Comprehensive association analysis of speech recognition thresholds after cisplatin-based chemotherapy in survivors of adult-onset cancer.

PURPOSE: Deficits in speech understanding constitute one of the most severe consequences of hearing loss. Here we investigate the clinical and genetic risk factors for symmetric deterioration of speech recognition thresholds (SRT) among cancer survivors treated with cisplatin. METHODS: SRT was measured using spondaic words and calculating the mean of measurements for both ears with symmetric SRT values. For clinical associations, SRT-based hearing disability (SHD) was defined as SRT≥15 dB hearing loss and clinical variables were derived from the study dataset. Genotyped blood samples were used for GWAS with rank-based inverse normal transformed SRT values as the response variable. Age was used as a covariate in association analyses. RESULTS: SHD was inversely associated with self-reported health (p = 0.004). Current smoking (p = 0.002), years of smoking (p = 0.02), BMI (p < 0.001), and peripheral motor neuropathy (p = 0.003) were positively associated with SHD, while physical activity was inversely associated with SHD (p = 0.005). In contrast, cumulative cisplatin dose, peripheral sensory neuropathy, hypertension, and hypercholesterolemia were not associated with SHD. Although no genetic variants had an association p value < 5 × 10-8 , 22 genetic variants were suggestively associated (p < 10-5 ) with SRT deterioration. Three of the top variants in 10 respective linkage disequilibrium regions were either positioned within the coding sequence or were eQTLs for genes involved in neuronal development (ATE1, ENAH, and ZFHX3). CONCLUSION: Current results improve our understanding of risk factors for SRT deterioration in cancer survivors. Higher BMI, lower physical activity, and smoking are associated with SHD. Larger samples would allow for expansion of the current findings on the genetic architecture of SRT.

Changes in the Vaginal Microbiome and Associated Toxicities Following Radiation Therapy for Gynecologic Cancers.

Postmenopausal women often suffer from vaginal symptoms associated with atrophic vaginitis. Additionally, gynecologic cancer survivors may live for decades with additional, clinically significant, persistent vaginal toxicities caused by cancer therapies, including pain, dyspareunia, and sexual dysfunction. The vaginal microbiome (VM) has been previously linked with vaginal symptoms related to menopause (i.e. dryness). Our previous work showed that gynecologic cancer patients exhibit distinct VM profiles from healthy women, with low abundance of lactobacilli and prevalence of multiple opportunistic pathogenic bacteria. Here we explore the association between the dynamics and structure of the vaginal microbiome with the manifestation and persistence of vaginal symptoms, during one year after completion of cancer therapies, while controlling for clinical and sociodemographic factors. We compared cross-sectionally the vaginal microbiome in 134 women, 64 gynecologic patients treated with radiotherapy and 68 healthy controls, and we longitudinally followed a subset of 52 women quarterly (4 times in a year: pre-radiation therapy, 2, 6 and 12 months post-therapy). Differences among the VM profiles of cancer and healthy women were more pronounced with the progression of time. Cancer patients had higher diversity VMs and a variety of vaginal community types (CTs) that are not dominated by Lactobacilli, with extensive VM variation between individuals. Additionally, cancer patients exhibit highly unstable VMs (based on Bray-Curtis distances) compared to healthy controls. Vaginal symptoms prevalent in cancer patients included vaginal pain (40%), hemorrhage (35%), vaginismus (28%) and inflammation (20%), while symptoms such as dryness (45%), lack of lubrication (33%) and dyspareunia (32%) were equally or more prominent in healthy women at baseline. However, 24% of cancer patients experienced persistent symptoms at all time points, as opposed to 12% of healthy women. Symptom persistence was strongly inversely correlated with VM stability; for example, patients with persistent dryness or abnormally high pH have the most unstable microbiomes. Associations were identified between vaginal symptoms and individual bacterial taxa, including: Prevotella with vaginal dryness, Delftia with pain following vaginal intercourse, and Gemillaceaea with low levels of lubrication during intercourse. Taken together our results indicate that gynecologic cancer therapy is associated with reduced vaginal microbiome stability and vaginal symptom persistence.

