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2.
Cancers (Basel) ; 13(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802509

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially permanent adverse effect of chemotherapeutic agents including taxanes such as paclitaxel and platinum-based compounds such as oxaliplatin and carboplatin. Previous studies have suggested that genetics may impact the risk of CIPN. We conducted genome-wide association studies (GWASs) for CIPN in two independent populations who had completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-CIPN20 assessments (a CIPN-specific 20-item questionnaire which includes three scales that evaluate sensory, autonomic, and motor symptoms). The study population N08Cx included 692 participants from three clinical trials (North Central Cancer Treatment Group (NCCTG) N08C1, N08CA, and N08CB) who had been treated with paclitaxel, paclitaxel plus carboplatin, or oxaliplatin. The primary endpoint for the GWAS was the change from pre-chemotherapy CIPN20 sensory score to the worse score over the following 18 weeks. Study population The Mayo Clinic Breast Disease Registry (MCBDR) consisted of 381 Mayo Clinic Breast Disease Registry enrollees who had been treated with taxane or platinum-based chemotherapy. The primary endpoint for the GWAS assessed was the earliest CIPN20 sensory score available after the completion of chemotherapy. In multivariate model analyses, chemotherapy regimen (p = 3.0 × 10-8) and genetic ancestry (p = 0.007) were significantly associated with CIPN in the N08Cx population. Only age (p = 0.0004) was significantly associated with CIPN in the MCBDR population. The SNP most associated with CIPN was rs56360211 near PDE6C (p =7.92 × 10-8) in N08Cx and rs113807868 near TMEM150C in the MCBDR (p = 1.27 × 10-8). Due to a lack of replication, we cannot conclude that we identified any genetic predictors of CIPN.

3.
Int J Cancer ; 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33675538

RESUMO

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.

4.
Hum Mol Genet ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33751038

RESUMO

Inherited genetic risk factors play a role in multiple myeloma (MM), yet considerable missing heritability exists. Rare risk variants at genome-wide association study (GWAS) loci are a new avenue to explore. Pleiotropy between lymphoid neoplasms (LNs) has been suggested in family history and genetic studies, but no studies have interrogated sequencing for pleiotropic genes or rare risk variants. Sequencing genetically enriched cases can help discover rarer variants. We analyzed exome sequencing in familial or early-onset MM cases to identify rare, functionally relevant variants near GWAS loci for a range of LNs. A total of 149 distinct and significant LN GWAS loci have been published. We identified six recurrent, rare, potentially deleterious variants within 5 kb of significant GWAS SNPs in 75 MM cases. Mutations were observed in BTNL2, EOMES, TNFRSF13B, IRF8, ACOXL, and TSPAN32. All six genes replicated in an independent set of 255 early-onset MM or familial MM or precursor cases. Expansion of our analyses to the full length of these six genes resulted in a list of 39 rare and deleterious variants, 7 of which segregated in MM families. Three genes also had significant rare variant burden in 733 sporadic MM cases compared with 935 control individuals: IRF8 (p = 1.0x10-6), EOMES (p = 6.0x10-6), and BTNL2 (p = 2.1x10-3). Together, our results implicate six genes in MM risk, provide support for genetic pleiotropy between LN subtypes, and demonstrate the utility of sequencing genetically enriched cases to identify functionally relevant variants near GWAS loci.

