Concomitant angiosarcoma and lymphoproliferative disorder in solid organ transplant recipients

An increased risk of posttransplant malignancy has been consistently reported following various solid organ transplants. The malignancies most commonly encountered are non-melanoma skin cancers, carcinomas of lung or breast and posttransplant lymphoproliferative disorders. Angiosarcoma, an uncommon vascular mesenchymal neoplasm, is rare in the posttransplant setting. This report describes two patients who developed high-grade angiosarcoma following a solid organ transplant. Notably, in both patients, the diagnosis of angiosarcoma was preceded by diagnosis of a lymphoproliferative disorder with monoclonal immunoglobulin heavy chain rearrangement

Decreased BECN1 mRNA Expression in Human Breast Cancer is Associated With Estrogen Receptor-Negative Subtypes and Poor Prognosis

AbstractBoth BRCA1 and Beclin 1 (BECN1) are tumor suppressor genes, which are in close proximity on the human chromosome 17q21 breast cancer tumor susceptibility locus and are often concurrently deleted. However, their importance in sporadic human breast cancer is not known. To interrogate the effects of BECN1 and BRCA1 in breast cancer, we studied their mRNA expression patterns in breast cancer patients from two large datasets: The Cancer Genome Atlas (TCGA) (n=1067) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n=1992). In both datasets, low expression of BECN1 was more common in HER2-enriched and basal-like (mostly triple-negative) breast cancers compared to luminal A/B intrinsic tumor subtypes, and was also strongly associated with TP53 mutations and advanced tumor grade. In contrast, there was no significant association between low BRCA1 expression and HER2-enriched or basal-like subtypes, TP53 mutations or tumor grade. In addition, low expression of BECN1 (but not low BRCA1) was associated with poor prognosis, and BECN1 (but not BRCA1) expression was an independent predictor of survival. These findings suggest that decreased mRNA expression of the autophagy gene BECN1 may contribute to the pathogenesis and progression of HER2-enriched, basal-like, and TP53 mutant breast cancers

Immunohistochemical Analysis for Cytokeratin 7, KIT, and PAX2 Value in the Differential Diagnosis of Chromophobe Cell Carcinoma

Immunohistochemical staining for cytokeratin 7 (CK7), KIT, and PAX2 expression was performed on 91 renal neoplasms, 37 conventional (clear cell) renal cell carcinomas (CRCCs), 20 papillary RCCs (PRCCs), 11 chromophobe RCCs (ChCs), and 23 oncocytomas, with available karyotypes. All ChCs, 19 PRCCs, 2 CRCCs, and 1 oncocytoma were CK7+; all ChCs, 22 oncocytomas, 2 CRCCs, and no PRCCs expressed KIT; PAX2 was positive in 31 CRCCs, 17 PRCCs, 20 oncocytomas, and 1 ChC. The predominant expression profiles were as follows: CRCC, CK7–/KIT–/PAX2+ (26/37); PRCC, CK7+/KIT–/PAX2+ (17/20); ChC, CK7+/KIT+/PAX2– (10/11); and oncocytoma, CK7–/KIT+/PAX2+ (19/23). Cytogenetic analysis showed that the sole PAX2+ ChC had a retained chromosome 10, and all ChCs with chromosome 10 loss were PAX2–. These results identify specific staining patterns of the 4 major histologic subtypes of renal neoplasms and raise the question of a relationship between chromosome 10 loss and loss of PAX2 expression in ChC

Clinical Features, Survival and Prognostic Factors of Glycogen-Rich Clear Cell Carcinoma (GRCC) of the Breast in the U.S. Population

The World Health Organization (WHO) defines glycogen-rich clear cell carcinoma (GRCC) of the breast as a carcinoma with glycogen accumulation in more than 90% of its tumor cells. Due to the rarity of this disease, its reported survival and clinical associations have been inconsistent due to reliance on case reports and limited case series. As a result, the prognostic implication of this cancer subtype remains unclear. Using the U.S. Surveillance, Epidemiology, and End Results (SEER) program database, we compared the incidence, demographics and prognostic factors of 155 cases of GRCC of the breast to 1,251,584 cases of other (non-GRCC) breast carcinomas. We demonstrate that GRCC is more likely to be identified as high grade, advanced stage, and more likely to have triple negative receptor status. GRCC cases display a poorer prognosis than non-GRCC carcinomas of the breast irrespective of age, AJCC staging, tumor grade, joint hormone receptor/human epidermal growth factor receptor 2 (HER2) status, and treatment. Similar to non-GRCC carcinomas, older age and higher American Joint Committee on Cancer (AJCC)/TNM staging were associated with poorer prognosis for GRCC, while treatment with surgery and radiation were associated with improved survival. Radiation, specifically in the setting of breast-conserving surgery, further improved survival compared to surgery alone. Our study highlights the poorer prognosis associated with glycogen accumulation in breast cancers and hence stresses the importance of identifying this more aggressive tumor type

