RESUMEN
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.
Asunto(s)
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
The purpose of this quality improvement initiative was to identify anxious/distressed lung cancer patients and address their mental health needs directly related to the COVID-19. A total of 441 patients were screened utilizing a national distress thermometer. 47% were counseled by the NP, 32% sent for referral to the social worker. Patients reported reasons for distress as fear of delaying testing, contracting the virus and changes in their lifestyle. We found that screening all patients during the pandemic, yielded a higher than normal percentage of patients who were in need of some level of mental health services.
RESUMEN
INTRODUCTION: Lung cancer is the leading cause of cancer death in the USA, claiming more than 140,000 deaths annually. Delays in diagnosis and treatment can lead to missed opportunities for both curative and life prolonging therapies. This study aimed to evaluate duration of time to diagnosis and first treatment, as well as investigate reasons for delays in care. METHODS: This retrospective study included all lung cancer cases diagnosed by Stony Brook's Lung Cancer Evaluation Center (LCEC) between 2013 and 2019. Demographic, radiologic, pathologic and clinical variables were investigated, including cancer staging, histology, and medical and family histories. Evaluations included the determination of median time from initial encounter to diagnosis, median time from diagnosis to start of treatment and an exploration of the factors that influence possible causes for delays in care. RESULTS: The LCEC's comprehensive multidisciplinary lung nodule program yielded a median length of time from CT to PET of 11 days, PET to procedure of 13 days, procedure to treatment consult of 9 days, and from consult to treatment of 9 days. LCEC patients experienced an overall median of 44 days from initial presentation to first treatment compared to the national ideal of 62 days, thereby representing a 29% reduction in time from first CT to onset of treatment. CONCLUSION: Delays in lung cancer diagnosis and treatment can negatively impact patient morbidity and mortality. This study suggests that a coordinated multidisciplinary lung cancer program may reduce delays in care, thereby improving patient outcomes.
Asunto(s)
Carcinoma/diagnóstico , Carcinoma/terapia , Diagnóstico Tardío/prevención & control , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Tiempo de Tratamiento , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Derivación y Consulta , Estudios Retrospectivos , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single-nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome-wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP-level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway-, gene-, or SNP-level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (p = 0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway-level p = 0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI = 1.24-1.91, padj = 0.007). In conclusion, we found no evidence to support an association between vitamin D status and breast cancer risk in women of African ancestry, suggesting that vitamin D is unlikely to have significant effect on breast carcinogenesis. Interestingly, TYRP1 might be related to breast cancer through a non-vitamin D relevant mechanism but further studies are needed.
Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad/genética , Vitamina D/genética , Adulto , Población Negra , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina's HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5 Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P = 1.8 × 10 − 8). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 × 10 − 10) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 × 10 − 8) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Cromosomas Humanos Par 3/genética , Negro o Afroamericano/genética , Alelos , Población Negra/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Polimorfismo de Nucleótido Simple/genética , Receptores de Estrógenos/genética , Factores de Riesgo , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismoRESUMEN
BACKGROUND: Few studies have evaluated the performance of existing breast cancer risk prediction models among women of African ancestry. In replication studies of genetic variants, a change in direction of the risk association is a common phenomenon. Termed flip-flop, it means that a variant is risk factor in one population but protective in another, affecting the performance of risk prediction models. METHODS: We used data from the genome-wide association study (GWAS) of breast cancer in the African diaspora (The Root consortium), which included 3686 participants of African ancestry from Nigeria, USA, and Barbados. Polygenic risk scores (PRSs) were constructed from the published odds ratios (ORs) of four sets of susceptibility loci for breast cancer. Discrimination capacity was measured using the area under the receiver operating characteristic curve (AUC). RESULTS: Flip-flop phenomenon was observed among 30~40% of variants across studies. Using the 34 variants with consistent directionality among previous studies, we constructed a PRS with AUC of 0.531 (95% confidence interval [CI]: 0.512-0.550), which is similar to the PRS using 93 variants and ORs from European ancestry populations (AUC = 0.525, 95% CI: 0.506-0.544). Additionally, we found the 34-variant PRS has good discriminative accuracy in women with family history of breast cancer (AUC = 0.586, 95% CI: 0.532-0.640). CONCLUSIONS: We found that PRS based on variants identified from prior GWASs conducted in women of European and Asian ancestries did not provide a comparable degree of risk stratification for women of African ancestry. Further large-scale fine-mapping studies in African ancestry populations are desirable to discover population-specific genetic risk variants.
Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Pronóstico , Adulto , Anciano , Pueblo Asiatico , Población Negra/genética , Neoplasias de la Mama/patología , Femenino , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Nigeria/epidemiología , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Gene expression changes within the Hippo pathway were found to be associated with large tumor size and metastasis in breast cancer. The combined effect of genetic variants in genes of this pathway may have a causal role in breast cancer development. We examined 7086 SNPs that were not highly correlated (r2 < 0.8) in 35 Hippo pathway genes using data from the genome-wide association study of breast cancer from the Root Consortium, which includes 3686 participants of African ancestry from Nigeria, United States of America, and Barbados: 1657 cases (403 estrogen receptor-positive [ER+], 374 ER-) and 2029 controls. Gene-level analyses were conducted using improved AdaJoint test for large-scale genetic association studies adjusting for age, study site and the first four eigenvectors from the principal component analysis. SNP-level analyses were conducted with logistic regression. The Hippo pathway was significantly associated with risk of ER+ breast cancer (pathway-level P = 0.019), with WWC1 (Padj = 0.04) being the leading gene. The pathway-level significance was lost without WWC1 (P = 0.12). rs147106204 in the WWC1 gene was the most statistically significant SNP after gene-level adjustment for multiple comparisons (OR = 0.53, 95%CI = 0.41-0.70, Padj = 0.025). We found evidence of an association between genetic variations in the Hippo pathway and ER+ breast cancer. Moreover, WWC1 was identified as the most important genetic susceptibility locus highlighting the importance of genetic epidemiology studies of breast cancer in understudied populations.
Asunto(s)
Población Negra/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal/genética , Barbados , Neoplasias de la Mama/etnología , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo , Genotipo , Vía de Señalización Hippo , Humanos , Persona de Mediana Edad , Nigeria , Receptores de Estrógenos/metabolismo , Estados UnidosRESUMEN
Functional studies have elucidated the role of the mammalian target of rapamycin (mTOR) pathway in breast carcinogenesis, but to date, there is a paucity of data on its contribution to breast cancer risk in women of African ancestry. We examined 47628 SNPs in 61 mTOR pathway genes in the genome wide association study of breast cancer in the African Diaspora study (The Root consortium), which included 3686 participants (1657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10994 SNPs that were not highly correlated (r2 < 0.8). Odds ratio (OR) and 95% confidence interval (CI) were estimated with logistic regression for each single-nucleotide polymorphism. The mTOR pathway was significantly associated with overall and estrogen receptor-negative (ER-) breast cancer risk (P = 0.003 and 0.03, respectively). PRKAG3 (Padj = 0.0018) and RPS6KA3 (Padj = 0.061) were the leading genes for the associations with overall breast cancer risk and ER- breast cancer risk, respectively. rs190843378 in PRKAG3 was statistically significant after gene-level adjustment for multiple comparisons (OR = 0.50 for each T allele, 95% CI = 0.38-0.66, Padj = 3.6E-05), with a statistical power of 0.914. These results provide new insights on the biological relevance of the mTOR pathway in breast cancer progression and underscore the need for more genetic epidemiology studies of breast cancer in the African Diaspora.