5.
Int J Epidemiol ; 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33755131

RESUMO

BACKGROUND: Rigorous evaluation of the calibration and discrimination of breast-cancer risk-prediction models in prospective cohorts is critical for applications under clinical guidelines. We comprehensively evaluated an integrated model incorporating classical risk factors and a 313-variant polygenic risk score (PRS) to predict breast-cancer risk. METHODS: Fifteen prospective cohorts from six countries with 239 340 women (7646 incident breast-cancer cases) of European ancestry aged 19-75 years were included. Calibration of 5-year risk was assessed by comparing expected and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50-70 years in those countries was evaluated by the proportion of women and future cases crossing clinically relevant risk thresholds. RESULTS: Among women <50 years old, the median (range) expected-to-observed ratio for the integrated model across 15 cohorts was 0.9 (0.7-1.0) overall and 0.9 (0.7-1.4) at the highest-risk decile; among women ≥50 years old, these were 1.0 (0.7-1.3) and 1.2 (0.7-1.6), respectively. The proportion of women identified above a 3% 5-year risk threshold (used for recommending risk-reducing medications in the USA) ranged from 7.0% in Germany (∼841 000 of 12 million) to 17.7% in the USA (∼5.3 of 30 million). At this threshold, 14.7% of US women were reclassified by adding the PRS to classical risk factors, with identification of 12.2% of additional future cases. CONCLUSION: Integrating a 313-variant PRS with classical risk factors can improve the identification of European-ancestry women at elevated risk who could benefit from targeted risk-reducing strategies under current clinical guidelines.

6.
Cancers (Basel) ; 13(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578652

RESUMO

Health-related quality of life (HRQOL) is an important prognostic patient-reported outcome in oncology. Because prior studies suggest that HRQOL is, in part, heritable, we performed a GWAS to elucidate genetic factors associated with HRQOL in breast cancer survivors. Physical and mental HRQOL were measured via paper surveys that included the PROMIS-10 physical and mental health domain scales in 1442 breast cancer survivors participating in the Mayo Clinic Breast Disease Registry (MCBDR). In multivariable regression analyses, age and financial concerns were significantly associated with global physical health (age: p = 1.6 × 10-23; financial concerns: p = 4.8 × 10-40) and mental health (age: p = 3.5 × 10-7; financial concerns: p = 2.0 × 10-69). Chemotherapy was associated with worse global mental health (p = 0.01). In the GWAS, none of the SNPs reached the genome-wide association significance threshold of 5 × 10-8 for associations with either global physical or global mental health, however, a cluster of SNPs in SCN10A, particularly rs112718371, appeared to be linked to worse global physical health (p = 5.21 × 10-8). Additionally, SNPs in LMX1B, SGCD, PARP12 and SEMA5A were also moderately associated with worse physical and mental health (p < 10-6). These biologically plausible candidate SNPs warrant further study as possible predictors of HRQOL.

7.
N Engl J Med ; 384(5): 440-451, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471974

RESUMO

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Razão de Chances , Risco , Análise de Sequência de DNA , Adulto Jovem
8.
Artigo em Inglês | MEDLINE | ID: mdl-33392844

RESUMO

PURPOSE: We evaluated the association of percent mammographic density (PMD), absolute dense area (DA), and non-dense area (NDA) with risk of "intrinsic" molecular breast cancer (BC) subtypes. METHODS: We pooled 3492 invasive BC and 10,148 controls across six studies with density measures from prediagnostic, digitized film-screen mammograms. We classified BC tumors into subtypes [63% Luminal A, 21% Luminal B, 5% HER2 expressing, and 11% as triple negative (TN)] using information on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor grade. We used polytomous logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CI) for density measures (per SD) across the subtypes compared to controls, adjusting for age, body mass index and study, and examined differences by age group. RESULTS: All density measures were similarly associated with BC risk across subtypes. Significant interaction of PMD by age (P = 0.001) was observed for Luminal A tumors, with stronger effect sizes seen for younger women < 45 years (OR = 1.69 per SD PMD) relative to women of older ages (OR = 1.53, ages 65-74, OR = 1.44 ages 75 +). Similar but opposite trends were seen for NDA by age for risk of Luminal A: risk for women: < 45 years (OR = 0.71 per SD NDA) was lower than older women (OR = 0.83 and OR = 0.84 for ages 65-74 and 75 + , respectively) (P < 0.001). Although not significant, similar patterns of associations were seen by age for TN cancers. CONCLUSIONS: Mammographic density measures were associated with risk of all "intrinsic" molecular subtypes. However, findings of significant interactions between age and density measures may have implications for subtype-specific risk models.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33277321

