Mutation of a U2 snRNA gene causes global disruption of alternative splicing and neurodegeneration.

Although uridine-rich small nuclear RNAs (U-snRNAs) are essential for pre-mRNA splicing, little is known regarding their function in the regulation of alternative splicing or of the biological consequences of their dysfunction in mammals. Here, we demonstrate that mutation of Rnu2-8, one of the mouse multicopy U2 snRNA genes, causes ataxia and neurodegeneration. Coincident with the observed pathology, the level of mutant U2 RNAs was highest in the cerebellum and increased after granule neuron maturation. Furthermore, neuron loss was strongly dependent on the dosage of mutant and wild-type snRNA genes. Comprehensive transcriptome analysis identified a group of alternative splicing events, including the splicing of small introns, which were disrupted in the mutant cerebellum. Our results suggest that the expression of mammalian U2 snRNA genes, previously presumed to be ubiquitous, is spatially and temporally regulated, and dysfunction of a single U2 snRNA causes neuron degeneration through distortion of pre-mRNA splicing.

Seryl-tRNA synthetase promotes translational readthrough by mRNA binding and involvement of the selenocysteine incorporation machinery.

Translational readthrough of UGA stop codons by selenocysteine-specific tRNA (tRNASec) enables the synthesis of selenoproteins. Seryl-tRNA synthetase (SerRS) charges tRNASec with serine, which is modified into selenocysteine and delivered to the ribosome by a designated elongation factor (eEFSec in eukaryotes). Here we found that components of the human selenocysteine incorporation machinery (SerRS, tRNASec, and eEFSec) also increased translational readthrough of non-selenocysteine genes, including VEGFA, to create C-terminally extended isoforms. SerRS recognizes target mRNAs through a stem-loop structure that resembles the variable loop of its cognate tRNAs. This function of SerRS depends on both its enzymatic activity and a vertebrate-specific domain. Through eCLIP-seq, we identified additional SerRS-interacting mRNAs as potential readthrough genes. Moreover, SerRS overexpression was sufficient to reverse premature termination caused by a pathogenic nonsense mutation. Our findings expand the repertoire of selenoprotein biosynthesis machinery and suggest an avenue for therapeutic targeting of nonsense mutations using endogenous factors.

Structural basis for impaired 5' processing of a mutant tRNA associated with defects in neuronal homeostasis.

SignificanceUnderstanding and treating neurological disorders are global priorities. Some of these diseases are engendered by mutations that cause defects in the cellular synthesis of transfer RNAs (tRNAs), which function as adapter molecules that translate messenger RNAs into proteins. During tRNA biogenesis, ribonuclease P catalyzes removal of the transcribed sequence upstream of the mature tRNA. Here, we focus on a cytoplasmic tRNAArgUCU that is expressed specifically in neurons and, when harboring a particular point mutation, contributes to neurodegeneration in mice. Our results suggest that this mutation favors stable alternative structures that are not cleaved by mouse ribonuclease P and motivate a paradigm that may help to understand the molecular basis for disease-associated mutations in other tRNAs.

ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase.

Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aars sti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, we identified Ankrd16, a gene that acts epistatically with the Aars sti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS. Serine that is misactivated by AlaRS is captured by the lysine side chains of ANKRD16, which prevents the charging of serine adenylates to tRNAAla and precludes serine misincorporation in nascent peptides. The deletion of Ankrd16 in the brains of Aarssti/sti mice causes widespread protein aggregation and neuron loss. These results identify an amino-acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery that is essential to the prevention of severe pathologies that arise from defects in editing.

Publisher Correction: ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase.

In the Fig. 3b western blot of this Article, 'Myc-AlaRS' in row one should have been 'Myc-AAD Aars', 'AlaRS' in row two should have been 'Aars' and 'ANKRD16' in row four should have been 'Ankrd16'. In Fig. 4f, 'ANKRD16' and 'ANKRD16(3xR)' should have been 'Ankrd16' and 'Ankrd163xR; and in Fig. 3c the position of the molecular mass markers had shifted. These figures have been corrected online, and see Supplementary Information to the accompanying Amendment for the original figure.

The Clp1 R140H mutation alters tRNA metabolism and mRNA 3' processing in mouse models of pontocerebellar hypoplasia.

