[Pharmacogenetics in psychiatry: state of the art]. / Pharmakogenetik in der Psychiatrie: eine Standortbestimmung.

In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine. The main obstacle for a broad application of pharmacogenetic tests in psychiatry remains the lack of large prospective studies, for both single gene-drug pair and cobinatorial pharmacogenetic tests, to evaluate the benefits of genetic testing. Psychiatrists, geneticists and funding agencies are encouraged to increase their efforts for the future benefit of psychiatric patients.

The effect of 5-HTTLPR and a serotonergic multi-marker score on amygdala, prefrontal and anterior cingulate cortex reactivity and habituation in a large, healthy fMRI cohort.

Major depressive disorder (MDD) is characterized by low mood for at least two weeks. Impaired emotion regulation has been suggested to be the consequence of dysfunctional serotonergic regulation of limbic and prefrontal regions, especially the amygdala, the anterior cingulate cortex (ACC) and the prefrontal cortex (PFC). The impact of genetic variation on brain function can be investigated with intermediate phenotypes. A suggested intermediate phenotype of MDD is emotion recognition: The 5-HTTLPR polymorphism of SLC6A4 as well as other serotonergic genes have been associated with amygdala and prefrontal function during emotion recognition. Previously, it has been suggested that habituation is a more reliable index of emotion recognition than functional activation. We examined the relationship of genes involved in serotonergic signaling with amygdala as well as prefrontal functional activation and habituation during an emotion recognition task in 171 healthy subjects. While effects of 5-HTTLPR and of a serotonergic multi-marker score (5-HTTLPR, TPH1(rs1800532), TPH2(rs4570625), HTR1A(rs6295) and HTR2A(rs6311)) on amygdala activation did not withstand correction for multiple regions of interest, we observed a strong correlation of the multi-marker score and habituation in the amygdala, DLPFC, and ACC. We replicated a well-studied intermediate phenotype for association with 5-HTTLPR and provided additional evidence for polygenic involvement. Furthermore, we showed that task habituation may be influenced by genetic variation in serotonergic signaling, particularly by a serotonergic multi-marker score. We provided preliminary evidence that PFC activation is an important intermediate phenotype of MDD. Future studies are needed to corroborate the results in larger samples.

Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia.

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

Polygenic risk has an impact on the structural plasticity of hippocampal subfields during aerobic exercise combined with cognitive remediation in multi-episode schizophrenia.

Preliminary studies suggest that, besides improving cognition, aerobic exercise might increase hippocampal volume in schizophrenia patients; however, results are not consistent. Individual mechanisms of volume changes are unknown but might be connected to the load of risk genes. Genome-wide association studies have uncovered the polygenic architecture of schizophrenia. The secondary analysis presented here aimed to determine the modulatory role of schizophrenia polygenic risk scores (PRSs) on volume changes in the total hippocampus and cornu ammonis (CA) 1, CA2/3, CA4/dentate gyrus (DG) and subiculum over time. We studied 20 multi-episode schizophrenia patients and 23 healthy controls who performed aerobic exercise (endurance training) combined with cognitive remediation for 3 months and 21 multi-episode schizophrenia patients allocated to a control intervention (table soccer) combined with cognitive remediation. Magnetic resonance imaging-based assessments were performed at baseline and after 3 months with FreeSurfer. No effects of PRSs were found on total hippocampal volume change. Subfield analyses showed that the volume changes between baseline and 3 months in the left CA4/DG were significantly influenced by PRSs in schizophrenia patients performing aerobic exercise. A larger genetic risk burden was associated with a less pronounced volume increase or a decrease in volume over the course of the exercise intervention. Results of exploratory enrichment analyses reinforced the notion of genetic risk factors modulating biological processes tightly related to synaptic ion channel activity, calcium signaling, glutamate signaling and regulation of cell morphogenesis. We hypothesize that a high polygenic risk may negatively influence neuroplasticity in CA4/DG during aerobic exercise in schizophrenia.

