Identification of long non-coding RNAs and RNA binding proteins in breast cancer subtypes

Breast cancer is a heterogeneous disease classified into four main subtypes with different clinical outcomes, such as patient survival, prognosis, and relapse. Current genetic tests for the differential diagnosis of BC subtypes showed a poor reproducibility. Therefore, an early and correct diagnosis of molecular subtypes is one of the challenges in the clinic. In the present study, we identified differentially expressed genes, long non-coding RNAs and RNA binding proteins for each BC subtype from a public dataset applying bioinformatics algorithms. In addition, we investigated their interactions and we proposed interacting biomarkers as potential signature specific for each BC subtype. We found a network of only 2 RBPs (RBM20 and PCDH20) and 2 genes (HOXB3 and RASSF7) for luminal A, a network of 21 RBPs and 53 genes for luminal B, a HER2-specific network of 14 RBPs and 30 genes, and a network of 54 RBPs and 302 genes for basal BC. We validated the signature considering their expression levels on an independent dataset evaluating their ability to classify the different molecular subtypes with a machine learning approach. Overall, we achieved good performances of classification with an accuracy >0.80. In addition, we found some interesting novel prognostic biomarkers such as RASSF7 for luminal A, DCTPP1 for luminal B, DHRS11, KLC3, NAGS, and TMEM98 for HER2, and ABHD14A and ADSSL1 for basal. The findings could provide preliminary evidence to identify putative new prognostic biomarkers and therapeutic targets for individual breast cancer subtypes.

Diagnostic performance of superb microvascular imaging combined with shear-wave elastography in distinguishing invasive ductal carcinoma molecular subtypes

IntroductionTo explore the diagnostic value of combining superb microvascular imaging (SMI), shear-wave elastography (SWE), and Breast Imaging Reporting and Data System (BI-RADS) to distinguish different molecular subtypes of invasive ductal carcinoma (IDC).Material and methodsA total of 239 surgically confirmed IDC masses in 201 patients underwent conventional ultrasound, SMI, and SWE examination, the information such as echo pattern, posterior features, margins, SMI pixels, and hardness of the masses was recorded. According to the St. Gallen standard, breast masses were classified as Luminal A, Luminal B, HER2 overexpression, and triple-negative subtype. We further explored the differences between different molecular subtypes of IDC.ResultsLuminal A subtype had the following characteristics: low histologic grade, posterior acoustic shadowing (p= 0.019), spiculated margins (p<0.001) , and relatively soft. Luminal B subtype was characterized by low histological grade (p <0.0001), posterior acoustic shadowing or indifference, and indistinct margins. HER2 overexpression breast cancers were characterized by high histological grade, enhanced posterior acoustics or indifference, calcifications (p= 0.005), spiculated or indistinct margins, vascularity (p=0.005), and relative stiffness. Triple-negative breast cancers had the characteristics of high histological grade, posterior echogenic enhancement, lack of calcifications, circumscribed or microlobulated margins, low blood flow signals, and stiff tissue (p=0.013).ConclusionsOur study demonstrated the significant differences and trends among the IDC four subtypes by the combined application of SMI, SWE, and BI-RADS lexicon, which are of great significance for early diagnosis, selection of treatment methods, and evaluation of prognosis of IDC.

Drivers of Disparities in Stage at Diagnosis Among Women With Breast Cancer: South African Breast Cancers and HIV Outcomes Cohort

Objective In low- and middle-income countries (LMICs), advanced stage diagnosis of breast cancer (BC) is common, and this contributes to poor survival. By understanding the determinants of the stage at diagnosis will aid in designing interventions to downstage disease and improve survival from BC in LMICs. MethodsWithin the South African Breast Cancers and HIV Outcomes (SABCHO) cohort, we examined factors affecting the stage at diagnosis of histologically confirmed invasive breast cancer at five tertiary hospitals in South Africa. The stage was assessed clinically. To examine the associations of the health system, socio-economic/household and individual factors, hierarchical multivariate logistic regression with odds of late-stage at diagnosis (stage III-IV), was used. Results The majority (59%) of the included 3497 women were diagnosed with late-stage BC disease (59%). The effect of health system-level factors on late-stage BC diagnosis was consistent and significant even when adjusted for both socio-economic- and individual-level factors. Women diagnosed in a tertiary hospital that predominantly serves a rural population were almost 3 times (OR=2.89 (95% CI: 1.40-5.97) likely to be associated with late-stage BC diagnosis when compared to those diagnosed at a hospital that predominantly serves an urban population. Taking more than 3 months from identifying the BC problem to first health system entry (OR=1.66 (95% CI: 1.38–2.00)), and receptor subtypes [luminal B (OR=1.49 (95% CI: 1.19–1.87)), HER2 enriched (OR=1.64 (95% CI: 1.16–2.32))] were associated with a late-stage diagnosis. Whilst having a higher socio-economic level (a wealth index of 5) reduced the probability of late-stage BC, OR=0.64 (95% CI: 0.47 – 0.85). ConclusionAdvanced stage diagnosis of BC among women in SA who access health services through the public health system was associated with both modifiable health system-level factors and non-modifiable individual-level factors. These may be considered as elements in interventions to reduce the time to diagnosis of breast cancer in women.