RESUMO

BACKGROUND: Clinical use of breast cancer risk prediction requires simplified models. We evaluate a simplified version of the validated Rosner-Colditz model and add percent mammographic density (MD) and polygenic risk score (PRS), to assess performance from ages 45-74. We validate using prospective data from the Mayo Mammography Health Study (MMHS). METHODS: We derived the model in the Nurses' Health Study (NHS) based on: MD, 77SNP PRS and a questionnaire score (QS) (lifestyle and reproductive factors). 2799 invasive breast cancer cases were diagnosed from 1990-2000. MD (using Cumulus software) and PRS were assessed in a nested case-control study. We assess model performance using this case-control data set and evaluate 10-year absolute breast cancer risk. The prospective MMHS validation dataset includes 21.8% of women age <50, and 434 incident cases identified over 10 years of follow-up. RESULTS: In the NHS, MD has the highest odds ratio (OR) for 10-year risk prediction: OR per SD =1.48 (95% CI 1.31 - 1.68), followed by PRS, OR per SD = 1.37 (95% CI 1.21 - 1.55) and QS, OR per SD = 1.25 (95% CI 1.11 - 1.41). In MMHS, the AUC adjusted for age was 0.595; for age+MD 0.636; for age+MD+QS 0.650; for age+MD+QS+PRS 0.687. CONCLUSIONS: A simplified assessment of QS, MD and PRS performs consistently to discriminate those at high 10-year breast cancer risk. IMPACT: This simplified model provides accurate estimation of 10-year risk of invasive breast cancer that can be used in a clinic setting to identify women who may benefit from chemopreventive intervention.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33097489

RESUMO

Endocrine therapy (ET) is underutilized to reduce breast cancer (BC) incidence among women at increased risk. Polygenic risk scores (PRSs) assessing 77 BC genetic susceptibility loci personalizes risk estimates. We examined effect of personalized PRS BC risk prediction on intention to take and ET uptake among women recruited from BC clinics. Eligible participants had a 10-year BC risk >5% by Tyrer-Cuzick model (International Breast Cancer Intervention Study [IBIS]) or >3.0 % 5-year Gail Model risk with no BC history or hereditary BC syndrome. At baseline, BC calculators estimated risk, ET options were reviewed, and questionnaires assessed ET intent. After genotyping, PRS-updated BC risk estimates, ET options, and intent to take ET were reassessed; ET uptake was assessed during follow-up. From March 2016 to October 2017, 151 patients were enrolled (median [range] age, 56.1 [36.0-76.4] years). Median 10-year and lifetime IBIS risks were 7.9% and 25.3%. Inclusion of PRS increased lifetime IBIS BC risk estimates for 81 patients (53.6%) and reduced risk for 70 (46.4%). Of participants with increased BC risk by PRS, 39 (41.9%) had greater intent to take ET; of those with decreased BC risk by PRS, 28 (46.7%) had less intent to take ET (P<.001). On multivariable regression, increased BC risk by PRS was associated with greater intent to take ET (P<.001). ET uptake was greater among participants with increased BC risk by PRS (53.4%) than with decreased risk (20.9%) (P<.001). PRS testing influenced intent to take and ET uptake. Assessing PRS effect on ET adherence is needed.