Genetic effects influencing risk for major depressive disorder in China and Europe.

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

Functional neuroimaging effects of recently discovered genetic risk loci for schizophrenia and polygenic risk profile in five RDoC subdomains.

Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single-nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (PFWE(ROI)=0.047) and social cognition (PFWE(ROI)=0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (PFWE(ROI)=1.63 × 10-4, surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N=150; PFWE(ROI)<0.025). Other SNP effects previously associated with imaging phenotypes were nominally significant, but did not withstand correction for the number of SNPs tested. To assess whether there was true signal within our data, we repeated single SNP analyses with 105 randomly chosen non-schizophrenia-associated variants, observing fewer significant results and lower association probabilities. Applying stringent methodological procedures, we found preliminary evidence for the notion that genetic risk for schizophrenia conferred by rs9607782 may be mediated by amygdala function. We critically evaluate the potential caveats of the methodological approaches employed and offer suggestions for future studies.

Genome-wide association study of pathological gambling.

BACKGROUND: Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence. METHODS: Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence. RESULTS: No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value=6.63×10(-3)); 5'-adenosine monophosphate-activated protein kinase signalling (P-value=9.57×10(-3)); and apoptosis (P-value=1.75×10(-2)) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status. CONCLUSIONS: The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies.

Circadian genes and lithium response in bipolar disorders: associations with PPARGC1A (PGC-1α) and RORA.

Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene-based association analyses of 22 core clock genes were conducted. In the first sample (H660 chip), the RAR-related orphan receptor-a gene (RORA) and the Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha gene (PPARGC1A or PGC-1α) were significantly associated with the Li response (empirical P-value = 0.0015 and 0.04, respectively), and remained significant only for RORA after Bonferroni correction. In the second sample (OE chip), PPARGC1A was significantly associated with the Li response (empirical P-value = 0.04), and did not remain significant after Bonferroni correction. PPARGC1A is a master regulator of mitochondrial function and a key component of the endogenous clock that stimulates the expression of Bmal1 and Rev-erb-alpha through coactivation of RORA. Although the observed associations deserve further replication and investigation, our results suggest genetic associations between Li response and these two close biological partners: PPARGC1A and RORA involved in circadian rhythms and bioenergetics processes in Li response.

The Problem of Mammographic Breast Density - The Position of the DEGUM Working Group on Breast Ultrasound.

Mammographic breast density correlates with breast cancer risk and also with the number of false-negative calls. In the USA these facts lead to the "Breast Density and Mammography Reporting Act" of 2011. In the case of mammographically dense breasts, the Working Group on Breast Ultrasound in Germany recommends explaining the advantages of adjunct imaging to women, depending on the individual breast cancer risk. Due to the particular structure of German healthcare, quality-assured breast ultrasound would be the first choice. Possible overdiagnosis, costs, potentially increased emotional stress should be addressed. In high familial breast cancer risk, genetic counselling and an intensified early detection program should be performed.

High loading of polygenic risk in cases with chronic schizophrenia.

Genomic risk profile scores (GRPSs) have been shown to predict case-control status of schizophrenia (SCZ), albeit with varying sensitivity and specificity. The extent to which this variability in prediction accuracy is related to differences in sampling strategies is unknown. Danish population-based registers and Neonatal Biobanks were used to identify two independent incident data sets (denoted target and replication) comprising together 1861 cases with SCZ and 1706 controls. A third data set was a German prevalent sample with diagnoses assigned to 1773 SCZ cases and 2161 controls based on clinical interviews. GRPSs were calculated based on the genome-wide association results from the largest SCZ meta-analysis yet conducted. As measures of genetic risk prediction, Nagelkerke pseudo-R(2) and variance explained on the liability scale were calculated. GRPS for SCZ showed positive correlations with the number of psychiatric admissions across all P-value thresholds in both the incident and prevalent samples. In permutation-based test, Nagelkerke pseudo-R(2) values derived from samples enriched for frequently admitted cases were found to be significantly higher than for the full data sets (Ptarget=0.017, Preplication=0.04). Oversampling of frequently admitted cases further resulted in a higher proportion of variance explained on the liability scale (improvementtarget= 50%; improvementreplication= 162%). GRPSs are significantly correlated with chronicity of SCZ. Oversampling of cases with a high number of admissions significantly increased the amount of variance in liability explained by GRPS. This suggests that at least part of the effect of common single-nucleotide polymorphisms is on the deteriorative course of illness.

Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder.

Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.

Identification and functional characterization of rare SHANK2 variants in schizophrenia.

Recent genetic data on schizophrenia (SCZ) have suggested that proteins of the postsynaptic density of excitatory synapses have a role in its etiology. Mutations in the three SHANK genes encoding for postsynaptic scaffolding proteins have been shown to represent risk factors for autism spectrum disorders and other neurodevelopmental disorders. To address if SHANK2 variants are associated with SCZ, we sequenced SHANK2 in 481 patients and 659 unaffected individuals. We identified a significant increase in the number of rare (minor allele frequency<1%) SHANK2 missense variants in SCZ individuals (6.9%) compared with controls (3.9%, P=0.039). Four out of fifteen non-synonymous variants identified in the SCZ cohort (S610Y, R958S, P1119T and A1731S) were selected for functional analysis. Overexpression and knockdown-rescue experiments were carried out in cultured primary hippocampal neurons with a major focus on the analysis of morphological changes. Furthermore, the effect on actin polymerization in fibroblast cell lines was investigated. All four variants revealed functional impairment to various degrees, as a consequence of alterations in spine volume and clustering at synapses and an overall loss of presynaptic contacts. The A1731S variant was identified in four unrelated SCZ patients (0.83%) but not in any of the sequenced controls and public databases (P=4.6 × 10(-5)). Patients with the A1731S variant share an early prodromal phase with an insidious onset of psychiatric symptoms. A1731S overexpression strongly decreased the SHANK2-Bassoon-positive synapse number and diminished the F/G-actin ratio. Our results strongly suggest a causative role of rare SHANK2 variants in SCZ and underline the contribution of SHANK2 gene mutations in a variety of neuropsychiatric disorders.

Investigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder.

Bipolar disorder (BD) is a highly heritable psychiatric disease characterized by recurrent episodes of mania and depression. To identify new BD genes and pathways, the present study employed a three-step approach. First, gene-expression profiles of BD patients were assessed during both a manic and an euthymic phase. These profiles were compared intra-individually and with the gene-expression profiles of controls. Second, those differentially expressed genes that were considered potential trait markers of BD were validated using data from the Psychiatric Genomics Consortiums' genome-wide association study (GWAS) of BD. Third, the implicated molecular mechanisms were investigated using pathway analytical methods. In the present patients, this novel approach identified: (i) sets of differentially expressed genes specific to mania and euthymia; and (ii) a set of differentially expressed genes that were common to both mood states. In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 × 10(-4)) after adjustment for multiple testing. STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set. Pathway analyses in the mania versus control comparison revealed three distinct clusters of pathways tagging molecular mechanisms implicated in BD, for example, energy metabolism, inflammation and the ubiquitin proteasome system. The present findings suggest that STAB1 is a new and highly promising candidate gene in this region. The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD.

[Evaluation of the nationwide DEGUM breast ultrasound training program]. / Evaluation der DEGUM-Mammasonografiekurse nach objektivierbaren Kriterien.

PURPOSE: The aim of this study was to evaluate the quality standard of the nationwide breast ultrasound training program of the German Society of Ultrasound in Medicine (DEGUM) through objective parameters. MATERIALS AND METHODS: 10 quality criteria, based on the recommendations of The National Association of Statutory Health Insurance Physicians (KBV), were defined for this study. All training units of the DEGUM received a questionnaire. The questionnaires and training material were analyzed. RESULTS: All units met the required criteria pertaining to the trainer's qualification, duration per training course and the maximum number of participants per ultrasound machine. Only 1 course did not fulfill the required 50 % practical training time. The requirements to participate in the graduate course (200 self-made and documented cases) were not clearly conceived and a defined training log could be improved. CONCLUSION: DEGUM breast ultrasound training offers trainees a high level of education based on the requirements of the KBV. Despite the high quality of training, the content of course announcements could be improved and an official and structured educational index could be meaningful.

