SUMMARYRNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1–6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.

The histological and molecular subtypes of breast cancer demand distinct therapeutic approaches. Invasive ductal carcinoma (IDC) is subtyped according to estrogen-receptor (ER), progesterone-receptor (PR), and HER2 status, among other markers. Desorption-electrospray-ionization-mass-spectrometry imaging (DESI-MSI) is an ambient-ionization MS technique that has been previously used to diagnose IDC. Aiming to investigate the robustness of ambient-ionization MS for IDC diagnosis and subtyping over diverse patient populations and interlaboratory use, we report a multicenter study using DESI-MSI to analyze samples from 103 patients independently analyzed in the United States and Brazil. The lipid profiles of IDC and normal breast tissues were consistent across different patient races and were unrelated to country of sample collection. Similar experimental parameters used in both laboratories yielded consistent mass-spectral data in mass-to-charge ratios ( m/ z) above 700, where complex lipids are observed. Statistical classifiers built using data acquired in the United States yielded 97.6% sensitivity, 96.7% specificity, and 97.6% accuracy for cancer diagnosis. Equivalent performance was observed for the intralaboratory validation set (99.2% accuracy) and, most remarkably, for the interlaboratory validation set independently acquired in Brazil (95.3% accuracy). Separate classification models built for ER and PR statuses as well as the status of their combined hormone receptor (HR) provided predictive accuracies (>89.0%), although low classification accuracies were achieved for HER2 status. Altogether, our multicenter study demonstrates that DESI-MSI is a robust and reproducible technology for rapid breast-cancer-tissue diagnosis and therefore is of value for clinical use.

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BackgroundAluminum is used in a wide range of applications and is a potential environmental hazard. The known genotoxic effects of aluminum might play a role in the development of breast cancer. However, the data currently available on the subject are not sufficient to establish a causal relationship between aluminum exposure and the augmented risk of developing breast cancer. To achieve maximum sensitivity and specificity in the determination of aluminum levels, we have developed a detection protocol using graphite furnace atomic absorption spectrometry (GFAAS). The objective of the present study was to compare the aluminum levels in the central and peripheral areas of breast carcinomas with those in the adjacent normal breast tissues, and to identify patient and/or tumor characteristics associated with these aluminum levels.MethodsA total of 176 patients with breast cancer were included in the study. Samples from the central and peripheral areas of their tumors were obtained, as well as from the surrounding normal breast tissue. Aluminum quantification was performed using GFAAS.ResultsThe average (mean ± SD) aluminum concentrations were as follows: central area, 1.88 ± 3.60 mg/kg; peripheral area, 2.10 ± 5.67 mg/kg; and normal area, 1.68 ± 11.1 mg/kg. Overall and two-by-two comparisons of the aluminum concentrations in these areas indicated no significant differences. We detected a positive relationship between aluminum levels in the peripheral areas of the tumors, age and menopausal status of the patients (P = .02).ConclusionsUsing a sensitive quantification technique we detected similar aluminum concentrations in the central and peripheral regions of breast tumors, and in normal tissues. In addition, we did not detect significant differences in aluminum concentrations as related to the location of the breast tumor within the breast, or to other relevant tumor features such as stage, size and steroid receptor status. The next logical step is the assessment of whether the aluminum concentration is related to the key genomic abnormalities associated with breast carcinogenesis.

ABSTRACT. Partial trisomy 13q is an uncommon chromosomal abnormality with variable phenotypic expression. We report prenatal diagnosis of partial trisomy 13q in a fetus with partial agenesis of the cerebellar vermis, partial agenesis of the corpus callosum, hydrops and polyhydramnios. G-banding karyotyping, spectral karyotyping and array comparative genomic hybridization (aCGH) analysis of fetal blood were performed. Cytogenetic analysis of fetal blood displayed 46,XX,add(4) (q28). The parental karyotypes were normal. A girl was delivered at 34 weeks gestation; she died within 2 h. Autopsy confirmed all the prenatal findings and also showed agenesis of the diaphragm. Spectral karyotyping identified the additional material's origin as chromosome 13. aCGH was carried out and showed amplification of distal regions of the long arm of chromosome 13 from region 13q14 to qter. This is the first report of a fetus with molecular characterization of a partial trisomy 13q (q14→qter), present as a de novo unbalanced translocation at chromosome 4q. This case demonstrates the usefulness of molecular characterization of malformed fetuses for prenatal diagnosis and counseling.

Background As the most incident tumor among women worldwide, breast cancer is a heterogeneous disease. Tremendous efforts have been made to understand how tumor characteristics as histological type, molecular subtype, and tumor microenvironment collectively influence disease diagnosis to treatment, which impact outcomes. Differences between populations and environmental and cultural factors have impacts on the origin and evolution of the disease, as well as the therapeutic challenges that arise due to these factors. We, then, compared copy number variations (CNVs) in mucinous and nonmucinous luminal breast tumors from a Brazilian cohort to investigate major CNV imbalances in mucinous tumors versus non‐mucinous luminal tumors, taking into account their clinical and pathological features. Methods 48 breast tumor samples and 48 matched control blood samples from Brazilian women were assessed for CNVs by chromosome microarray. Logistic regression and random forest models were used in order to assess CNVs in chromosomal regions from tumors. Results CNVs that were identified in chromosomes 1, 5, 8, 17, 19, and 21 classify tumors according to their histological type, ethnicity, disease stage, and familial history. Conclusion Copy number alterations described in this study provide a better understanding of the landscape of genomic aberrations in mucinous breast cancers that are associated with clinical features.

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It has long been hypothesized that body tissue uptake of aluminum may have biological implications in breast cancer. In vitro and in vivo studies have shown that aluminum may trigger genomic instability by interfering with DNA strands. The objective of this study was to examine the relationship between aluminum concentrations in the peripheral and central areas of breast tumors with the instability of three key genes in breast cancer, ERBB2, C-MYC, and CCND1 and aneuploidy of the chromosomes harboring these genes. Tissue samples of 118 women treated for breast cancer were obtained. Evaluation of aluminum content was carried out using graphite furnace atomic absorption spectrometry. A tissue microarray slide containing the tumor samples was used in FISH assays to assess ERBB2, C-MYC, and CCND1 expressions as well as the statuses of their respective chromosomes 17, 8, and 11. Clinicopathological data were obtained from patient's records. Aluminum levels of >2.0 mg/kg were found in 20.3 and 22.1% of the central and peripheral breast tumor areas, respectively. Amplification and/or aneuploid-positive statuses for ERBB2/CEP17, C-MYC/CEP8, and CCND1/CEP11 were detected in 24, 36.7, and 29.3% of the tumors, respectively. We found that aluminum concentration was not related to these altered gene statuses. Our findings suggest that aluminum concentration does not affect genomic stability in breast tissues. Tissue microenvironment modifications, due to the presence of aluminum compounds, seem more appealing as a possible target for future studies to determine the implications of aluminum in breast carcinogenesis.