Serum 25-Hydroxyvitamin D and the risk of breast cancer in women from Southern Morocco: A case-control study

OBJECTIVES: Assessing Vitamin-D status and checking if low serum 25(OH)D is a factor in breast cancer (BC) for Southern Moroccan women. MATERIALS/METHODS: Study conducted in Morocco about women with BC (n = 90) and controls (n = 90). 25-hydroxy-vitamin-D Biological analyzes executed during the first consultation. Social data and anthropometric parameters were collected for all participants. RESULTS: These women constituted 67.78 % for the cases and 85.6% for the controls. The average age was 48.72±9.71 (cases) and 46.40±12.52 (controls). We found that 53.33% of cases and 40% of controls were postmenopausal and that hypovitaminosis-D affected 80 and 64.4% of cases and controls, respectively. Statistical analysis showed that hypovitaminosis-D was a significative risk factor for BC in Southern Moroccan women. The Odds Ratio was of 5 (p < 0.0001). The BC subtypes had Odds Ratios greater than 1. The highest value was obtained with Luminal B subtype (Odds ratio = 6.25; p = 0.0007). CONCLUSION: This study reinforces the evidence implicating hypovitaminosis-D among modifiable risk factors for BC. Further studies are needed to assess the extent of hypovitaminosis-D in Moroccan women with BC.

Incidence of breast cancer subtypes in immigrant and non-immigrant women in Norway

Background Breast cancer incidence differs between non-immigrants and immigrants from low- and middle-income countries. This study investigates whether immigrants also have different subtype-specific incidences. Methods We used national health registries in Norway and calculated subtype-specific incidence rate ratios (IRRs) for invasive breast cancer among women aged 20–75 and 20–49 years between 2005 and 2015. Immigrant groups were classified by country of birth broadly defined based on WHO regional groupings. Subtype was defined using estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2) status as luminal A-like (ER+ PR+ HER2-), luminal B-like/HER2- (ER+ PR- HER2-), luminal B-like/HER2+ (ER+ PR any HER2+), HER2+ (ER-PR-HER2+) and triple-negative breast cancer (TNBC) (ER-PR-HER2-). Results Compared to non-immigrants, incidence of the luminal A-like subtype was lower in immigrants from Sub-Saharan Africa (IRR 0.43 95% CI 0.28–0.66), South East Asia (IRR 0.63 95% CI 0.51–0.79), South Asia (IRR 0.67 95% CI 0.52–0.86) and Eastern Europe (IRR 0.86 95% CI 0.76–0.99). Immigrants from South Asia had higher rates of HER2 + tumors (IRR 2.02 95% CI 1.26–3.23). The rates of TNBC tended to be similar regardless of region of birth, except that women from South East Asia had an IRR of 0.54 (95% CI 0.32–0.91). Conclusions Women from Eastern Europe, Sub-Saharan Africa and Asia had different subtype-specific incidences compared to women from high-income countries (including non-immigrants). These differences in tumor characteristics between immigrant groups should be taken into consideration when planning preventive or screening strategies.

Elevated SOX11 expression distinguishes basal-like human breast cancer.

Patients diagnosed with basal-like breast cancer face a more aggressive disease course and more dismal prognosis than patients diagnosed with luminal A and luminal B breast cancer molecular subtypes (1-4). We mined published microarray data (5, 6) to understand in an unbiased fashion the most distinguishing transcriptional features of tumors from patients with basal or basal-like subtype breast cancer. We observed transcriptome-wide differential expression of SRY-box 11, SOX11, when comparing tumors of patients with basal-like breast cancer with that of other PAM50 molecular subtypes. SOX11 mRNA was present at significantly higher quantities in the tumors of patients with basal-like breast cancer. Analysis of patient survival data revealed that SOX11 primary tumor expression was correlated with overall survival, with higher SOX11 associated with inferior outcomes - in basal-like patients but not in luminal A, luminal B, HER2+, or normal-like patients. Elevated SOX11 expression appears to distinguish basal-like human breast cancer from the other molecular subtypes.