11.
AJR Am J Roentgenol ; 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32755210

RESUMO

BACKGROUND: Background parenchymal uptake (BPU) on molecular breast imaging (MBI) was identified as a breast cancer risk factor beyond mammographic density in a case-control study, but has not been confirmed in a cohort study. OBJECTIVE: To examine association of BPU with breast cancer, and to estimate absolute risk and discriminatory accuracy of BPU using a cohort study. METHODS: A retrospective cohort of women having MBI from 2004-2015, without prior breast cancer, was established. Radiologists, blinded to future breast cancer diagnoses, assessed BPU at baseline MBI as low (photopenic or minimal) or elevated (mild, moderate, or marked). Associations of BPU with breast cancer were estimated with multivariable Cox proportional hazards models of time to diagnosis. Five-year absolute risk was calculated for study subgroups. Discriminatory accuracy of BPU was assessed. RESULTS: Among 2992 women with mean age 56.3 years (sd 10.6) at MBI, breast cancer events occurred in 144 over 7.3 years median follow-up. Median time to diagnosis was 4.2 years (range 0.5-11.6 years) after MBI. Elevated BPU was associated with greater breast cancer risk (HR=2.39 [1.68, 3.41]; p=<0.001). This association remained in postmenopausal women (HR=3.50 [2.31, 5.31; p<0.001]) but was not significant in premenopausal women (HR=1.29 [0.72, 2.32]; p=0.39). Women with elevated BPU had five-year absolute risk of 4.3% (2.9, 5.7) vs. 2.5% (1.8, 3.1) for those with low BPU. Postmenopausal women with dense breasts and elevated BPU had five-year absolute risk of 8.1% (4.3, 11.8) vs. 2.8% (1.8, 3.8) for those with low BPU. Among postmenopausal women, discriminatory accuracy for invasive cancer was improved with addition of BPU over Gail risk score alone (C-statistic 65.1 vs. 59.1; p=0.04) and over BCSC risk score alone (66.4 vs. 60.4; p=0.04). CONCLUSION: BPU on MBI is an independent breast cancer risk factor, with the strongest association observed among postmenopausal women with dense breasts. In postmenopausal women, BPU provides incremental discrimination in breast cancer risk prediction when combined with the Gail model or BCSC model. CLINICAL IMPACT: Elevated BPU on MBI may identify a subset of women with dense breasts who would benefit most from supplemental screening or preventive options.

12.
Cancer Prev Res (Phila) ; 13(11): 967-976, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32718942

RESUMO

Over one million women in the United States receive biopsy diagnoses of benign breast disease (BBD) each year, which confer a 1.5-4.0-fold increase in breast cancer risk. Studies in the general population suggest that nonsteroidal anti-inflammatory agents (NSAID) lower breast cancer risk; however, associations among women with BBD are unknown. We assessed whether NSAID use among women diagnosed with BBD is associated with lower breast cancer risk. Participants included 3,080 women (mean age = 50.3 ± 13.5 years) in the Mayo BBD surgical biopsy cohort diagnosed between January 1, 1992 and December 31, 2001 who completed breast cancer risk factor questionnaires that assessed NSAID use, and whose biopsies underwent detailed pathology review, masked to outcome. Women were followed from date of BBD biopsy to breast cancer diagnosis (main outcome) or censoring (death, prophylactic mastectomy, reduction mammoplasty, lobular carcinoma in situ or last contact). Median follow-up time was 16.4 ± 6.0 years. Incident breast cancer was diagnosed among 312 women over a median follow-up of 9.9 years. Regular non-aspirin NSAID use was associated with lower breast cancer risk [HR = 0.63; 95% confidence interval (CI) = 0.46-0.85; P = 0.002] with trends of lower risk (highest tertiles of use vs. nonuse) for greater number of years used [HR = 0.55; 95% CI = 0.31-0.97; P trend = 0.003), days used per month (HR = 0.51; 95% CI = 0.33-0.80; P trend = 0.001) and lifetime number of doses taken (HR = 0.53; 95% CI = 0.31-0.89; P trend = 0.003). We conclude that nonaspirin NSAID use is associated with statistically significant lower breast cancer risk after a BBD biopsy, including a dose-response effect, suggesting a potential role for NSAIDs in breast cancer prevention among patients with BBD.

13.
Blood Adv ; 4(12): 2789-2797, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32569378

RESUMO

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.

