Optical genome mapping reveals balanced and unbalanced genetic changes associated with tumor-forming potential in an early-stage prostate cancer epithelial subline (M2205).

BACKGROUND: Identifying cytogenetic changes in tumors can aid in diagnosis/prognosis and disease management. Complete cytogenetic characterization has historically required a multimethod/time-consuming approach. Optical genome mapping (OGM) offers a potential solution to this challenge by detecting both balanced and unbalanced abnormalities in a single assay. METHODS: Genetic changes acquired with tumor-forming potential in a prostate xenograft subline [M2205] (derived from a Black male) that were detected using cytogenetic versus OGM analyses were compared to assess the utility of OGM for analyzing solid tumors. RESULTS: Cytogenetic/OGM concordance was noted for (a) copy number gains (16, 1p, 3q, 5q, 7p, 8q, 9q, 11p, 11q, 15q, 20q), (b) copy number losses (Y, 3p, 4p, 6p, 7p, 9p, 11q), and (c) structural changes, including multibreak rearrangements. Discordance was noted for two structural findings, both of which had breakpoints localized to repetitive sequences. The OGM studies identified new findings and confirmed/further characterized 8q24 structural abnormalities. It also detected genes gained/disrupted in the 8q24 region (e.g., MYC, DEPTOR, and EXT1); but recognizing a jumping translocation required cytogenetic analyses. CONCLUSION: These results support using OGM as a tool to analyze solid tumors in clinical/research settings. Moreover, this OGM analysis expanded the characterization of cytogenetic changes present in the M2205 subline, including alterations associated with tumors from Black males diagnosed with prostate cancer.

Chromosome 6p25 deletion syndrome: A case report and review of ophthalmic features.

The 6p25 deletion syndrome is a rare genetic disorder characterized by a wide spectrum of congenital anomalies. Ophthalmic abnormalities appear to be highly associated with the syndrome, although this relationship has not been well characterized to date. We conducted a systematic literature review to highlight the ocular features in patients with this deletion syndrome and describe a 7-month-old female who has a 6.07 MB 6p25.1p25.3 deletion and a 4.25 MB 17q25.3 duplication. Our patient presented with multiple congenital anomalies, including macrocephaly, frontal bossing, low set ears, tent-shaped mouth, saddle nose, flat midface, and hearing impairment. Her ophthalmic features included proptosis, down-slanting palpebral fissures, hypertelorism, nystagmus, bilateral posterior embryotoxon, and decentered and abnormally shaped pupils. A systematic review of the published cases with sufficient clinical eye descriptions included 63 cases with a confirmed 6p25 deletion. The most common eye findings observed were posterior embryotoxon, iris hypoplasia, corectopia, cornea opacity, and glaucoma.

Ophthalmic manifestations of Lamb-Shaffer syndrome: a case presentation and literature review.

Lamb-Shaffer syndrome, caused by haploinsufficiency of SOX5, leads to a unique constellation of dysmorphic features and intellectual delay. The SOX5 family of proteins plays an integral role in neuronal development. We present the clinical traits of an 11-year-old boy with Lamb-Shaffer syndrome and highlight the ocular findings of the syndrome reported thus far in the literature. Approximately 55% of all patients reviewed had some form of ocular abnormality associated with Lamb-Shaffer syndrome, including, predominantly, strabismus as well as optic nerve abnormalities, epicanthal folds, and refractive errors, highlighting the potential significance of SOX5 on neurologic development.

Exploring the relationship between DNA methylation age measures and psychoneurological symptoms in women with early-stage breast cancer.

