Copy number alterations associated with clinical features in an underrepresented population with breast cancer

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.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.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.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.77FAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo2013/25683-3; 2015/18830-

MMP-9/RECK imbalance: a mechanism associated with high-grade cervical lesions and genital infection by Human Papillomavirus (HPV) and Chlamydia trachomatis

"Manuscript"BACKGROUND: Matrix metalloproteinases (MMP) are important enzymes in the tumor microenvironment associated with progression of cervical intraepithelial neoplasia (CIN) toward squamous cell carcinoma (SCC) of the cervix. However, the role of MMPs in the inflammatory process associated with Chlamydia trachomatis infection concomitant with the carcinogenic process driven by HPV has not yet been addressed. In the present study, we analyzed the state of the MMP-9-RECK axis in cervical carcinogenesis. METHODS: The levels of MMP-9 and RECK expression were analyzed by immunocytochemistry in liquid-based cytology samples from 136 women with high-grade cervical lesions (CIN2/CIN3) and cervical SCC diagnosed by LLETZ, and in 196 women without cervical neoplasia or CIN1. Real-time qPCR was performed to analyze expression of MMP-9 and RECK in 15 cervical samples. The presence of HPV-DNA and other genital pathogens was evaluated by PCR. RESULTS: We found a higher expression of MMP-9 [OR, 4.2; 95% confidence interval (CI), 2.2-7.8] and lower expression of RECK (OR, 0.4; 95% CI, 0.2-0.7) in women with CIN2/CIN3/SCC when compared with women from the control group (no neoplasia/CIN1). A statistically significant association was also found between MMP-9/RECK imbalance and infection by alpha-9 HPV and C. trachomatis. The prevalence of C. trachomatis infection was significantly higher in women with high-grade cervical disease (OR, 3.7; 95% CI, 1.3-11.3). CONCLUSIONS: MMP-9/RECK imbalance in cervical smears is significantly associated with high-grade cervical diseases and infection by alpha-9 HPV and C. trachomatis. IMPACT: MMP-9/RECK imbalance during cervical inflammation induced by C. trachomatis might play a role in HPV-mediated cervical carcinogenesis.This work was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), numbers 2008/03232-1 (to L.L. Villa) and 2012/09746-2 (to M.G. Discacciati and S.S. Maria-Engler) and National Counsel of Technological and Scientific Development pharmaceutical innovation (CNPQ-INCT-if; to S.S. Maria-Engler)

Prognostic Significance Of Pd-l1 And Pd-l2 In Breast Cancer.

PD-L1 and PD-L2 constitute an important antitumor immune response. In breast cancer, their prognostic value is still to be defined. In this study, we investigate the correlation between PD-L1 and PD-L2 protein expressions with clinical and pathologic features and disease-free survival and overall survival. To assess PD-L1 and PD-L2 expressions, we conducted immunohistochemistry studies using a breast cancer tissue microarray encompassing a total of 192 breast cancer cases, stages I, II, and III, with detailed clinical and outcome data. PD-L1 expression was present in 56.6% (107/189), and PD-L2 expression was identified in 50.8% (97/191) of breast cancer cases. Younger age at diagnosis, lymph node positivity, negative estrogen receptor, and recurrence at distant sites were all associated with both PD-L1 and PD-L2 expressions. The presence of larger tumors was associated only with PD-L1 expression. In our study, PD-L1 expression was significantly associated with better overall survival (P = .04) in breast cancer patients. Despite its association with poor clinical and pathologic features, PD-L1 expression emerges as a positive prognostic biomarker in breast cancer. This survival result might be due to the presence of a strong antitumor immune response leading to PD-L1 expression.4778-8

Metastatic Mucinous Carcinomas In The Ovary: A Practical Approach To Diagnosis Related To Gross Aspects And To Immunohistochemical Evaluation.

Ovarian mucinous carcinomas are uncommon, and the differential diagnosis is metastatic carcinoma mainly from the gastrointestinal tract. The aim was to verify the importance of immunohistochemical reactions and the algorithm described in literature on the basis of laterality and tumor size. Twenty-five cases identified as metastatic mucinous adenocarcinomas were reviewed, along with clinical records; a tissue microarray was created, and immunohistochemical reactions for CK7, CK20, Ca125, hormonal receptors, WT1, DPC4, β-catenin, and Cdx2 were determined. The median age was 51, and only 9 patients had a history of cancer. Sixteen patients (64%) had bilateral tumors, with sizes ranging from 5 to 36 cm (average, 20.5 cm); 9 (36%) had unilateral tumors varying from 5.5 to 38 cm (average, 21.8 cm). Algorithm agreement was 76%; most unilateral tumors were >13 cm. Common positive markers were Dpc4 (88%), Cdx2 (68%), CK20 (60%), and CK7 (44%). The useful markers were CK7, CK20, and Cdx2, although there were cases with overlapping results. The most common primary tumor was of colorectal origin (14 cases). The mean survival age was 32.6 mo. Although the proposed algorithm and immunohistochemical reactions are useful tools for diagnosis, some mucinous tumors cannot be definitively classified as primary or metastatic without further clinical evaluation, emphasizing the limits of this challenging diagnosis.31313-

Hpv Dna Test And Pap Smear In Detection Of Residual And Recurrent Disease Following Loop Electrosurgical Excision Procedure Of High-grade Cervical Intraepithelial Neoplasia.