Comparisons of Depression, Sexual Function, and Quality of Life Between Women With Gynecological Cancers and Race-Matched Healthy Controls.

BACKGROUND: Although higher incidence and mortality of gynecological cancer (GynCa) are documented in black compared with white women, few studies have documented quality of life (QOL) or healthy control comparisons. OBJECTIVE: This study compared depression, sexual function, and QOL between patients with GynCa and race-matched healthy controls. METHODS: Patients with GynCa and healthy controls completed the Patient Health Questionnaire-9, Female Sexual Function Index, and Functional Assessment of Cancer Therapy-General measures at baseline; GynCa patients were assessed again at 6 months post-radiation therapy (RT). RESULTS: Analyses included 84 participants (51% white, 49% black), including 28 GynCa patients and 56 controls with similar marital status. Compared with healthy controls, patients were younger, had a higher body mass index, and had more depression (P = .01); 82% of the patients and 71% of the healthy controls met criteria for sexual dysfunction at baseline (P = .29). Patients pre-RT had greater sexual dysfunction and lower QOL (P = .001) than controls did; patients at 6-month post-RT showed improved sexual function scores compared with pre-RT, with similar results to controls. White GynCa patients reported less sexual desire (P = .02), more pain (P = .05), and lower total Female Sexual Function Index scores (P = .01) than did black GynCa patients. Both black and white GynCa patients reported lower total QOL than their race-matched controls did (P = .07 and P = .002). CONCLUSIONS: Women with GynCa reported more depression and lower QOL than did healthy controls pre-RT. Among GynCa patients, white women had more sexual dysfunction than black women did. IMPLICATIONS FOR PRACTICE: The differences in sexual dysfunction between white and black women with GynCa suggest developing guidelines directing routine sexual assessment and rehabilitation in women treated for GynCa.

Comparison of vaginal microbiota in gynecologic cancer patients pre- and post-radiation therapy and healthy women.

BACKGROUND: While the importance of commensal microbes in vaginal health is well appreciated, little is known about the effects of gynecological cancer (GynCa) and radiation therapy (RT) on the vaginal microbiome (VM) of postmenopausal women. METHODS: We studied women with GynCa, pre- (N = 65) and post-RT (N = 25) and a group of healthy controls (N = 67) by sequencing the V4 region of the 16S rRNA gene from vaginal swabs and compared the diversity and composition of VMs between the three groups accounting for potential confounding factors in multivariate analysis of variance. RESULTS: Comparisons of cancer vs healthy groups revealed that Lactobacillus and Bifidobacterium have significantly higher relative abundance in the healthy group, while the cancer group was enriched in 16 phylogroups associated with bacterial vaginosis (BV) and inflammation, including Sneathia, Prevotella, Peptoniphilus, Fusobacterium, Anaerococcus, Dialister, Moryella, and Peptostreptococcus. In our sample, RT affected the α-diversity and correlated with higher abundance of typically rare VM species, including several members of the Lacnospiraceae family, a taxon previously linked to vaginal dysbiosis. In addition to cancer and treatment modalities, age and vaginal pH were identified as significant parameters that structure the VM. CONCLUSIONS: This is among the first reports identifying VM changes among postmenopausal women with cancer. RT alone seems to affect several phylogroups (12 bacterial genera), while gynecological cancer and its treatment modalities are associated with even greater significant shifts in the vaginal microbiota including the enrichment of opportunistic bacterial pathogens, which warrants further attention.

Capturing cancer initiating events in OncoCL, a cancer cell ontology.

We have developed an ontology, OncoCL, to classify cancer cells and provide a framework for consistent annotation of cancer-associated data from conventional surgical pathology and cancer molecular biology for the purpose of access, comparison, and analysis. The cell type ontology, CL, describes normal cell types and was not designed to capture the pathology of cancer cells. OncoCL builds upon CL, as a canonical cell (represented in CL) undergoes oncogenic change and tumorigenesis with the acquisition of the cancer hallmarks described by Hanahan and Weinberg.

Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of Paclitaxel-induced sensory peripheral neuropathy.

PURPOSE: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results. EXPERIMENTAL DESIGN: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis. RESULTS: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel. CONCLUSIONS: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients.

Chemotherapeutic-induced apoptosis: a phenotype for pharmacogenomics studies.

AIM: To determine whether cellular apoptosis is a suitable phenotypic trait for pharmacogenomics studies by evaluating caspase 3/7-mediated activity in lymphoblastoid cell lines after treatment with six chemotherapeutic agents: 5'-deoxyfluorouridine, pemetrexed, cytarabine, paclitaxel, carboplatin, and cisplatin. MATERIALS AND METHODS: Using monozygotic twin pair and sibling pair lymphoblastoid cell lines, we identified conditions for measurement of caspase 3/7 activity in lymphoblastoid cell lines. Genome-wide association studies were performed with over 2 million single nucleotide polymorphisms (SNPs) and cisplatin-induced apoptosis in HapMap CEU cell lines (n=77). RESULTS: Although treatment with 5'-deoxyfluorouridine and pemetrexed for up to 24 h resulted in low levels of apoptosis or interindividual variation in caspase-dependent cell death; paclitaxel, cisplatin, carboplatin, and cytarabine treatment for 24 h resulted in 9.4-fold, 9.1-fold, 7.0-fold, and 6.0-fold increases in apoptosis relative to control, respectively. There was a weak correlation between caspase activity and cytotoxicity (r(2)=0.03-0.29) demonstrating that cytotoxicity and apoptosis are two distinct phenotypes that may produce independent genetic associations. Estimated heritability (h(2)) for apoptosis was 0.57 and 0.29 for cytarabine (5 and 40 µmol/l, respectively), 0.22 for paclitaxel (12.5 nmol/l), and 0.34 for cisplatin (5 µmol/l). In the genome-wide association study using the HapMap CEU panel, we identified a significant enrichment of cisplatin-induced cytotoxicity SNPs within the significant cisplatin-induced apoptosis SNPs and an enrichment of expression quantitative trait loci (eQTL). Among these eQTLs, we identified several eQTLs with known function related to apoptosis and/or cytotoxicity. CONCLUSION: Our study identifies apoptosis as a phenotype for pharmacogenomic studies in lymphoblastoid cell lines after treatment with paclitaxel, cisplatin, carboplatin, and cytarabine that may have utility for discovering biomarkers to predict response to certain chemotherapeutics.

PACdb: a database for cell-based pharmacogenomics.

We have developed Pharmacogenomics And Cell database (PACdb), a results database that makes available relationships between single nucleotide polymorphisms, gene expression, and cellular sensitivity to various drugs in cell-based models to help determine genetic variants associated with drug response. The current version also supports summary analysis on differentially expressed genes between the HapMap samples of European and African ancestry, as well as queries for summary information of correlations between gene expression and pharmacological phenotypes. At present, data generated on the following anticancer agents are included: carboplatin, cisplatin, etoposide, daunorubicin, and cytarabine (Ara-C). The database is also available to assist in the investigation of the effects of potential confounding variables (e.g. cell proliferation rate) in lymphoblastoid cell lines. PACdb will be regularly updated to include more drugs and new datasets (e.g. baseline microRNA levels). PACdb will be linked into PharmGKB to benefit the next wave of pharmacogenetic and pharmacogenomic discovery.

Endometrial cancer risk among younger, overweight women.