Homozygous mutation of the RNA kinase CLP1 (cleavage factor polyribonucleotide kinase subunit 1) causes pontocerebellar hypoplasia type 10 (PCH10), a pediatric neurodegenerative disease. CLP1 is associated with the transfer RNA (tRNA) splicing endonuclease complex and the cleavage and polyadenylation machinery, but its function remains unclear. We generated two mouse models of PCH10: one homozygous for the disease-associated Clp1 mutation, R140H, and one heterozygous for this mutation and a null allele. Both models exhibit loss of lower motor neurons and neurons of the deep cerebellar nuclei. To explore whether Clp1 mutation impacts tRNA splicing, we profiled the products of intron-containing tRNA genes. While mature tRNAs were expressed at normal levels in mutant mice, numerous other products of intron-containing tRNA genes were dysregulated, with pre-tRNAs, introns, and certain tRNA fragments up-regulated, and other fragments down-regulated. However, the spatiotemporal patterns of dysregulation do not correlate with pathogenicity for most altered tRNA products. To elucidate the effect of Clp1 mutation on precursor messenger RNA (pre-mRNA) cleavage, we analyzed poly(A) site (PAS) usage and gene expression in Clp1R140H/- spinal cord. PAS usage was shifted from proximal to distal sites in the mutant mouse, particularly in short and closely spaced genes. Many such genes were also expressed at lower levels in the Clp1R140H/- mouse, possibly as a result of impaired transcript maturation. These findings are consistent with the hypothesis that select genes are particularly dependent upon CLP1 for proper pre-mRNA cleavage, suggesting that impaired mRNA 3' processing may contribute to pathogenesis in PCH10.

From ER to Eph receptors: new roles for VAP fragments.

Dominantly inherited mutations in an endoplasmic reticulum protein called VAPB have been found in a subset of patients with a rare familial form of amyotrophic lateral sclerosis (ALS). In this issue, Tsuda et al. (2008) identify a secreted form of VAPB that binds directly to Eph receptors inducing their activation and signaling, providing fresh insights into ALS pathogenesis, including non-neuronal aspects of this disorder.

Regulation of ex-translational activities is the primary function of the multi-tRNA synthetase complex.

During mRNA translation, tRNAs are charged by aminoacyl-tRNA synthetases and subsequently used by ribosomes. A multi-enzyme aminoacyl-tRNA synthetase complex (MSC) has been proposed to increase protein synthesis efficiency by passing charged tRNAs to ribosomes. An alternative function is that the MSC repurposes specific synthetases that are released from the MSC upon cues for functions independent of translation. To explore this, we generated mammalian cells in which arginyl-tRNA synthetase and/or glutaminyl-tRNA synthetase were absent from the MSC. Protein synthesis, under a variety of stress conditions, was unchanged. Most strikingly, levels of charged tRNAArg and tRNAGln remained unchanged and no ribosome pausing was observed at codons for arginine and glutamine. Thus, increasing or regulating protein synthesis efficiency is not dependent on arginyl-tRNA synthetase and glutaminyl-tRNA synthetase in the MSC. Alternatively, and consistent with previously reported ex-translational roles requiring changes in synthetase cellular localizations, our manipulations of the MSC visibly changed localization.

mRNA Translation Gone Awry: Translation Fidelity and Neurological Disease.

Errors during mRNA translation can lead to a reduction in the levels of functional proteins and an increase in deleterious molecules. Advances in next-generation sequencing have led to the discovery of rare genetic disorders, many caused by mutations in genes encoding the mRNA translation machinery, as well as to a better understanding of translational dynamics through ribosome profiling. We discuss here multiple neurological disorders that are linked to errors in tRNA aminoacylation and ribosome decoding. We draw on studies from genetic models, including yeast and mice, to enhance our understanding of the translational defects observed in these diseases. Finally, we emphasize the importance of tRNA, their associated enzymes, and the inextricable link between accuracy and efficiency in the maintenance of translational fidelity.

Changes in Breast Density Reporting Patterns of Radiologists After Publication of the 5th Edition BI-RADS Guidelines: A Single Institution Experience.