Total hemoglobin reduction in the tumor volume correlates with response to breast cancer neoadjuvant chemotherapy within two weeks of treatment

Optical imaging techniques have emerged as a possible alternative to predict pathological complete response (pCR) in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). Our team developed a so-called diffuse optical tomographic breast imaging system (DOTBIS) which does not require the use of contrast agents or compression, and enables imaging of the whole breast volume using low intensity near infrared light capable to measure tissue concentration of oxy-hemoglobin (ctO2Hb), deoxy-hemoglobin (ctHHb) and water percentage. In this retrospective study, ctTHb changes in the tumor region of 16 breast cancer patients were analyzed across NAC. Both breasts of all patients have been scanned simultaneously with our DOTBIS system, Figure 1, which employs four wavelengths and gathers data from a total of 64 sources and 128 detectors per breast. A PDE-constrained multispectral image reconstruction code creates 3D image maps of total hemoglobin (ctHbT = ctO2Hb+ ctHHb). Tumor volume is selected by entering radiologic information such as tumor side, clock position and distance from the nipple (FN). An automated code was designed to select the highest value from the distance FN and the quadrant referent to the clock position. Subsequently, a region-based image segmentation method is implemented to examine neighboring pixels of the highest value point considering a mask of 90%. After tumor volume segmentation, we calculate the mean ctHbT extracted from the region of interest. An independent-samples t-test was run to determine if there were differences in ctTHb reduction in the tumor region before the third cycle of taxane between responders (n=4) and non-responders (n=12). ctTHb reduction was greater to pCR (45.71 ± 25.16 mM) than non-pCR tumors (-9.67 ± 25.65 mM), a statistically significant difference of 55.38 mM (95% CI, 23.74 to 87), t(14) = 3.755, p = .002, in Figure 2 we can see an example. From the ROC plot results, we can observe that ctTHb reduction in the tumor region after 2 cycles of Taxane is a good indicator to anticipate pCR status. With an area under the curve of 0.958, the best cut-off that maximizes sensitivity and specificity is 16.86mM. At this reduction level, the sensitivity is 100% and specificity is 91.7%. In conclusion, our findings indicate that DOTBIS-measured total hemoglobin in the tumor region may be a strong and independent predictor of treatment response to NAC. Please click Additional Files below to see the full abstract

Modification of the association between recreational physical activity and survival after breast cancer by promoter methylation in breast cancer-related genes

Background: Mechanisms underlying the inverse association between physical activity and survival after breast cancer are unresolved, but DNA methylation may play a role. We hypothesized that promoter methylation of breast cancer-related genes, as well as global methylation, may modify the association between prediagnostic recreational physical activity (RPA) and breast cancer mortality. Methods: Using a population-based sample of 1254 women diagnosed with first primary breast cancer, we examined modification of the RPA-mortality association by gene-specific promoter methylation and global methylation. Average lifetime RPA was assessed from menarche to diagnosis through structured in-home interviews. Promoter methylation of 13 breast cancer-related genes was evaluated in archived tumor by methylation-specific polymerase chain reaction and MethyLight assay. Global methylation in white blood cell DNA was determined at long interspersed nucleotide element 1 and by the luminometric methylation assay. After approximately 15 years of follow-up, 486 patients had died, and 186 of the deaths were breast cancer-related. We used Cox proportional hazards regression to estimate HRs and 95% CIs as well as likelihood ratio tests to assess multiplicative interactions. Results: All-cause mortality was lower only among physically active women with methylated promoter of APC (HR 0.60, 95% CI 0.40–0.80), CCND2 (HR 0.56, 95% CI 0.32–0.99), HIN (HR 0.55, 95% CI 0.38–0.80), and TWIST1 (HR 0.28, 95% CI 0.14–0.56) in tumors, but not among those with unmethylated tumors (significant interaction p < 0.05). We found no interaction between RPA and global methylation. Conclusions: The improved survival after breast cancer that is associated with RPA may be more pronounced in women with promoter tumor methylation in biologically plausible genes

Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation

Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer

Tobacco, alcohol, and p53 overexpression in early colorectal neoplasia

Background: The p53 tumor suppressor gene is commonly mutated in colorectal cancer. While the effect of p53 mutations on colorectal cancer prognosis has been heavily studied, less is known about how epidemiologic risk factors relate to p53 status, particularly in early colorectal neoplasia prior to clinically invasive colorectal cancer (including adenomas, carcinoma in situ (CIS), and intramucosal carcinoma). Methods: We examined p53 status, as measured by protein overexpression, in 157 cases with early colorectal neoplasia selected from three New York City colonoscopy clinics. After collecting paraffin-embedded tissue blocks, immunohistochemistry was performed using an anti-p53 monoclonal mouse IgG2a [BP53-12-1] antibody. We analyzed whether p53 status was different for risk factors for colorectal neoplasia relative to a polyp-free control group (n = 508). Results: p53 overexpression was found in 10.3%, 21.7%, and 34.9%, of adenomatous polyps, CIS, and intramucosal cases, respectively. Over 90% of the tumors with p53 overexpression were located in the distal colon and rectum. Heavy cigarette smoking (30+ years) was associated with cases not overexpressing p53 (OR = 1.8, 95% CI = 1.1–2.9) but not with those cases overexpressing p53 (OR = 1.0, 95% CI = 0.4–2.6). Heavy beer consumption (8+ bottles per week) was associated with cases overexpressing p53 (OR = 4.0, 95% CI = 1.3–12.0) but not with cases without p53 overexpression (OR = 1.6, 95% CI = 0.7–3.7). Conclusion: Our findings that p53 overexpression in early colorectal neoplasia may be positively associated with alcohol intake and inversely associated with cigarette smoking are consistent with those of several studies of p53 expression and invasive cancer, and suggest that there may be relationships of smoking and alcohol with p53 early in the adenoma to carcinoma sequence

Genomewide scan for loss of heterozygosity and chromosomal amplification in breast carcinoma using single-nucleotide polymorphism arrays

AbstractIn an effort to identify novel genes implicated in breast carcinogenesis, a genomewide scan for loss of heterozygosity (LOH) and copy number changes in paired-DNA samples extracted from normal and tumor tissue of frozen sections from women undergoing surgery for invasive breast cancer was conducted. The Affymetrix 10K SNP array was used to examine genomewide LOH of chromosomal regions. The number of LOH events, number of informative loci, percent heterozygosity, and percent fractional allelic loss (%FAL) were calculated. Although LOH events were detected in all samples, the proportion of LOH ranged from 0.1 to 57.2%. Elevated LOH events were detected in two samples, with a %FAL of 57.2 and 56.2. Chromosomal regions exceeding a threshold value for a P-value curve based on multiple-testing adjusted permutation methods were identified as significant regions of shared LOH across samples. Regions with significant LOH included 2p25.3; 2p21; 2p15∼p16.1, 2q23.3; and, 16q12.1. Chromosomal region 1q32.1 was identified as a region with significant copy number amplification. Regions of LOH and copy number changes identified from this analysis may provide insights into the underlying processes of and genes involved in breast carcinogenesis. The present study demonstrates a feasible methodological approach for the assessment of LOH and copy number changes

Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer

Background Despite extensive analysis, the dynamic changes in prostate epithelial cell states during tissue homeostasis as well as tumor initiation and progression have been poorly characterized. However, recent advances in single-cell RNA-sequencing (scRNA-seq) technology have greatly facilitated studies of cell states and plasticity in tissue maintenance and cancer, including in the prostate. Methods We have performed meta-analyses of new and previously published scRNA-seq datasets for mouse and human prostate tissues to identify and compare cell populations across datasets in a uniform manner. Using random matrix theory to denoise datasets, we have established reference cell type classifications for the normal mouse and human prostate and have used optimal transport to compare the cross-species transcriptomic similarities of epithelial cell populations. In addition, we have integrated analyses of single-cell transcriptomic states with copy number variants to elucidate transcriptional programs in epithelial cells during human prostate cancer progression. Results Our analyses demonstrate transcriptomic similarities between epithelial cell states in the normal prostate, in the regressed prostate after androgen-deprivation, and in primary prostate tumors. During regression in the mouse prostate, all epithelial cells shift their expression profiles toward a proximal periurethral (PrU) state, demonstrating an androgen-dependent plasticity that is restored to normal during androgen restoration and gland regeneration. In the human prostate, we find substantial rewiring of transcriptional programs across epithelial cell types in benign prostate hyperplasia and treatment-naïve prostate cancer. Notably, we detect copy number variants predominantly within luminal acinar cells in prostate tumors, suggesting a bias in their cell type of origin, as well as a larger field of transcriptomic alterations in non-tumor cells. Finally, we observe that luminal acinar tumor cells in treatment-naïve prostate cancer display heterogeneous androgen receptor (AR) signaling activity, including a split between AR-positive and AR-low profiles with similarity to PrU-like states. Conclusions Taken together, our analyses of cellular heterogeneity and plasticity provide important translational insights into the origin and treatment response of prostate cancer. In particular, the identification of AR-low tumor populations suggests that castration-resistance and predisposition to neuroendocrine differentiation may be pre-existing properties in treatment-naïve primary tumors that are selected for by androgen-deprivation therapies