Characteristics of HER2-negative breast cancers with FISH-equivocal status according to 2018 ASCO/CAP guideline

Background According to 2018 ASCO/CAP guideline, HER2 FISH-equivocal breast cancers will be categorized as HER2 negative except those with IHC 3+. However, whether or not HER2 FISH-equivocal breast cancers was a heterogeneous group has not been well illustrated. Methods 195 HER2 FISH-equivocal breast cancer samples were collected from 2014 to 2018. The molecular subtype was identified according to 2013 St Gallen consensus, and HER2 status was also re-determined following 2018 ASCO/CAP guideline. All samples were classified into 4 groups according to the average HER2 copy number (4.0–4.4, 4.5–4.9, 5.0–5.4, 5.5–5.9 signals/cell). The relationship between HER2 copy number and clinicopathological parameters was analyzed. Results 183 (93.8%) of 195 FISH-equivocal cases were classified as luminal-like subtype, while the other 12 (6.2%) were undetermined. Following 2018 ASCO/CAP guideline, all FISH-equivocal cases were recategorized as HER2 negative. Therefore, 31(15.9%) cases were luminal A-like, 152 (77.9%) were luminal B-like (HER2 negative) and 12 (6.2%) were triple negative. The average HER2 copy number showed a positive correlation with chromosome 17 polysomy, but had no significant association with other clinicopathological parameters as well as prognosis. 17 (8.7%) patients were treated with trastuzumab, but showed no difference in prognosis with those who didn’t receive targeted therapy. Conclusions In this study, all HER2 FISH-equivocal breast cancers were recategorized as HER2 negative according to 2018 ASCO/CAP guideline. Most of these patients were luminal B-like (HER2 negative). The average HER2 copy number had no significant association with clinicopathological parameters, as well as prognosis.

High VEGF-A expression distinguishes basal-like human breast cancer.

Patients diagnosed with basal-like breast cancer face a more aggressive disease course and more dismal prognosis than patients diagnosed with luminal A and luminal B breast cancer molecular subtypes (1-4). We mined published microarray data (5, 6) to understand in an unbiased fashion the most distinguishing transcriptional features of tumors from patients with basal or basal-like subtype breast cancer. We observed transcriptome-wide differential expression of the vascular endothelial growth factor A, VEGFA, when comparing tumors of patients with basal-like breast cancer with that of other PAM50 molecular subtypes. VEGF-A mRNA was present at significantly higher quantities in the tumors of patients with basal-like breast cancer. Analysis of patient survival data revealed that VEGF-A primary tumor expression was correlated with recurrence-free survival, with higher VEGF-A associated with inferior outcomes - in basal-like patients but not in luminal A, luminal B, HER2+, or normal-like patients. High VEGF-A expression appears to distinguish basal-like human breast cancer from the other molecular subtypes.

Low GATA3 expression distinguishes basal-like human breast cancer.

Patients diagnosed with basal-like breast cancer face a more aggressive disease course and more dismal prognosis than patients diagnosed with luminal A and luminal B breast cancer molecular subtypes (1-4). We mined published microarray data (5, 6) to understand in an unbiased fashion the most distinguishing transcriptional features of tumors from patients with basal or basal-like subtype breast cancer. We observed transcriptome-wide differential expression of the transcription factor GATA3 when comparing tumors of patients with basal-like breast cancer with that of other PAM50 molecular subtypes. GATA3 mRNA was present at significantly reduced quantities in the tumors of patients with basal-like breast cancer. Analysis of patient survival data revealed that GATA3 primary tumor expression was correlated with distant metastasis-free survival, with low GATA3 expression correlated with inferior survival outcomes. Low GATA3 expression appears to distinguish basal-like human breast cancer from the other molecular subtypes.

Neuroendocrine Neoplasms of Breast:A Rare Breast Tumor Worthy of Attention

Background: Neuroendocrine neoplasms of breast(NENB) is a rare and underrecognized subtype of breast neoplasms.The clinical significance, prognostic risk factors and optimal treatment modalities are limited. This study was focused on clinical and pathological features of 27 NENB cases to improve the understanding of these diseases and to further investigate the behavior of these neoplasms and to provide more factual evidence.Methods: We retrospectively analyzed the clinicopathological features and follow-up data of 27 patients diagnosed with NENB at the First Affiliated Hospital of Bengbu Medical College between February 2003 and February 2015.Results: The proportion of NENB from all invasive breast carcinomas(BC) in our hospital was 0.24% (27/11352). The expression of specific immunohistochemical markers was different: 48.1% cases showed the expression of chromogranin A (CgA)(13/27), CD56 was positive in 77.8%cases (21/27), the positive rate of INSM1 and synaptophysin (Syn) were 85.2%（23/27）and 100.0% (27/27). NENB occurred in older patients (median age,64 ).11cases (40.7%) were well-differentiated NETs and 16 cases (59.3%) were poorly differentiated NEC. In NETs, The positive rate of ER was 10/11 (90.9%) , while in NECs, The positive rate of ER was 9/16(56.3%) , On the basis of immunophenotypes, most of NENBs were of the luminal molecular subtype ,6 cases were luminal A and 15cases were luminal B ,6 cases were triple negative breast cancer(TNBC) and had no HER-2 overexpression subtypes. Conclusions: NENB more likely occures in elderly patients.Well-differentiated NETs are more often positive for hormone receptors than poorly differentiated NEC. NENBs are almost negative for HER-2. The combination of INSM1 is an effective supplement and improvement for traditional neuroendocrine markers.