We compared the performance of cervical cytology and HPV DNA test in detection of residual or recurrent disease following the treatment of cervical intraepithelial neoplasia (CIN) 2/3 with loop electrosurgical excision procedure (LEEP). A series of 107 women subjected to LEEP due to histologically confirmed CIN 2/3 between March 2001 and December 2002 were followed-up biannually until January 2004. Follow-up visits consisted of interview and gynecological examination including cervical cytology, hybrid capture II (HCII), and colposcopy. Patients presenting with abnormal colposcopy or high-grade squamous intraepithelial lesion (HSIL) smear were subjected to new excision procedure, and presence of histologically confirmed CIN 2/3 or higher was considered as residual or recurrent disease. Performance indicators were calculated for cytology and HCII assay in detecting residual or recurrent disease. Eleven (10.2%) women showed residual or recurrent disease during the follow-up. Considering HCII and Pap smear as stand-alone tests, both techniques showed similar sensitivity, detecting 100% of CIN 2/3 at the first follow-up visit. At the second follow-up visit, Pap smear showed better specificity and positive predictive value (PPV) than HCII, and both tests had fairly the same high negative predictive value (NPV) and sensitivity. The combined positive HCII and abnormal cytology had the same sensitivity as each of the tests alone, but specificity and PPV were significantly higher than those of single tests. When only one of the tests was positive, the sensitivity and the NPV of the combination remained the same, but its specificity and PPV were lower than that of the combined two positive tests and that of the individual test, at both follow-up visits. Both tests performed well in detecting residual or recurrent disease after LEEP and combination of the tests did not increase sensitivity of the single tests.94181-

Molecular Signatures of High-Grade Cervical Lesions

Cervical cancer is the fourth most common neoplasia in women and the infection with human papilloma virus (HPV) is its necessary cause. Screening methods, currently based on cytology and HPV DNA tests, display low specificity/sensitivity, reducing the efficacy of cervical cancer screening programs. Herein, molecular signatures of cervical cytologic specimens revealed by liquid chromatography-mass spectrometry (LC-MS), were tested in their ability to provide a metabolomic screening for cervical cancer. These molecules were tested whether they could clinically differentiate insignificant HPV infections from precancerous lesions. For that, high-grade squamous intraepithelial lesions (HSIL)-related metabolites were compared to those of no cervical lesions in women with and without HPV infection. Samples were collected from women diagnosed with normal cervix (N = 40) and from those detected with HSIL from cytology and colposcopy (N = 40). Liquid-based cytology diagnosis, DNA HPV-detection test, and LC-MS analysis were carried out for all the samples. The same sample, in a customized collection medium, could be used for all the diagnostic techniques employed here. The metabolomic profile of cervical cancer provided by LC-MS was found to indicate unique molecular signatures for HSIL, being two ceramides and a sphingosine metabolite. These molecules occurred independently of women’s HPV status and could be related to the pre-neoplastic phenotype. Statistical models based on such findings could correctly discriminate and classify HSIL and no cervical lesion women. The results showcase the potential of LC-MS as an emerging technology for clinical use in cervical cancer screening, although further validation with a larger sample set is still necessary

Human papillomavirus (HPV) infections as risk factors for cytological and histological abnormalities in baseline PAP smear-negative women followed-up for 2 years in the LAMS study

Objective To assess the role of HPV as determinant of the incident cytological abnormalities (SIL) and cervical lesions (CIN) during a 24-month follow-up of baseline PAP smear-negative subgroup of women included in the Latin American Screening study (LAMS). Study design A group of 365 women with normal Pap smear and negative or positive high-risk Hybrid Capture II test were prospectively followed-up for 24 months at Campinas and São Paulo (Brazil). The incidence rate (IR) and risk ratio (RR and 95% CI) of developing cytological or histological abnormality during the follow-up was calculated for HPV-negative and HPV-positive women. Results During the 12-month follow-up, women HPV-positive at baseline had developed a significantly higher rate of incident LSIL (IR = 3.5%, RR = 1.4; 95% CI 1.1–1.7) and HSIL (IR = 0.7%, RR = 1.5; 95% CI 1.4–1.7) abnormality. For HSIL, the IR increased to 2.1% and the RR increased to 1.7 (95% CI 1.5–1.9) among those followed for 24 months. Similarly, women with positive HPV tests were at a higher risk of developing CIN 2–3 (IR = 2.6%, RR = 1.5; 95% CI 1.4–1.6) during the first 12 months of follow-up, and for those followed for 24 months, this RR increased further to 1.7 (95% CI 1.5–1.9) although the IR was 0.7%. Conclusions Oncogenic HPV infections comprise a significant risk factor for incident cervical abnormalities, and HPV test is a useful adjunct to cytology in detecting the high-risk patients among baseline PAP smear-negative women.This study was funded by European Commission, INCO DEV Contract #ICA4-CT-2001-10013