PURPOSE: The epigenetic clock has been acknowledged as an indicator for molecular aging, but few studies have examined possible associations of DNA methylation (DNAm) age or age acceleration (AA) with symptom burden in individuals who are treated for cancer. This study explored the association of DNAm age or AA with psychoneurological (PN) symptoms, including cognitive impairment, fatigue, sleep disturbances, pain, and depressive symptoms, in breast cancer survivors over a 2-year period. METHODS: We measured PN symptoms using reliable instruments and DNAm levels by Infinium HumanMethylation450K BeadChip (N = 72). DNAm age was calculated by the Horvath, Grim, and Hannum-based intrinsic and extrinsic age estimations. AA was defined by the residual regressing estimated epigenetic age on chronological age. Mixed regression models were fitted for AA and changes in AA to study the association over time. Separate linear regression models and a mixed-effects model were fitted for AA at each time point. RESULTS: Horvath-AA, Grim-AA, and extrinsic epigenetic AA were significantly changed over time, while intrinsic epigenetic AA did not exhibit any temporal changes. Increased AA was associated with greater anxiety and fatigue, as well as worse cognitive memory, adjusting for race, BMI, income, chemotherapy, radiation therapy, and chronological age. Increased DNAm age was associated with greater anxiety over 2 years. CONCLUSION: Our findings suggest DNAm age and AA may be associated with PN symptoms over the course of cancer treatment and survivorship. Some PN symptoms may be amenable to preventive interventions targeted to epigenetic clocks that influence aging-associated processes.

Outreach and Engagement Efforts in Research on Down Syndrome: An NIH INCLUDE Working Group Consensus Statement.

The National Institutes of Health formulated the Outreach and Engagement Working Group in Fall of 2019 to support the objectives of the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE). This Working Group consisted of a multi-disciplinary team of stakeholders in research on Down syndrome that met to discuss best practices for outreach and engagement to Down syndrome communities, with an emphasis on representation and diversity. This review and consensus paper describes the importance of increasing representation in DS research for future cohort building and summarizes the priority issues identified by the Working Group members. An overview of Working Group activities is then presented, followed by consensus recommendations and a discussion of future opportunities and challenges.

Too Sensitive or Just Right?

OBJECTIVES: To compare the performance of the rabbit monoclonal antihuman CD246 antibody (D5F3 clone) with the established ALK1 clone for immunohistochemical assessment of anaplastic large cell lymphoma (ALCL). METHODS: Archival cases of ALCL (n = 27) were assessed immunohistochemically by use of ALK1 and D5F3 clones under standard Clinical Laboratory Improvement Amendments-compliant conditions. The intensity of cytoplasmic staining (0 = none; 1 = faint; 2 = moderate; 3+ = strong) and proportion of neoplastic cells (0%, <5%, 5%-50%, >50%) were evaluated and compared with clinical ALK break-apart fluorescence in situ hybridization (FISH) assays. RESULTS: Nine ALCL specimens were positive for ALK expression by ALK1 staining (33%; 1 = 1+; 0 = 2+; 8 = 3+), while 14 were positive by D5F3 staining (48%; 3 = 1+; 1 = 2+; 10 = 3+). Across the cohort, D5F3 staining showed a significantly greater proportion of cells staining positive (P = .02) and greater intensity (P = .03). Of 3 cases positive for D5F3 only with FISH results, none showed rearrangements, although 1 showed copy number gains at the ALK locus in a subset of cells. CONCLUSIONS: Overall, D5F3 showed greater stain intensity and proportion staining than ALK1 in ALK-positive ALCL cases, which is especially helpful in limited samples. Caution and consideration of orthogonal ALK testing types is recommended, especially for cases with weak or focal staining.

Acute megakaryoblastic leukemia with trisomy 3 and CBFA2T3::GLIS2: A case report.

Non-Down-syndrome-related acute megakaryoblastic leukemia (non-DS-AMKL) is a rare form of leukemia that can present with a variety of initial symptoms, including fever, rash, bruising, bleeding, or other more clinically challenging symptoms. Herein, we describe a 19-month-old female patient who presented with left lower extremity pain and language regression who was diagnosed with AMKL, not otherwise specified (NOS), on the basis of peripheral blood and bone marrow analysis, as well as cytogenetic and molecular diagnostic phenotyping. Of note, in addition to this patient's karyotype showing trisomy 3, a fusion between CBFA2T3 (core-binding factor, alpha subunit 2, translocated to, 3) on chromosome 16 and GLIS2 (GLIS family zinc finger protein 2), also on chromosome 16, was observed. Patients with AMKL who have trisomy 3 with CBFA2T3::GLIS2 fusions are rare, and it is not known if the co-occurrence of these abnormalities is coincidental or biologically related. This highlights the continued need for further expansion of genetic testing in individuals with rare disease to establish the groundwork for identifying additional commonalities that could potentially be used to identify therapeutic targets or improve prognostication.

Severe Graft-Versus-Host Disease Following Solid-Organ Transplant Confirmed by Chimerism Studies and Cytogenetic Analyses.