OBJECTIVE: The objective of our study was to determine the impact of 5th edition BI-RADS breast density assessment guidelines on density reporting patterns in our clinical practice. MATERIALS AND METHODS: PenRad reporting system was used to collect mammographic breast density data reported by five radiologists: 16,907 density assignments using 5th edition BI-RADS guidelines were compared with 19,066 density assessments using 4th edition guidelines. Changes in the density assessment pattern were noted between the 4th and 5th edition guidelines, and agreement in density distribution was compared using the intraclass correlation coefficient. A chi-square analysis was conducted for each reader to examine the change in the proportion of dense versus nondense assignments and on each category type to examine specific changes in proportion of density assignments from the 4th to the 5th edition. All reported p values are two-sided, and statistical significance was considered at the p < 0.001 threshold. RESULTS: Using the 5th edition, there was an overall 5.0% decrease in fatty assessments (p < 0.001), 2.8% increase in scattered densities (p < 0.001), 2.6% increase in heterogeneously dense (p < 0.001), and 0.4% decrease in extremely dense assessments (p = 0.15). Comparing the dense with nondense categories, there was a 2.3% overall increase in the dense assessments (p < 0.001) using 5th edition guidelines, mainly in the heterogeneously dense category. Two radiologists showed increased dense assessments (p < 0.001) using the 5th edition, and three radiologists showed no change (p = 0.39, 0.67, and 0.76). CONCLUSION: There was an overall increase in the dense assessments using the 5th edition, but individual radiologists in our clinical practice showed a variable adaptation to new guidelines.

Effectiveness of a Mobile Mammography Program.

OBJECTIVE: Mobile mammography units have increasingly been used to address patient health care disparities; however, there are limited data comparing mobile units to stationary sites. This study aims to evaluate the characteristics of women who underwent mammography screening in a mobile unit versus those who underwent mammography screening at a cancer center. MATERIALS AND METHODS: In this retrospective study, we analyzed all screening mammography examinations performed in a mobile unit in 2014 (n = 1433 examinations). For comparison, we randomized and reviewed an equivalent number of screening mammography examinations performed at our cancer center in 2014 (n = 1434 examinations). BI-RADS assessment, adherence to follow-up, biopsies performed, cancer detection rate, and sociodemographic variables were recorded. An independent-samples t test was conducted to identify potential differences in age between cancer center patients and mobile unit patients. Chi-square analyses were used to test for associations between location and factors such as health insurance, race, marital status, geographic area, adherence to screening guidelines, recall rate, adherence to follow-up, and cancer detection rates. RESULTS: Patients visiting our cancer center (mean = 57.74 years; SD = 10.55) were significantly older than those visiting the mobile unit (mean = 52.58 years; SD = 8.19; p < 0.001). There was a significant association between location and health insurance status (χ2 = 610.92; p < 0.001) with more uninsured patients undergoing screening in the mobile van (cancer center = 3.70%, mobile unit = 38.73%). There was a significant association between screening location and patient race (χ2 = 118.75, p < 0.001), with more white patients being screened at the cancer center (cancer center = 47.28%, mobile unit = 33.30%), more black patients being screened in the mobile van (cancer center = 49.30%, mobile unit = 54.15%), and more Hispanic patients being screened in the mobile van (cancer center = 1.05%, mobile unit = 6.77%). There was a significant association between location and patient marital status (χ2 = 135.61, p < 0.001), with more married patients screened at the cancer center (cancer center = 49.16%, mobile unit = 38.31%), more single patients screened in the mobile van (cancer center = 25.17%, mobile unit = 34.47%), and more widowed patients being screened at the cancer center (cancer center = 8.09%, mobile unit = 4.47%). There was a significant association between location and geographic area (χ2 = 33.33, p < 0.001), with both locations reaching more urban than rural patients (cancer center = 79.99%, mobile unit = 70.62%). There was a significant association between location and adherence to screening guidelines (χ2 = 179.60, p < 0.001), with patients screened at the cancer center being more compliant (cancer center = 56.90%, mobile unit = 34.47%). Finally, there was a significant association between location and recall rate (χ2 = 4.06, p < 0.001). The cancer center had a lower recall rate (13.32%) than the mobile van (15.98%). Of those patients with BI-RADS 0, there was a significant association between location and adherence to follow-up (χ2 = 22.75, p < 0.001) with patients using the mobile unit less likely to return for additional imaging (cancer center = 2.65%, mobile unit = 17.03%). CONCLUSION: Significant differences were found among patients visiting the cancer center versus the mobile mammography van. The cancer center's population is older and more adherent to guidelines, whereas the mobile mammography population exhibited greater racial and marital diversity, higher recall rate, and lack of adherence to follow-up recommendations. By identifying these characteristics, we can develop programs and materials that meet these populations' needs and behaviors, ultimately increasing mammography screening and follow-up rates among underserved populations.