14.
Radiology ; 296(1): 24-31, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32396041

RESUMO

Background The associations of density measures from the publicly available Laboratory for Individualized Breast Radiodensity Assessment (LIBRA) software with breast cancer have primarily focused on estimates from the contralateral breast at the time of diagnosis. Purpose To evaluate LIBRA measures on mammograms obtained before breast cancer diagnosis and compare their performance to established density measures. Materials and Methods For this retrospective case-control study, full-field digital mammograms in for-processing (raw) and for-presentation (processed) formats were obtained (March 2008 to December 2011) in women who developed breast cancer an average of 2 years later and in age-matched control patients. LIBRA measures included absolute dense area and area percent density (PD) from both image formats. For comparison, dense area and PD were assessed by using the research software (Cumulus), and volumetric PD (VPD) and absolute dense volume were estimated with a commercially available software (Volpara). Density measures were compared by using Spearman correlation coefficients (r), and conditional logistic regression (odds ratios [ORs] and 95% confidence intervals [CIs]) was performed to examine the associations of density measures with breast cancer by adjusting for age and body mass index. Results Evaluated were 437 women diagnosed with breast cancer (median age, 62 years ± 17 [standard deviation]) and 1225 matched control patients (median age, 61 years ± 16). LIBRA PD showed strong correlations with Cumulus PD (r = 0.77-0.84) and Volpara VPD (r = 0.85-0.90) (P < .001 for both). For LIBRA, the strongest breast cancer association was observed for PD from processed images (OR, 1.3; 95% CI: 1.1, 1.5), although the PD association from raw images was not significantly different (OR, 1.2; 95% CI: 1.1, 1.4; P = .25). Slightly stronger breast cancer associations were seen for Cumulus PD (OR, 1.5; 95% CI: 1.3, 1.8; processed images; P = .01) and Volpara VPD (OR, 1.4; 95% CI: 1.2, 1.7; raw images; P = .004) compared with LIBRA measures. Conclusion Automated density measures provided by the Laboratory for Individualized Breast Radiodensity Assessment from raw and processed mammograms correlated with established area and volumetric density measures and showed comparable breast cancer associations. © RSNA, 2020 Online supplemental material is available for this article.

15.
Am J Hematol ; 95(8): 906-917, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32279347

RESUMO

Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10-8 ; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10-14 ). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Linfocítica Crônica de Células B/genética , Linfocitose/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
17.
Cancer Epidemiol Biomarkers Prev ; 29(3): 599-605, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31932411

RESUMO

BACKGROUND: The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (CDH1, GATA3, KMT2C, MAP2K4, MAP3K1, NCOR1, PIK3CA, RUNX1, and TP53) in a subset of The Cancer Genome Atlas (TCGA). METHODS: Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites (n = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status. RESULTS: Increasing BMI was associated with increasing SCNV in all women (P = 0.039) and among women with ER- tumors (P = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers (P < 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers (P < 0.05 all women and among women with ER+ tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER- disease. GATA3 mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction. CONCLUSIONS: This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations. IMPACT: This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations.

18.
J Am Coll Radiol ; 17(3): 391-404, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31756308

RESUMO

PURPOSE: To assess changes in breast density (BD) awareness, knowledge, and attitudes among US women over a period of 5 years. METHODS: Using a probability-based web panel representative of the US population, we administered an identical BD survey in 2012 and 2017 to women aged 40 to 74 years. RESULTS: In 2017, 65.8% had heard of BD (versus 57.5% in 2012; P = .0002). BD awareness in both 2012 and 2017 was significantly associated with race, income, and education. Among women aware of BD in 2017, 76.5% had knowledge of BD's relationship to masking (versus 71.5% in 2012; P = .04); 65.5% had knowledge of BD's relationship to cancer risk (versus 58.5%; P = .009); and 47.3% had discussed BD with a provider (versus 43.1% in 2012; P = .13). After multivariable adjustment, residence in a state with BD legislation was associated in 2017 with knowledge of BD's relationship to risk but not to masking. Most women wanted to know their BD (62.5% in 2017 versus 59.8% in 2012; P = .46); this information was anticipated to cause anxiety in 44.8% (versus 44.9% in 2012; P = .96); confusion in 35.9% (versus 43.0%; P = .002); and feeling informed in 89.7% (versus 90.4%; P = .64). Over three-quarters supported federal BD legislation in both surveys. Response rate to the 2017 survey was 55% (1,502 of 2,730) versus 65% (1,506 of 2,311) in 2012. CONCLUSION: Although BD awareness has increased, important disparities persist. Knowledge of BD's impact on risk has increased; knowledge about masking and BD discussions with providers have not. Most women want to know their BD, would not feel anxious or confused as a result of knowing, and would feel empowered to make decisions. The federal BD notification legislation presents an opportunity to improve awareness and knowledge and encourage BD conversations with providers.