Graft-versus-host disease is an uncommon complication of solid-organ transplant and is associated with a high rate of mortality. Here, we describe a female patient with primary biliary cholangitis who developed graft-versus-host disease following an orthotopic liver and renal allotransplant from a deceased male donor. Systemic donor lymphoid chimerism is one of several important findings to confirm a diagnosis of graft-versus-host disease after solid-organ transplant, along with clinical and histologic findings. In this case, cytogenetic analyses and chimerism studies performed on blood, blood components, and bone marrow specimens obtained at several timepoints supported the diagnosis of graft-versus-host disease and demonstrated sustained near-complete donor engraftment of the lymphoid compartment. This case report illustrates the utility of chimerism testing to rapidly diagnose this serious condition in patients who have received a solid-organ transplant.

Eye, Ocular Adnexa, and Facial Manifestations of Tetrasomy 18p.

Tetrasomy 18p is often the result of an additional isochromosome for the short arm of chromosome 18. Although many organ systems are affected phenotypically, the ocular manifestations associated with tetrasomy 18p have not been well characterized in the literature. This case report presents the ocular and facial features associated with tetrasomy 18p in a 4-year-old Black girl, along with a review of clinical presentations previously reported in the literature. A systematic review of the literature in PubMed was conducted to summarize the reported eye, ocular adnexa, and distinctive facial features in individuals with confirmed tetrasomy 18p. Searching "Tetrasomy 18p" generated 65 article results, of which 28 articles had sufficient eye and facial descriptions. Including the patient in this report, 90 patients had confirmed tetrasomy 18p. The most common features noted in these 90 patients, with a roughly equal male-to-female ratio of impact (7:8), were as follows: microcephaly (57%), triangular facies (18%), anomalous palpebral fissures (31%), strabismus (48%), low-set ears (52%), hearing loss to some extent (16%), depressed or flat nasal bridge (18%), smooth philtrum (41%), thin upper lip (27%), and highly arched palate (21%). Additionally, many were noted to have feeding difficulties (28%), developmental delay (58%), and abnormal brain findings on imaging (20%). Muscle tone was abnormal in 23% of the patients. This report elucidates the reoccurring eye, ocular adnexa, and distinctive facial features associated with tetrasomy 18p. This knowledge may assist in timely diagnosis and encourage providers to use a multidisciplinary approach for the treatment of affected individuals. [J Pediatr Ophthalmol Strabismus. 2021;58(6):e44-e48.].

Maternal biological age assessed in early pregnancy is associated with gestational age at birth.

Maternal age is an established predictor of preterm birth independent of other recognized risk factors. The use of chronological age makes the assumption that individuals age at a similar rate. Therefore, it does not capture interindividual differences that may exist due to genetic background and environmental exposures. As a result, there is a need to identify biomarkers that more closely index the rate of cellular aging. One potential candidate is biological age (BA) estimated by the DNA methylome. This study investigated whether maternal BA, estimated in either early and/or late pregnancy, predicts gestational age at birth. BA was estimated from a genome-wide DNA methylation platform using the Horvath algorithm. Linear regression methods assessed the relationship between BA and pregnancy outcomes, including gestational age at birth and prenatal perceived stress, in a primary and replication cohort. Prenatal BA estimates from early pregnancy explained variance in gestational age at birth above and beyond the influence of other recognized preterm birth risk factors. Sensitivity analyses indicated that this signal was driven primarily by self-identified African American participants. This predictive relationship was sensitive to small variations in the BA estimation algorithm. Benefits and limitations of using BA in translational research and clinical applications for preterm birth are considered.

Trisomy 21-associated increases in chromosomal instability are unmasked by comparing isogenic trisomic/disomic leukocytes from people with mosaic Down syndrome.