Asunto(s)
Proteínas Quinasas Activadas por AMP/genética , Neoplasias de la Mama/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Serina-Treonina Quinasas TOR/genética , Alelos , Población Negra/genética , Neoplasias de la Mama/patología , Carcinogénesis/genética , Carcinogénesis/patología , Receptor alfa de Estrógeno/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Transducción de SeñalRESUMEN
MicroRNAs (miRNA) regulate breast biology by binding to specific RNA sequences, leading to RNA degradation and inhibition of translation of their target genes. While germline genetic variations may disrupt some of these interactions between miRNAs and their targets, studies assessing the relationship between genetic variations in the miRNA network and breast cancer risk are still limited, particularly among women of African ancestry. We systematically put together a list of 822 and 10,468 genetic variants among primary miRNA sequences and 38 genes in the miRNA biogenesis pathway, respectively; and examined their association with breast cancer risk in the ROOT consortium which includes women of African ancestry. Findings were replicated in an independent consortium. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). For overall breast cancer risk, three single-nucleotide polymorphisms (SNPs) in miRNA biogenesis genes DROSHA rs78393591 (OR = 0.69, 95 % CI: 0.55-0.88, P = 0.003), ESR1 rs523736 (OR = 0.88, 95 % CI: 0.82-0.95, P = 3.99 × 10(-4)), and ZCCHC11 rs114101502 (OR = 1.33, 95 % CI: 1.11-1.59, P = 0.002), and one SNP in primary miRNA sequence (rs116159732 in miR-6826, OR = 0.74, 95 % CI: 0.63-0.89, P = 0.001) were found to have significant associations in both discovery and validation phases. In a subgroup analysis, two SNPs were associated with risk of estrogen receptor (ER)-negative breast cancer, and three SNPs were associated with risk of ER-positive breast cancer. Several variants in miRNA and miRNA biogenesis pathway genes were associated with breast cancer risk. Risk associations varied by ER status, suggesting potential new mechanisms in etiology.
Asunto(s)
Neoplasias de la Mama/genética , Proteínas de Unión al ADN/genética , Receptor alfa de Estrógeno/genética , MicroARNs/genética , Ribonucleasa III/genética , Adulto , Anciano , Anciano de 80 o más Años , Población Negra , Neoplasias de la Mama/patología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , MicroARNs/biosíntesis , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
BACKGROUND Five-year survival rates among stage IIIA lung cancer patients range between 2% and 15%, and there is currently no consensus regarding optimal treatment approaches for these patients. The current investigation evaluated survival outcomes among stage IIIA lung cancer patients receiving 2 different treatment modalities, neoadjuvant chemotherapy followed by resection versus chemoradiation alone. MATERIAL AND METHODS This retrospective study is based on 127 patients attending the Lung Cancer Evaluation Center at Stony Brook Cancer Center between 2002 and 2014. Patients were treated either with neoadjuvant chemotherapy followed by resection or a regimen of chemoradiation alone. Kaplan-Meier curves were used to compare survival outcomes between groups and Cox proportional hazard models were used to evaluate treatment effects on survival, while adjusting for possible confounders. RESULTS Approximately one-fourth (n=33) of patients received neoadjuvant chemotherapy followed by surgery, whereas 94 patients received definitive chemoradiation. Patients in the surgical group were found to be significantly younger than those receiving chemoradiation alone (60.1 vs. 67.9 years, respectively; p=0.001). Five-year survival among patients receiving preoperative chemotherapy followed by resection was significantly higher than that among patients receiving chemoradiation alone (63% vs. 19%, respectively; p<0.001), whereas the hazard ratio (HR) was 3-4 times greater in the latter group (HR=3.77, 95% confidence interval=1.87, 7.61). CONCLUSIONS Findings from this study indicate that preoperative chemotherapy followed by resection can improve survival outcomes for stage IIIA lung cancer patients compared with chemoradiation alone. The results reflect a select surgical group of patients; thus, the data highlight the need to develop new therapies that may result in more patients being viable surgical candidates.
Asunto(s)
Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia , Quimioterapia Adyuvante , Terapia Combinada , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , New York/epidemiología , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.