19.
Blood ; 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33512457

RESUMO

CLL has one of the highest familial-risks among cancers. MBL, the precursor to CLL, has a higher prevalence (13-18%) in families with two or more members with CLL compared to the general population (5-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count³500/µL) is ~1-5%/year, no low-count MBLs has been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly-sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 United States population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, twelve individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline of whom 60 individuals subsequently developed MBL (two high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess to that in the general population.

20.
Trials ; 20(1): 744, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852492

RESUMO

BACKGROUND: Breast cancer is the most common cancer and the leading cause of cancer mortality among Latinas. As more is learned about the association between mammographic breast density (MBD) and breast cancer risk, a number of U.S. states adopted legislation and now a federal law mandates written notification of MBD along with mammogram results. These notifications vary in content and readability, though, which may limit their effectiveness and create confusion or concern, especially among women with low health literacy or barriers to screening. The purpose of this study is to determine whether educational enhancement of MBD notification results in increased knowledge, decreased anxiety, and adherence to continued mammography screening among Latina women in a limited-resources setting. METHODS: Latinas LEarning About Density (LLEAD) is a randomized clinical trial (RCT) comparing the impact of three notification approaches on behavioral and psychological outcomes in Latina women. Approximately 2000 Latinas undergoing screening mammography in a safety-net community clinic will be randomized 1:1:1 to mailed notification (usual care); mailed notification plus written educational materials (enhanced); or mailed notification, written educational materials, plus verbal explanation by a promotora (interpersonal). The educational materials and verbal explanations are available in Spanish or English. Mechanisms through which written or verbal information influences future screening motivation and behavior will be examined, as well as moderating factors such as depression and worry about breast cancer, which have been linked to diagnostic delays among Latinas. The study includes multiple psychological measures (anxiety, depression, knowledge about MBD, perceived risk of breast cancer, worry, self-efficacy) and behavioral outcomes (continued adherence to mammography). Measurement time points include enrollment, 2-4 weeks post-randomization, and 1 and 2 years post-randomization. Qualitative inquiry related to process and outcomes of the interpersonal arm and cost analysis related to its implementation will be undertaken to understand the intervention's delivery and transferability. DISCUSSION: Legislation mandating written MBD notification may have unintended consequences on behavioral and psychological outcomes, particularly among Latinas with limited health literacy and resources. This study has implications for cancer risk communication and will offer evidence on the potential of generalizable educational strategies for delivering information on breast density to Latinas in limited-resource settings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02910986. Registered on 21 September 2016. Items from the WHO Trial Registration Data Set can be found in this protocol.


Assuntos
Neoplasias da Mama/diagnóstico , Comunicação em Saúde/métodos , Hispano-Americanos/psicologia , Mamografia/psicologia , Educação de Pacientes como Assunto/métodos , Adulto , Idoso , Ansiedade/prevenção & controle , Ansiedade/psicologia , Densidade da Mama , Neoplasias da Mama/psicologia , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/psicologia , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Letramento em Saúde , Humanos , Programas de Rastreamento/métodos , Programas de Rastreamento/psicologia , Pessoa de Meia-Idade , Cooperação do Paciente/psicologia , Pesquisa Qualitativa , Ensaios Clínicos Controlados Aleatórios como Assunto
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