Down syndrome, which results from a trisomic imbalance for chromosome 21, has been associated with 80+ phenotypic traits. However, the cellular changes that arise in somatic cells due to this aneuploid condition are not fully understood. The primary aim of this study was to determine if germline trisomy 21 is associated with an increase in spontaneous somatic cell chromosomal instability frequencies (SCINF). To achieve this aim, we quantified SCINF in people with mosaic Down syndrome using a cytokinesis-blocked micronucleus assay. By comparing values in their isogenic trisomic/disomic cells, we obtained a measure of differences in SCINF that are directly attributable to a trisomy 21 imbalance, since differential effects attributable to "background" genetic factors and environmental exposures could be eliminated. A cross-sectional assessment of 69 people with mosaic Down syndrome (ages 1 to 44; mean age of 12.84 years) showed a significantly higher frequency of micronuclei in their trisomic (0.37 ± 0.35 [mean ± standard deviation]) compared to disomic cells (0.18 ± 0.11)(P <0.0001). The daughter binucleates also showed significantly higher levels of abnormal patterns in the trisomic (1.68 ± 1.21) compared to disomic (0.35 ± 0.45) cells (P <0.0001). Moreover, a significant Age x Cell Type interaction was noted (P = 0.0113), indicating the relationship between age and SCINF differed between the trisomic and disomic cells. Similarly, a longitudinal assessment (mean time interval of 3.9 years; range of 2 to 6 years) of 18 participants showed a mean 1.63-fold increase in SCINF within individuals over time for their trisomic cells (P = 0.0186), compared to a 1.13-fold change in their disomic cells (P = 0.0464). In summary, these results showed a trisomy 21-associated, age-related increase in SCINF. They also underscore the strength of the isogenic mosaic Down syndrome model system for "unmasking" cellular changes arising from a trisomy 21 imbalance.

PLK1 Induces Chromosomal Instability and Overrides Cell-Cycle Checkpoints to Drive Tumorigenesis.

Polo-like kinase 1 (PLK1) is an essential cell-cycle regulator that is frequently overexpressed in various human cancers. To determine whether Plk1 overexpression drives tumorigenesis, we established transgenic mouse lines that ubiquitously express increased levels of Plk1. High Plk1 levels were a driving force for different types of spontaneous tumors. Increased Plk1 levels resulted in multiple defects in mitosis and cytokinesis, supernumerary centrosomes, and compromised cell-cycle checkpoints, allowing accumulation of chromosomal instability (CIN), which resulted in aneuploidy and tumor formation. Clinically, higher expression of PLK1 positively associated with an increase in genome-wide copy-number alterations in multiple human cancers. This study provides in vivo evidence that aberrant expression of PLK1 triggers CIN and tumorigenesis and highlights potential therapeutic opportunities for CIN-positive cancers. SIGNIFICANCE: These findings establish roles for PLK1 as a potent proto-oncogene and a CIN gene and provide insights for the development of effective treatment regimens across PLK1-overexpressing and CIN-positive cancers.

Telomere lengths in women treated for breast cancer show associations with chemotherapy, pain symptoms, and cognitive domain measures: a longitudinal study.

BACKGROUND: Survival rates for breast cancer (BC) have improved, but quality of life post-diagnosis/treatment can be adversely affected, with survivors reporting a constellation of psychoneurological symptoms (PNS) including stress, anxiety, depression, pain, fatigue, sleep disturbance, and cognitive dysfunction. METHODS: To assess a potential relationship between telomere length (TL) and the development/persistence of PNS, we longitudinally studied 70 women (ages 23-71) with early stage BC (I-IIIA) at 5 time-points: prior to treatment (baseline), the mid-point of their chemotherapy cycle, 6 months, 1 year, and 2 years following the initiation of chemotherapy. Measures quantified included assessments of each of the PNS noted above and TL [using both a multiplex qPCR assay and a chromosome-specific fluorescence in situ hybridization (FISH) assay]. RESULTS: Variables associated with qPCR mean TLs were age (p = 0.004) and race (T/S ratios higher in Blacks than Whites; p = 0.019). Significant differences (mostly decreases) in chromosome-specific TLs were identified for 32 of the 46 chromosomal arms at the mid-chemo time-point (p = 0.004 to 0.049). Unexpectedly, the sequential administration of doxorubicin [Adriamycin], cyclophosphamide [Cytoxan], and docetaxel [Taxotere] (TAC regimen) was consistently associated with higher TLs, when compared to TLs in women receiving a docetaxel [Taxotere], Carboplatin [Paraplatin], and trastuzumab [Herceptin] [TCH] chemotherapy regimen [association was shown with both the qPCR and FISH assays (p = 0.036)]. Of the PNS, pain was significantly negatively associated with TL (higher pain; shorter telomeres) for a subset of chromosomal arms (5q, 8p, 13p, 20p, 22p, Xp, Xq) (p = 0.014-0.047). Chromosomal TLs were also associated with 7 of the 8 cognitive domains evaluated, with the strongest relationship being noted for chromosome 17 and the visual memory domain (shorter telomeres; lower scores). CONCLUSIONS: We showed that race and age were significantly associated with telomere length in women treated for early stage BC and that acquired telomere alterations differed based on the woman's treatment regimen. Our study also demonstrated that pain and cognitive domain measures were significantly related to telomere values in this study cohort. Expanding upon the knowledge gained from this longitudinal study could provide insight about the biological cascade of events that contribute to PNS related to BC and/or its treatment.