Asunto(s)
Población Negra/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Neoplasias de la Próstata/etnología , Neoplasias de la Próstata/genética , Estudios de Casos y Controles , Estudios de Cohortes , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Factores de RiesgoRESUMEN
BACKGROUND: African American men (AA) exhibit a disproportionate share of prostate cancer (PRCA) incidence, morbidity, and mortality. Several genetic association studies have implicated select 8q24 loci in PRCA risk in AA. The objective of this investigation is to evaluate the association between previously reported 8q24 risk alleles and PRCA in African-Barbadian (AB) men known to have high rates of PRCA. METHODS: Ten previously reported candidate tag SNPs were genotyped and/or imputed in the 8q24 region in 532 AB men with PRCA and 513 AB controls from the Prostate Cancer in a Black Population (PCBP) study. RESULTS: Rs2124036 was significant in AB men, (OR = 2.7, 95% CI (1.3-5.3), P = 0.005, Empirical (max (T), corrected for multiple testing) P = 0.03) for the homozygous C/C genotype. Only a single SNP from this region remained statistically significant in our analysis of our AB population. These results may indicate the presence of a founder effect or due to the chosen SNPs not tagging an ancestral haplotype bearing the 8q24 risk allele(s) in this population or could reflect inadequate power to detect an association. We conducted a meta-analysis including our AB population along with two additional African Caribbean populations from Tobago and Jamaica for SNPs rs16901979 and rs1447295. Meta-analysis results were most significant for rs16901979 A allele (Z score 2.73; P = 0.006) with a summary OR = 1.31 (95% CI: 1.09-1.58). CONCLUSIONS: Additional studies are needed to provide deeper genotype coverage to further interrogate the 8q24 region to understand its contribution to PRCA in this population.
Asunto(s)
Alelos , Cromosomas Humanos Par 8/genética , Predisposición Genética a la Enfermedad/etnología , Predisposición Genética a la Enfermedad/genética , Neoplasias de la Próstata/etnología , Neoplasias de la Próstata/genética , África/etnología , Barbados/epidemiología , Región del Caribe/epidemiología , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad/epidemiología , Genotipo , Haplotipos , Humanos , Incidencia , Masculino , Polimorfismo de Nucleótido Simple/genética , Neoplasias de la Próstata/epidemiología , Factores de RiesgoRESUMEN
While advances in screening have resulted in declining rates of colorectal cancer (CRC) among adults ≥50 years of age since the mid-2000s, the incidence of early-onset CRC (EOCRC) has steadily increased over the last decade. This increase is not fully accounted for by hereditary factors, and the hypothesis that a sedentary lifestyle and obesity are the primary culprits is not fully supported by recent reports indicating that many affected individuals lead active lifestyles, maintain normal weight, and are otherwise healthy. Attention has shifted toward dietary patterns, notably the consumption of processed and ultra-processed foods found in Western diets, which are suspected of disrupting the gut microbiome balance that potentially leads to EOCRC. The impact of antibiotic use on the gut microbiome is also posited as a contributing factor, given its rising prevalence in medical and agricultural practices. We propose that a paradigm shift is necessary for EOCRC research, moving beyond metabolic factors to a broader exploration of dietary and microbial influences. Future research must prioritize understanding the relationship between dietary habits, particularly processed food intake, antibiotic exposure, and gut microbiome dynamics, to unravel the complex etiology of EOCRC. This will be crucial in developing comprehensive preventive strategies to address the increasing incidence of this malignancy in younger populations.
Asunto(s)
Neoplasias Colorrectales , Microbioma Gastrointestinal , Adulto , Humanos , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Dieta , Obesidad/epidemiología , AntibacterianosRESUMEN
African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.
Asunto(s)
Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Transcriptoma , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Población Negra/genética , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Negro o Afroamericano , Estados UnidosRESUMEN
We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.
Asunto(s)
Población Negra , Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Estudio de Asociación del Genoma Completo/métodos , Neoplasias de la Mama/genética , Población Negra/genética , Estudios de Casos y Controles , Factores de Riesgo , Neoplasias de la Mama Triple Negativas/genética , Alelos , Herencia Multifactorial/genética , Persona de Mediana Edad , Sitios Genéticos , Población Blanca/genéticaRESUMEN
Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.
Asunto(s)
Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Estudios de Casos y Controles , Factores de RiesgoRESUMEN
Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09-1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10(-16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Población Negra/genética , Neoplasias de la Mama/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Adulto , Alelos , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Mapeo Cromosómico/métodos , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 16/metabolismo , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 6/metabolismo , Intervalos de Confianza , Femenino , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido SimpleRESUMEN
Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of >1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10(-6) and 10(-5) in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3 × 10(-6); rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5 × 10(-5)). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample.
