Crook, Julia E.

A prospective analysis of women with terminal breast cancer admitted to CHNE from November 2006-August 2007 evaluated anecdotal observations that African American (AA) women are likelier than Caucasian women to evidence loco-regional recurrences (LRR). Women with terminal breast cancer who were admitted to CHNE, a not-for-profit hospice serving over 90% of Northeast Florida hospice patients, were eligible for participation. 134 terminal breast cancer patients were assessed by hospice nurses for LRR presence via chest wall examination. 80% of them (107) were Caucasian, 17% (23) were AA and 3% (4) were of other ethnicities. Evidence of LRR were noted in 13% of the women (17/134). The proportion of patients with LRR was higher in AA women than Caucasian women (26% vs. 10%, 6/23 vs. 11/107, respectively), although this difference was not statistically significant (p = 0.08). The majority of Caucasian women with LRR consented to a medical record review, but a minority of AA women consented (8/11 vs. 2/6, respectively, p = 0.16). Conclusion Evaluating disparities in breast cancer care outcomes is possible by reviewing data from patients served by hospice programs that aid a majority of patients within a community. This pilot data suggests that AA women with breast cancer have a higher incidence of loco-regional failure as a component of their terminal breast cancer disease than Caucasian women. A smaller proportion of AA patients and families agreed to participate in a medical record review study than Caucasians. Larger studies are necessary to confirm these findings, to elucidate factors contributing to disparities and to develop potential solutions.

Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in OBSCN (p = 0.0045–0.0009, MAF = 0.18–0.50) and two in TTN (both p = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (ILK, TCAP, DSC2, VCL, FXN, DSP and KCNQ1, p = 0.042–0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for OBSCN as well as TCAP, DSC2, VCL, NEXN, KCNJ2 and DMD (p = 0.044–0.008). Our results suggest that rare and common variants in OBSCN, as well as in other genes, could have modifying effects in cardiomyopathy.

AbstractIntroductionWe hypothesized that common Alzheimer's disease (AD)‐associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression.MethodsExpression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis.ResultsA variant within a DNase hypersensitive site 5′ of TREM2, rs9357347‐C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10−3 and 4.6 × 10−2, respectively). Meta‐analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10−2 and 3.5 × 10−3, Bonferroni‐corrected P = 6.7 × 10−2 and 7.1 × 10−3, respectively).DiscussionOur findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome‐wide association study meta‐analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.

AbstractIntroductionCompared to Caucasians, African Americans (AAs) have higher dementia prevalence, different genetic markers, and higher vascular risk factors. However, pathologic underpinnings are unknown.MethodsWe used neuropathologic and clinical data on 110 AA and 2500 Caucasians who were demented before death. The groups were compared regarding demographics, cognition, apolipoprotein E (APOE) genotype, comorbidities, and clinical and neuropathologic characteristics.ResultsAA and Caucasians differed in their demographics, cognition at the last visit before death, APOE genotype, presence of hypertension, primary clinical diagnoses, and AD, cerebrovascular disease (CVD), and other neuropathologies such as Lewy body disease (LBD).DiscussionAD, LBD, and CVD pathology were more common and TDP and frontotemporal lobar degeneration–tau less common in AA than in Caucasians. APOE accounted for most of the AD neuropathologic differences. If replicated, the observed differences in underlying neuropathology by race will be important for public health policy and recruitment for and interpreting of clinical trials.