A Reappraisal of Superficial Pleomorphic Liposarcoma.

OBJECTIVES: Superficial pleomorphic liposarcoma (PL) has a favorable prognosis compared to deeply seated PL. Given developments in the classification of lipomatous neoplasms, we reappraised a series of cases. METHODS: Retrospective clinicopathologic evaluation and genome-wide single-nucleotide polymorphism (SNP) microarray studies were performed for cases previously designated superficial PL. RESULTS: Four cases were identified (age, 48-70 years). Two were dermally confined, whereas two were superficial subcutaneous; no recurrences or metastases were reported. Tumors demonstrated pleomorphic spindled morphology with variable cellularity. Multivacuolated atypical lipoblasts were focal in 3 and abundant in 1. Dermal tumors demonstrated atypical cells within sclerotic collagen. Genome-wide SNP microarray studies revealed consistent gains and losses, including losses at the 13q14.2 locus encompassing RB1 and DLEU2 and deletion/disruption of the TP53 locus. Although subcutaneous examples showed genomic changes similar to deep PL, the dermal examples showed fewer genetic alterations, including changes reported in the spectrum of atypical spindle cell/pleomorphic lipomatous tumors (ASPLT). All lacked MDM2 amplification. CONCLUSIONS: Careful integration of histologic and genetic features may improve classification of lipomatous neoplasms with atypia, allowing reclassification of some superficial PL as ASPLT.

Replicated umbilical cord blood DNA methylation loci associated with gestational age at birth.

DNA methylation is highly sensitive to in utero perturbations and has an established role in both embryonic development and regulation of gene expression. The foetal genetic component has been previously shown to contribute significantly to the timing of birth, yet little is known about the identity and behaviour of individual genes. The aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with gestational age at birth (GA). Findings were validated in an independent sample and evidence for the regulation of gene expression was evaluated for cis gene relationships in specimens with multi-omic data. Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 450 K BeadChip, was associated with GA for 2,372 CpG probes (5% FDR) in both the Pregnancy, Race, Environment, Genes (PREG) and Newborn Epigenetic Study (NEST) cohorts. Significant probes mapped to 1,640 characterized genes and an association with nearby gene expression measures obtained by the Affymetrix HG-133A microarray was found for 11 genes. Differentially methylated positions were enriched for actively transcribed and enhancer chromatin states, were predominately located outside of CpG islands, and mapped to genes enriched for inflammation and innate immunity ontologies. In both PREG and NEST, the first principal component derived from these probes explained approximately one-half (58.1% and 47.8%, respectively) of the variation in GA. Gene pathways identified are consistent with the hypothesis of pathogen detection and response by the immune system to elicit premature labour as a consequence of unscheduled inflammation.

Ocular Findings in the 16p11.2 Microdeletion Syndrome: A Case Report and Literature Review.

The recurrent 16p11.2 microdeletion is characterized by developmental delays and a wide spectrum of congenital anomalies. It has been well reported that individuals with this ∼593-kb interstitial deletion have an increased susceptibility toward the autism spectrum disorder (ASD). Abnormalities of the eye and ocular adnexa are also commonly associated findings seen in individuals with the 16p11.2 microdeletion syndrome, although these ophthalmic manifestations have not been well characterized. We conducted an extensive literature review to highlight the eye features in patients with the 16p11.2 microdeletion syndrome and describe a 5-year-old boy with the syndrome. The boy initially presented with intellectual disability, speech delay, and defiant behavior; diagnoses of attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) were established. He had a Chiari malformation type 1. His ophthalmic features included strabismus, hyperopia, and ptosis, and a posterior embryotoxon was present bilaterally. From a systematic review of prior reported cases, the most common eye and ocular adnexa findings observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism.