[Sonoelastography usage among German DEGUM-certified breast ultrasound specialists]. / Einsatz der Sonoelastografie in der Mammadiagnostik: Analyse unter DEGUM-zertifizierten Untersuchern.

PURPOSE: Sonoelastography of the breast is an emerging technology with evident data in the literature suggesting diagnostic advantages. Our study investigates the current usage of sonoelastography among German DEGUM-certified breast ultrasound specialists. MATERIALS AND METHODS: We used a standardized questionnaire with 18 items. In 2012, the survey was sent to all members of the breast ultrasound section of the DEGUM (n = 654). RESULTS: The group of survey participants (n = 208) performs 193 025 breast ultrasound examinations and examines 20 110 breast cancers per year. 21.2 % of the participants in the survey use sonoelastography, mainly for diagnostic purposes in BI-RADS®-US 3 and 4 lesions, less often for other categories or under study conditions. The most commonly applied criteria for the evaluation of the elastogram are the Tsukuba Elasticity Score (43.2 %), the fat-lesion ratio (29.5 %) and the determination of tissue stiffness with shear wave elastography expressed in kilopascal (25.0 %). The majority of non-users of elastography (58.6 %) would like to have the option of using sonoelastography in the future. CONCLUSION: Sonoelastography is a feasible and helpful method in the evaluation of breast lesions. A significant number of German ultrasound specialists already apply this technology today. We expect a growing number of sonographers to perform sonoelastography in the near future, provided that they have the necessary ultrasound system and that they are trained in the method. Evidence from the literature and the recommendations of the medical societies support this development.

Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

The biology of malignant breast tumors has an impact on the presentation in ultrasound: an analysis of 315 cases.

BACKGROUND: The aim of this study was to evaluate the relation of some ultrasound morphological parameters to biological characteristics in breast carcinoma. METHODS: Ultrasound data from 315 breast masses were collected. We analyzed the ultrasound features of the tumors according to the ACR BI-RADS®-US classification system stratified by hormone receptor status, HER2 status, histology grade, tumor type (ductal versus lobular), triple-negativity, breast density, tumor size, lymph node involvement and patient's age. RESULTS: We found a variety of ultrasound features that varied between the groups. Invasive lobular tumors were more likely to have an angulated margin (39% versus 22%, p = 0.040) and less likely to show posterior acoustic enhancement (3% versus 16%, p = 0.023) compared to invasive ductal carcinoma. G3 tumors were linked to a higher chance of posterior acoustic enhancement and less shadowing and the margin of G3 tumors was more often described as lobulated or microlobulated compared to G1/G2 tumors (67% versus 46%, p = 0.001). Tumors with an over-expression of HER2 exhibited a higher rate of architectural distortions in the surrounding tissue, but there were no differences regarding the other features. Hormone receptor negative tumors were more likely to exhibit a lobulated or microlobulated margin (67% versus 50%, p = 0.037) and less likely to have an echogenic halo (39% versus 64%, p = 0.001). Furthermore, the posterior acoustic feature was more often described as enhancement (33% versus 13%, p = 0.001) and less often as shadowing (20% versus 47%, p < 0.001) compared to hormone receptor positive tumors. CONCLUSION: Depending on their biological and clinical profile, breast cancers are more or less likely to exhibit the typical criteria for malignancy in ultrasound. Moreover, certain types of breast cancer tend to possess criteria that are usually associated with benign masses. False-negative diagnosis may result in serious consequences for the patient. For the sonographer it is essential to be well aware of potential variations in the ultrasound morphology of breast tumors, as described in this paper.