTS: In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10-3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints. CONCLUSIONS/INTERPRETATION: Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis. DATA AVAILABILITY: Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer ( https://bcac.ccge.medschl.cam.ac.uk/bcacdata/ ); and overall prostate cancer ( http://practical.icr.ac.uk/blog/ ). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).
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Neoplasias de la Mama , Neoplasias Colorrectales , Diabetes Mellitus Tipo 2 , Neoplasias de la Próstata , Masculino , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicaciones , Factores de Riesgo , Glucosa , Estudio de Asociación del Genoma Completo , PPAR gamma/genética , Neoplasias de la Mama/genética , Neoplasias de la Próstata/complicaciones , Neoplasias Colorrectales/genética , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Breast cancer is one of the three most common cancers worldwide and is the most common malignancy in women. Treatment approaches for breast cancer are diverse and varied. Clinicians must balance risks and benefits when deciding treatments, and models have been developed to support this decision-making. Genomic risk scores (GRSs) may offer greater clinical value than standard clinicopathological models, but there is limited evidence as to whether these models perform better than the current clinical standard of care. METHODS: PREDICT and GRSs were adapted using data from the original papers. Univariable Cox proportional hazards models were produced with breast cancer-specific survival (BCSS) as the outcome. Independent predictors of BCSS were used to build multivariable models with PREDICT. Signatures which provided independent prognostic information in multivariable models were incorporated into the PREDICT algorithm and assessed for calibration, discrimination and reclassification. RESULTS: EndoPredict, MammaPrint and Prosigna demonstrated prognostic power independent of PREDICT in multivariable models for ER-positive patients; no score predicted BCSS in ER-negative patients. Incorporating these models into PREDICT had only a modest impact upon calibration (with absolute improvements of 0.2-0.8%), discrimination (with no statistically significant c-index improvements) and reclassification (with 4-10% of patients being reclassified). CONCLUSION: Addition of GRSs to PREDICT had limited impact on model fit or treatment received. This analysis does not support widespread adoption of current GRSs based on our implementations of commercial products.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Pronóstico , Mama/patología , Modelos de Riesgos Proporcionales , Expresión GénicaRESUMEN
BACKGROUND: Second primary cancer incidence is rising among breast cancer survivors. We examined the risks of non-breast second primaries, in combination and at specific cancer sites, through a systematic review and meta-analysis. METHODS: We conducted a systematic search of PubMed, Embase, and Web of Science, seeking studies published by March 2022. We included studies that reported standardized incidence ratios (SIRs), with associated standard errors, assessing the combined risk of second non-breast primaries following breast cancer. We performed meta-analyses of combined second primary risks, stratifying by age, follow-up duration, and geographic region. We also assessed second primary risks at several specific sites, stratifying by age. The inverse variance method with DerSimonian-Laird estimators was used in all meta-analyses, assuming a random-effects model. Associated biases and study quality were evaluated using the Newcastle-Ottawa scale. RESULTS: One prospective and twenty-seven retrospective cohort studies were identified. SIRs for second non-breast primaries combined ranged from 0.84 to 1.84. The summary SIR estimate was 1.24 (95% CI 1.14-1.36, I2: 99%). This varied by age: the estimate was 1.59 (95% CI 1.36-1.85) when breast cancer was diagnosed before age 50, which was significantly higher than in women first diagnosed at 50 or over (SIR: 1.13, 95% CI 1.01-1.36, p for difference: < 0.001). SPC risks were also significantly higher when based on Asian, rather than European, registries (Asia-SIR: 1.47, 95% CI 1.29-1.67. Europe-SIR: 1.16, 95% CI 1.04-1.28). There were significantly increased risks of second thyroid (SIR: 1.89, 95% CI 1.49-2.38), corpus uteri (SIR: 1.84, 95% CI 1.53-2.23), ovary (SIR: 1.53, 95% CI 1.35-1.73), kidney (SIR: 1.43, 95% CI 1.17-1.73), oesophagus (SIR: 1.39, 95% CI 1.26-1.55), skin (melanoma) (SIR: 1.34, 95% CI 1.18-1.52), blood (leukaemia) (SIR: 1.30, 95% CI 1.17-1.45), lung (SIR: 1.25, 95% CI 1.03-1.51), stomach (SIR: 1.23, 95% CI 1.12-1.36) and bladder (SIR: 1.15, 95% CI 1.05-1.26) primaries. CONCLUSIONS: Breast cancer survivors are at significantly increased risk of second primaries at many sites. Risks are higher for those diagnosed with breast cancer before age 50 and in Asian breast cancer survivors compared to European breast cancer survivors. This study is limited by a lack of data on potentially confounding variables. The conclusions may inform clinical management decisions following breast cancer, although specific clinical recommendations lie outside the scope of this review.
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Neoplasias de la Mama , Neoplasias Primarias Secundarias , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/complicaciones , Estudios Retrospectivos , Estudios Prospectivos , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Incidencia , Factores de RiesgoRESUMEN
Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability (hg2) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%-6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin.
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Carcinoma Epitelial de Ovario/genética , Proteínas Co-Represoras/genética , Cistadenocarcinoma Seroso/genética , Elementos de Facilitación Genéticos , Histonas/genética , Proteínas del Tejido Nervioso/genética , Neoplasias Ováricas/genética , Alelos , Sitios de Unión , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/patología , Mapeo Cromosómico , Proteínas Co-Represoras/metabolismo , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/patología , Femenino , Predisposición Genética a la Enfermedad , Genoma Humano , Estudio de Asociación del Genoma Completo , Histonas/metabolismo , Humanos , Patrón de Herencia , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/patología , Penetrancia , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
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.
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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 BlancaRESUMEN
OBJECTIVE: The presence of macroscopic residual disease after primary cytoreductive surgery (PCS) is an important factor influencing survival for patients with high-grade serous ovarian cancer (HGSC). More research is needed to identify factors associated with having macroscopic residual disease. We analyzed 12 lifestyle and personal exposures known to be related to ovarian cancer risk or inflammation to identify those associated with having residual disease after surgery. METHODS: This analysis used data on 2054 patients with advanced stage HGSC from the Ovarian Cancer Association Consortium. The exposures were body mass index, breastfeeding, oral contraceptive use, depot-medroxyprogesterone acetate use, endometriosis, first-degree family history of ovarian cancer, incomplete pregnancy, menopausal hormone therapy use, menopausal status, parity, smoking, and tubal ligation. Logistic regression models were fit to assess the association between these exposures and having residual disease following PCS. RESULTS: Menopausal estrogen-only therapy (ET) use was associated with 33% lower odds of having macroscopic residual disease compared to never use (OR = 0.67, 95%CI 0.46-0.97, p = 0.033). Compared to nulliparous women, parous women who did not breastfeed had 36% lower odds of having residual disease (OR = 0.64, 95%CI 0.43-0.94, p = 0.022), while there was no association among parous women who breastfed (OR = 0.90, 95%CI 0.65-1.25, p = 0.53). CONCLUSIONS: The association between ET and having no macroscopic residual disease is plausible given a strong underlying biologic hypothesis between this exposure and diagnosis with HGSC. If this or the parity finding is replicated, these factors could be included in risk stratification models to determine whether HGSC patients should receive PCS or neoadjuvant chemotherapy.
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Procedimientos Quirúrgicos de Citorreducción , Neoplasias Ováricas , Embarazo , Humanos , Femenino , Estudios Retrospectivos , Neoplasias Ováricas/tratamiento farmacológico , Carcinoma Epitelial de Ovario , ParidadRESUMEN
OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.