Differential DNA methylation following chemotherapy for breast cancer is associated with lack of memory improvement at one year.

The biological basis underlying cognitive dysfunction in women with early-stage breast cancer (BC) remains unclear, but could reflect gene expression changes that arise from the acquisition and long-term retention of soma-wide alterations in DNA methylation in response to chemotherapy. In this longitudinal study, we identified differences in peripheral methylation patterns present in women prior to treatment (T1) and 1 year after receiving chemotherapy (T4) and evaluated relationships among the differential methylation (DM) ratios with changes in cognitive function. A total of 58 paired (T1 and T4) blood specimens were evaluated. Methylation values were determined for DNA isolated from whole blood using a genome-wide array . Cognitive function was measured using the validated, computerized CNS Vital Signs platform. Relationships between methylation patterns and cognitive domain scores were compared using a stepwise linear regression analysis, with demographic variables as covariates. The symptom comparison analysis was restricted to 2,199 CpG positions showing significant methylation ratio changes between T1 and T4. The positions with DM were enriched for genes involved in the modulation of cytokine concentrations. Significant DM ratios were associated with memory domain (56 CpGs). Eight of the ten largest DM ratio changes associated with lack of memory improvement were localized to genes involved in either neural function (ECE2, PPFIBP2) or signalling processes (USP6NL, RIPOR2, KLF5, UBE2V1, DGKA, RPS6KA1). These results suggest that epigenetic changes acquired and retained for at least one year in non-tumour cells following chemotherapy may be associated with a lack of memory improvement following treatment in BC survivors.

Whole blood transcriptomic profiles can differentiate vulnerability to chronic low back pain.

The mechanisms underlying the transition from acute to chronic pain remain unclear. Here, we sought to characterize the transcriptome associated with chronic low back pain as well as the transcriptome of the transition from acute to chronic low back pain. For the analysis, we compared the whole blood transcriptome of: (a) patients at the onset of low back pain who no longer had pain within 6 weeks after onset (acute) with patients who developed chronic low back pain at 6 months (chronic T5); and, (b) patients at the onset of low back pain (chronic T1) who developed chronic pain at 6 months with healthy pain-free (normal) controls. The majority of differentially expressed genes were protein coding. We illustrate a unique chronic low back pain transcriptome characterized by significant enrichment for known pain genes, extracellular matrix genes, and genes from the extended major histocompatibility complex (MHC) genomic locus. The transcriptome of the transition from acute to chronic low back pain was characterized by significant upregulation of antigen presentation pathway (MHC class I and II) genes and downregulation of mitochondrial genes associated with oxidative phosphorylation, suggesting a unique genomic signature of vulnerability to low back pain chronicity.

Relationship of fatigue with cognitive performance in women with early-stage breast cancer over 2 years.

OBJECTIVE: Fatigue and cognitive dysfunction are major concerns for women with early-stage breast cancer during treatment and into survivorship. However, interrelationships of these phenomena and their temporal patterns over time are not well documented, thus limiting the strategies for symptom management interventions. In this study, changes in fatigue across treatment phases and the relationship among fatigue severity and its functional impact with objective cognitive performance were examined. METHODS: Participants (N = 75) were assessed at five time points beginning prior to chemotherapy to 24 months after initial chemotherapy. Fatigue severity and impact were measured on the Brief Fatigue Inventory. Central nervous system (CNS) Vital Signs was used to measure performance based cognitive testing. Temporal changes in fatigue were examined, as well as the relationship between fatigue and cognitive performance, at each time point using linear mixed effect models. RESULTS: Severity of fatigue varied as a function of phase of treatment. Fatigue severity and its functional impact were moderate at baseline, increased significantly during chemotherapy, and returned to near baseline levels by 2 years. At each time point, fatigue severity and impact were significantly associated with diminished processing speed and complex attention performance. CONCLUSIONS: A strong association between fatigue and objective cognitive performance suggests that they are likely functionally related. That cognitive deficits were evident at baseline, whereas fatigue was more chemotherapy dependent, implicates that two symptoms share some common bases but may differ in underlying mechanisms and severity over time. This knowledge provides a basis for introducing strategies for tailored symptom management that vary over time.