Pilot Study to Show the Feasibility of High-Resolution Sagittal Ultrasound Imaging of the Temporomandibular Joint.

PURPOSE: To show the feasibility of acquiring high-resolution sagittal ultrasound (US) images of the temporomandibular joint (TMJ). PATIENTS AND METHODS: We used commercially available US probes to assess the TMJ via a transoral soft tissue window to acquire sagittal images. Magnetic resonance imaging and clinical correlation were compared with the US findings by the consensus assessment of 2 of the senior investigators. RESULTS: The sample was composed of 10 TMJs (6 participants) with an age range of 34 to 71 years and a male-female ratio of 3:1. The condyle and subcondylar surface were visible in 10 of 10 joints (100%), the disc in 7 of 10 joints (70%), and the pterygoid muscles in 6 of 10 joints (60%). In the 5 joints with magnetic resonance correlation, disc position and configuration were confirmed in all cases. CONCLUSIONS: We show the first sagittal transoral sonograms of the TMJ disc and associated joint components.

Deficiencies in tRNA synthetase editing activity cause cardioproteinopathy.

Misfolded proteins are an emerging hallmark of cardiac diseases. Although some misfolded proteins, such as desmin, are associated with mutations in the genes encoding these disease-associated proteins, little is known regarding more general mechanisms that contribute to the generation of misfolded proteins in the heart. Reduced translational fidelity, caused by a hypomorphic mutation in the editing domain of alanyl-tRNA synthetase (AlaRS), resulted in accumulation of misfolded proteins in specific mouse neurons. By further genetic modulation of the editing activity of AlaRS, we generated mouse models with broader phenotypes, the severity of which was directly related to the degree of compromised editing. Severe disruption of the editing activity of AlaRS caused embryonic lethality, whereas an intermediate reduction in AlaRS editing efficacy resulted in ubiquitinated protein aggregates and mitochondrial defects in cardiomyocytes that were accompanied by progressive cardiac fibrosis and dysfunction. In addition, autophagic vacuoles accumulated in mutant cardiomyocytes, suggesting that autophagy is insufficient to eliminate misfolded proteins. These findings demonstrate that the pathological consequences of diminished tRNA synthetase editing activity, and thus translational infidelity, are dependent on the cell type and the extent of editing disruption, and provide a previously unidentified mechanism underlying cardiac proteinopathy.

Mutations in the microtubule-associated protein 1A (Map1a) gene cause Purkinje cell degeneration.

The structural microtubule-associated proteins (MAPs) are critical for the organization of neuronal microtubules (MTs). Microtubule-associated protein 1A (MAP1A) is one of the most abundantly expressed MAPs in the mammalian brain. However, its in vivo function remains largely unknown. Here we describe a spontaneous mouse mutation, nm2719, which causes tremors, ataxia, and loss of cerebellar Purkinje neurons in aged homozygous mice. The nm2719 mutation disrupts the Map1a gene. We show that targeted deletion of mouse Map1a gene leads to similar neurodegenerative defects. Before neuron death, Map1a mutant Purkinje cells exhibited abnormal focal swellings of dendritic shafts and disruptions in axon initial segment (AIS) morphology. Furthermore, the MT network was reduced in the somatodendritic and AIS compartments, and both the heavy and light chains of MAP1B, another brain-enriched MAP, was aberrantly distributed in the soma and dendrites of mutant Purkinje cells. MAP1A has been reported to bind to the membrane-associated guanylate kinase (MAGUK) scaffolding proteins, as well as to MTs. Indeed, PSD-93, the MAGUK specifically enriched in Purkinje cells, was reduced in Map1a(-/-) Purkinje cells. These results demonstrate that MAP1A functions to maintain both the neuronal MT network and the level of PSD-93 in neurons of the mammalian brain.

Loss of Clcc1 results in ER stress, misfolded protein accumulation, and neurodegeneration.