Asunto(s)
Población Negra/genética , Negro o Afroamericano/genética , Neoplasias de la Mama/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
Background: Non-Small Cell Lung Cancer (NSCLC), the leading cause of cancer-related death in the United States, is the most diagnosed form of lung cancer. While lung cancer incidence has steadily declined over the last decade, disparities in incidence and mortality rates persist among African American (AA), Caucasian American (CA), and Hispanic American (HA) populations. Researchers continue to explore how genetic ancestry may influence differential outcomes in lung cancer risk and development. The purpose of this evaluation is to highlight experimental research that investigates the differential impact of genetic mutations and ancestry on NSCLC incidence. Methods: This systematic review was conducted using PubMed and Google Scholar search engines. The following key search terms were used to select articles published between 2011 and 2022: "African/European/Latin American Ancestry NSCLC"; "Racial Disparities NSCLC"; "Genetic Mutations NSCLC"; "NSCLC Biomarkers"; "African Americans/Hispanic Americans/Caucasian Americans NSCLC incidence." Systematic reviews, meta-analyses, and studies outside of the US were excluded. A total of 195 articles were initially identified and after excluding 156 which did not meet eligibility criteria, 38 were included in this investigation. Results: Studies included in this analysis focused on racial/ethnic disparities in the following common genetic mutations observed in NSCLC: KRAS, EGFR, TP53, PIK3CA, ALK Translocations, ROS-1 Rearrangements, STK11, MET, and BRAF. Results across studies varied with respect to absolute differential expression. No significant differences in frequencies of specific genetic mutational profiles were noted between racial/ethnic groups. However, for HAs, lower mutational frequencies in KRAS and STK11 genes were observed. In genetic ancestry level analyses, multiple studies suggest that African ancestry is associated with a higher frequency of EGFR mutations. Conversely, Latin ancestry is associated with TP53 mutations. At the genomic level, several novel predisposing variants associated with African ancestry and increased risk of NSCLC were discovered. Family history among all racial/ethnic groups was also considered a risk factor for NSCLC. Conclusion: Results from racially and ethnically diverse studies can elucidate driving factors that may increase susceptibility and subsequent lung cancer risk across different racial/ethnic groups. Identification of biomarkers that can be used as diagnostic, prognostic, and therapeutic tools may help improve lung cancer survival among high-risk populations.
RESUMEN
Introduction: Colorectal cancer is the second most common cause of cancer-related death in the U.S. Lower SES and lack of health insurance coverage are 2 known risk factors for lower colorectal cancer survival. The primary objective of this research is to evaluate the survival rates of patients diagnosed with colorectal cancer who reside in an affluent suburb and to examine factors that may impact mortality. Methods: Information was collected from the Stony Brook Cancer Center registry for all cases of colorectal cancer diagnosed between 2010 and 2020. The Distressed Community Index, a proxy for SES based on geographic location and data obtained from the U.S. Census, was paired with patient ZIP codes to evaluate the impact of prosperity on survival. Chi-square tests, Kaplan-Meier survival curves, and hazard ratios are presented. Results: Among 946 patients with colorectal cancer, more than half resided in a prosperous (Distressed Community Index ≤ 20) ZIP code. Age and sex were similar between Distressed Community Index groups; however, a significant association was found between Black race and Distressed Community Index score >20 (p<0.01). Patients who were married were more likely to live in a prosperous ZIP code (p<0.01), whereas those with Medicaid health insurance were more likely to reside in a nonprosperous community (p<0.01). More than 75% of cases were diagnosed at Stage 2 or higher, and survival rates at 1 year and 5 years were 84.6% and 59.2%, respectively. Stage at diagnosis and overall survival were not associated with Distressed Community Index status. Older age (≥70 years) (hazard ratio=2.43, 95% CI=1.18, 5.01) and late stage at diagnosis (hazard ratio= 12.24, 95% CI=6.86, 21.81) were found to be associated with increased mortality at 5 years. Conclusions: In this relatively affluent study population from a tertiary care facility registry, improved survival rates among patients with colorectal cancer were not observed compared with national averages. Advanced stage of diagnosis and older age increased mortality in persons with colorectal cancer. Because early detection remains one of the most important tools for improving survival outcomes, efforts to increase screening education and reduce barriers as well as address challenges with screening adherence would likely benefit the population at risk, irrespective of community prosperity.