OBJECTIVE: To examine the risk for endometrial cancer among overweight women using the World Health Organization's clinical definitions of obesity based on body mass index (BMI). METHODS: Conducted in the early 1980s, the Cancer and Steroid Hormone study was a multicenter, population-based, case-control study of breast, ovarian, and endometrial cancers among women aged 20-54 years. Participants for the case group (n=421) were identified through cancer registries and had histologically confirmed endometrial cancer. Participants for the control group (n=3,159) were chosen by random-digit dialing methods in the same regions as those in the case group. Those in the case and control groups responded to the same questions during in-person interviews. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The relationship between endometrial cancer and BMI (calculated as weight [kg]/[height (m)]) was modified by age at last menstrual period (LMP). Of women who were younger than 45 years at LMP, those with BMIs of at least 35.0 had a greater risk of endometrial cancer (56%, 30/54) than did those with normal BMIs (4%, 59/1,492, adjusted OR 21.7, 95% CI 11.3-41.7). Of women age 45 or older at LMP, those with BMIs of at least 35.0 also had a greater risk (40%, 24/60) than did those with normal BMIs (14%, 168/1,235, adjusted OR 3.7, 95% CI 2.0-6.6). Women younger than 45 years at LMP and those with BMIs of at least 25.0 at 18 years and as adults (25%, 31/123) had an approximately sixfold increased risk (adjusted OR 5.8, 95% CI 3.4-9.8) compared with those with normal BMIs at 18 and as adults (4%, 58/1,460). CONCLUSION: Very obese women aged 20-54 years have an elevated endometrial cancer risk, which appears heightened by early menopause. LEVEL OF EVIDENCE: II.

AgBase: a functional genomics resource for agriculture.

BACKGROUND: Many agricultural species and their pathogens have sequenced genomes and more are in progress. Agricultural species provide food, fiber, xenotransplant tissues, biopharmaceuticals and biomedical models. Moreover, many agricultural microorganisms are human zoonoses. However, systems biology from functional genomics data is hindered in agricultural species because agricultural genome sequences have relatively poor structural and functional annotation and agricultural research communities are smaller with limited funding compared to many model organism communities. DESCRIPTION: To facilitate systems biology in these traditionally agricultural species we have established "AgBase", a curated, web-accessible, public resource http://www.agbase.msstate.edu for structural and functional annotation of agricultural genomes. The AgBase database includes a suite of computational tools to use GO annotations. We use standardized nomenclature following the Human Genome Organization Gene Nomenclature guidelines and are currently functionally annotating chicken, cow and sheep gene products using the Gene Ontology (GO). The computational tools we have developed accept and batch process data derived from different public databases (with different accession codes), return all existing GO annotations, provide a list of products without GO annotation, identify potential orthologs, model functional genomics data using GO and assist proteomics analysis of ESTs and EST assemblies. Our journal database helps prevent redundant manual GO curation. We encourage and publicly acknowledge GO annotations from researchers and provide a service for researchers interested in GO and analysis of functional genomics data. CONCLUSION: The AgBase database is the first database dedicated to functional genomics and systems biology analysis for agriculturally important species and their pathogens. We use experimental data to improve structural annotation of genomes and to functionally characterize gene products. AgBase is also directly relevant for researchers in fields as diverse as agricultural production, cancer biology, biopharmaceuticals, human health and evolutionary biology. Moreover, the experimental methods and bioinformatics tools we provide are widely applicable to many other species including model organisms.

Clinical breast examination: practical recommendations for optimizing performance and reporting.

Clinical breast examination (CBE) seeks to detect breast abnormalities or evaluate patient reports of symptoms to find palpable breast cancers at an earlier stage of progression. Treatment options for earlier-stage cancers are generally more numerous, include less toxic alternatives, and are usually more effective than treatments for later-stage cancers. For average-risk women aged 40 and younger, earlier detection of palpable tumors identified by CBE can lead to earlier therapy. After age 40, when mammography is recommended, CBE is regarded as an adjunct to mammography. Recent debate, however, has questioned the contributions of CBE to the detection of breast cancer in asymptomatic women and particularly to improved survival and reduced mortality rates. Clinicians remain widely divided about the level of evidence supporting CBE and their confidence in the examination. Yet, CBE is practiced extensively in the United States and continues to be recommended by many leading health organizations. It is in this context that this report provides a brief review of evidence for CBE's role in the earlier detection of breast cancer, highlights current practice issues, and presents recommendations that, when implemented, could contribute to greater standardization of the practice and reporting of CBE. These recommendations may also lead to improved evidence of the nature and extent of CBE's contribution to the earlier detection of breast cancer.