Folding of transmembrane and secretory proteins occurs in the lumen of the endoplasmic reticulum (ER) before transportation to the cell surface and is monitored by the unfolded protein response (UPR) signaling pathway. The accumulation of unfolded proteins in the ER activates the UPR that restores ER homeostasis by regulating gene expression that leads to an increase in the protein-folding capacity of the ER and a decrease in the ER protein-folding load. However, prolonged UPR activity has been associated with cell death in multiple pathological conditions, including neurodegeneration. Here, we report a spontaneous recessive mouse mutation that causes progressive cerebellar granule cell death and peripheral motor axon degeneration. By positional cloning, we identify the mutation in this strain as a retrotransposon insertion in the Clcc1 gene, which encodes a putative chloride channel localized to the ER. Furthermore, we demonstrate that the C3H/HeSnJ inbred strain has late onset cerebellar degeneration due to this mutation. Interestingly, acute knockdown of Clcc1 expression in cultured cells increases sensitivity to ER stress. In agreement, GRP78, the major HSP70 family chaperone in the ER, is upregulated in Clcc1-deficient granule cells in vivo, and ubiquitinated proteins accumulate in these neurons before their degeneration. These data suggest that disruption of chloride homeostasis in the ER disrupts the protein-folding capacity of the ER, leading to eventual neuron death.

Effects of Changes in BI-RADS Density Assessment Guidelines (Fourth Versus Fifth Edition) on Breast Density Assessment: Intra- and Interreader Agreements and Density Distribution.

OBJECTIVE: The objective of our study was to determine intra- and interreader agreements for density assessment using the fifth edition of the BI-RADS guidelines and to compare with those for density assessment using the fourth edition of the BI-RADS guidelines. MATERIALS AND METHODS: Five radiologists assessed breast density four times in 104 mammographic examinations: twice using the fourth edition of the BI-RADS guidelines and twice using the fifth edition. The intra- and interreader agreements for density assessment based on each guideline were determined and compared. The density distribution pattern under each of the four BI-RADS density categories using each guideline was also noted and compared. RESULTS: The intrareader agreement for density assessment using the fifth-edition criteria was lower than that using the fourth-edition criteria (p = 0.0179). The overall intrareader agreement (weighted kappa) using the old criteria was 0.84 (95% CI, 0.80-0.87), and the individual intrareader agreement values in five readers ranged from 0.78 (95% CI, 0.69-0.88) to 0.92 (95% CI, 0.87-0.97). The overall intrareader agreement using the new BI-RADS criteria was 0.77 (95% CI, 0.73-0.81), and the individual intrareader agreement values in five readers ranged from 0.74 (95% CI, 0.64-0.84) to 0.99 (95% CI, 0.98-1.00). The interreader agreement values obtained using the fifth-edition criteria were also lower than those obtained using the fourth-edition criteria (p = 0.006). The overall interreader agreement using the old BI-RADS criteria was 0.65 (95% CI, 0.61-0.69), whereas the overall interreader agreement using the new BI-RADS criteria was 0.57 (95% CI, 0.53-0.61). Overall a higher number of dense assessments were given when the fifth-edition guidelines were used (p < 0.0001). CONCLUSION: Compared with the intra- and interreader agreements obtained using the fourth edition of the BI-RADS guidelines, the intra- and interreader agreements were lower using the fifth-edition guidelines. An increased number of dense assessments were given when the fifth-edition guidelines were used.

Impact of fill volume on ultrafiltration with icodextrin in children on chronic peritoneal dialysis.

BACKGROUND: Icodextrin is a solution of glucose polymers developed to provide sustained ultrafiltration over an extended dwell. Our aim was to determine whether or not fill volume with icodextrin contributes to the ability to achieve ultrafiltration in children. METHODS: The charts of all children on chronic peritoneal dialysis between January 2000 and July 2014 were screened for the use of an icodextrin day dwell. Data were extracted from the electronic chart and the HomeChoice™ Pro card and corrected for body surface area (BSA). RESULTS: Fifty children had an icodextrin day dwell. A linear correlation was found between the daytime fill volume and net ultrafiltration (p < 0.001). More ultrafiltration was achieved with a fill volume above 550 ml/m(2) BSA (107 ± 75 ml/m(2) BSA) than with smaller fill volumes (-8 ± 99 ml; p = 0.004). Ultrafiltration was achieved in 88 % of children with a fill volume above 550 ml/m(2) BSA versus only 44 % of patients with a smaller fill volume (p = 0.001). Icodextrin was well tolerated. CONCLUSIONS: Our observations reveal that the larger the fill volume the higher the likelihood of achieving ultrafiltration with icodextrin and suggest that a minimum day dwell volume of 550 ml/m(2) BSA seems to facilitate ultrafiltration in children. To our knowledge this is the largest study addressing ultrafiltration with icodextrin in children.

Assessing the Relationship of Mammographic Breast Density and Proliferative Breast Disease.

Increased breast density and a history of benign breast biopsy are both considered risk factors for developing breast cancer. Understanding the specifics of these risk factors and their relationship to each other can lead to a better understanding of a patient's propensity for breast cancer development and improved surveillance strategies. We included 245 women who underwent a benign breast biopsy without atypia between October 2011 and June 2013. Biopsies were performed for suspicious calcifications as well as masses and architectural distortion. Lesions biopsied were divided into two groups: calcified and noncalcified lesions. The patient's breast density was assessed on most recent mammogram and was classified using the American College of Radiology BI-RADS density categories. Based on histologic diagnosis, each case was classified as proliferative or nonproliferative breast disease. The median age of the cohort (n = 245) was 55 years (range, 40-84 years). There were 162 (66%) postmenopausal women in the study. A core biopsy was performed for calcifications in 33.5% cases and for noncalcified lesions in 58% cases. In patients with dense breast tissue, an underlying proliferative histology was found significantly more frequently with calcifications (66.7%) as opposed to noncalcified lesions (35.9%) (RR = 2.3 (1.3-4.0); χ(2) = 8.7; p = 0.003). In nondense breast patients, there was no significant difference (RR = 1.1 (0.7-1.8); χ(2) = 0.1; p = 0.738). In the postmenopausal group, women with dense breasts had proliferative histology significantly more frequently than women with nondense breasts (55.3% versus 38.3%; p < 0.05), regardless of the underlying lesion type. Postmenopausal women with dense breasts who underwent a breast biopsy with benign histology had a significantly higher likelihood of having proliferative breast disease, regardless of underlying lesion type. Women with dense breasts also showed proliferative histology significantly more often for calcifications as opposed to noncalcified lesions.

Comparative accuracy of preoperative tumor size assessment on mammography, sonography, and MRI: Is the accuracy affected by breast density or cancer subtype?

PURPOSE: To compare the accuracy of preoperative breast tumor size measurements obtained on three imaging modalities (mammography [MM], sonography [US], and MRI) with those obtained on final pathologic examination for different breast densities and various tumor types. METHODS: Records from patients who underwent breast cancer lumpectomy between 2008 and 2012 and in whom tumor was seen on all three imaging modalities were retrospectively reviewed for maximum tumor size measurements. Patients with positive tumor margins and those who had undergone neoadjuvant chemotherapy were excluded. Tumor size measurements obtained on the three imaging modalities were compared for accuracy with those obtained during the final pathologic examination. Differences were analyzed for the whole group and for subgroups according to breast density and tumor type. RESULTS: In total, 57 patients were included, in whom wire-localization lumpectomy was performed without neoadjuvant chemotherapy; negative surgical margins for tumor were obtained, and tumor was preoperatively visualized on all three imaging modalities. The mean (± SEM) tumor size measured on MRI was significantly greater than that measured on pathology (p < 0.001), whereas the sizes measured on US and MM were not statistically significantly different from that measured on pathology (p = 0.62 and p = 0.57). Tumor size measured on MRI was greater than that measured on both US and MM (p = 0.003 and p < 0.001). Compared with the measurements obtained on pathology, that obtained on US showed moderate agreement (Lin concordance correlation coefficient [CCC], 0.71; 95% confidence interval [CI], 0.56-0.82); poorer agreement was found for the sizes obtained on MM (CCC, 0.58; 95% CI, 0.38-0.72) and MRI (CCC, 0.50; 95% CI, 0.31-0.65). No difference in comparative accuracy of size measurement was noted between dense and nondense breast tissue. MRI overestimated tumor size in ductal cancers (p < 0.001) and slightly underestimated it in lobular cancers. CONCLUSIONS: Preoperative MRI significantly overestimated tumor size. Measurements obtained on US and MM were more accurate irrespective of breast density, with US measurements being slightly more accurate than MM measurements.