New Advances in the Study of CMTM6, a Focus on Its Novel Non-Canonical Cellular Locations, and Functions beyond Its Role as a PD-L1 Stabilizer.

CMTM6 is a membrane protein that acts as a regulator of PD-L1, maintaining its expression on the cell surface, and can prevent its lysosome-mediated degradation. It is unknown if CMTM6 is present in the plasma of patients with cervical cancer, and if it has non-canonical subcellular localizations in cell lines derived from cervical cancer. Our objective was to determine whether CMTM6 is found in plasma derived from cervical cancer patients and its subcellular localization in cell lines. Patient plasma was separated into exosome-enriched, exosome-free, and total plasma fractions. The levels of CMTM6 in each fraction were determined using ELISA and Western blot. Finally, for the cellular model, HeLa, SiHa, CaSki, and HaCaT were used; the subcellular locations of CMTM6 were determined using immunofluorescence and flow cytometry. Soluble CMTM6 was found to be elevated in plasma from patients with cervical cancer, with a nearly three-fold increase in patients (966.27 pg/mL in patients vs. 363.54 pg/mL in controls). CMTM6 was preferentially, but not exclusively, found in the exosome-enriched plasma fraction, and was positively correlated with exosomal PD-L1; CMTM6 was identified in the membrane, intracellular compartments, and culture supernatant of the cell lines. These results highlight that CMTM6, in its various presentations, may play an important role in the biology of tumor cells and in immune system evasion.

The VEGFA rs3025039 Variant Is a Risk Factor for Breast Cancer in Mexican Women.

Breast cancer (BC) is the leading cause of death from tumors in women worldwide, influenced by various factors, including genetics. The T allele of the single nucleotide variant (SNV) rs3025039 at position +936 of the VEGFA gene has been reported to affect the mRNA regulatory mechanisms, potentially altering VEGFA expression and increasing BC risk. This study aimed to investigate the association between rs3025039 and BC in Mexican women residing in Jalisco, Mexico. The study included 231 women with a confirmed diagnosis of BC and 201 healthy subjects as a reference group (RG). PCR-RFLP was employed for the genotyping of rs3025039, with the visualization of amplified products using polyacrylamide gel electrophoresis. Significant differences were observed in rs3025039 alleles and genotypes between BC cases and the RG (p = 0.0038). The frequency of the T allele and the CT genotype was higher in the BC group compared to the RG, with a significant difference (p = 0.0006). In conclusion, this research suggests that the SNV rs3025039 is associated with a higher risk of BC in Mexican women. These findings enhance our understanding of the genetic underpinnings of BC in this population, offering potential insights for future studies and interventions.

Implementing Standard Diagnosis and Treatment for Locally Advanced Breast Cancer Through Global Research in Latin America: Results From a Multicountry Pragmatic Trial.

PURPOSE: Breast cancer mortality rates in Latin America (LA) are higher than those in the United States, possibly because of advanced disease presentation, health care disparities, or unfavorable molecular subtypes. The Latin American Cancer Research Network was established to address these challenges and to promote collaborative clinical research. The Molecular Profiling of Breast Cancer Study (MPBCS) aimed to evaluate the clinical characteristics and treatment outcomes of LA participants with locally advanced breast cancer (LABC). PATIENTS AND METHODS: The MPBCS enrolled 1,449 participants from Argentina, Brazil, Chile, Mexico, and Uruguay. Through harmonized procedures and quality assurance measures, this study evaluated clinicopathologic characteristics, neoadjuvant chemotherapy response, and survival outcomes according to residual cancer burden (RCB) and the type of surgery. RESULTS: Overall, 711 and 480 participants in the primary surgery and neoadjuvant arms, respectively, completed the 5-year follow-up period. Overall survival was independently associated with RCB (worse survival for RCBIII-adjusted hazard ratio, 8.19, P < .001, and RCBII [adjusted hazard ratio, 3.69, P < .008] compared with RCB0 [pathologic complete response or pCR]) and type of surgery (worse survival in mastectomy than in breast-conserving surgery [BCS], adjusted hazard ratio, 2.97, P = .001). The hormone receptor-negative-human epidermal growth factor receptor 2-positive group had the highest proportion of pCR (48.9%). The analysis of the ASCO Quality Oncology Practice Initiative breast module revealed high compliance with pathologic standards but lower adherence to treatment administration standards. Notably, compliance with trastuzumab administration varied widely among countries (33.3%-88.7%). CONCLUSION: In LABC, we demonstrated the survival benefit of BCS and the prognostic effect of the response to available neoadjuvant treatments despite an important variability in access to key treatments. The MPBCS represents a significant step forward in understanding the real-world implementation of oncologic procedures in LA.

HLA-G 14 bp Ins/Del (rs66554220) Variant Is Not Associated with Breast Cancer in Women from Western Mexico.

HLA-G is a physiology and pathologic immunomodulator detrimentally related to cancer. Its gene is heavily transcriptionally and post-transcriptionally regulated by variants located in regulator regions like 3'UTR, being the most studied Ins/Del of 14-bp (rs66554220), which is known to influence the effects of endogen cell factors; nevertheless, the reports are discrepant and controversial. Herein, the relationship of the 14-bp Ins/Del variant (rs66554220) with breast cancer (BC) and its clinical characteristics were analyzed in 182 women with non-familial BC and 221 disease-free women as a reference group. Both groups from western Mexico and sex-age-matched (sm-RG). The rs66554220 variant was amplified by SSP-PCR and the fragments were visualized in polyacrylamide gel electrophoresis. The variant rs66554220 was not associated with BC in our population. However, we suggest the Ins allele as a possible risk factor for developing BC at clinical stage IV (OR = 3.05, 95% CI = 1.16-7.96, p = 0.01); nevertheless, given the small stratified sample size (n = 11, statistical power = 41%), this is inconclusive. In conclusion, the 14-bp Ins/Del (rs66554220) variant of HLA-G is not associated with BC in the Mexican population, but might be related to advanced breast tumors. Further studies are required.

Elevated Serum Low-Density Lipoproteins-Cholesterol Levels and B1B2/B2B2 CETP Genotype Are Positively Associated with Nonalcoholic Fatty Liver Disease in Women with Gallstone Disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is generated by the interaction between environmental and genetic factors, and the presence of metabolic alterations. Since Taq1B cholesteryl ester transfer protein (CETP) polymorphism is associated with abnormal serum lipid values, it could be related to NAFLD. The aim of this study was to determine the role of the Taq1B CETP polymorphism with serum lipids, anthropometric variables, and the extent of steatosis in Mexican-mestizo women with gallstone disease (GD). Methods: Sixty-two women were enrolled in this cross-sectional study. Serum lipids were determined by dry chemistry. The Taq1B CETP polymorphism was determined by allelic discrimination. CETP serum levels were measured by enzyme-linked immunosorbent assay, and the extent of steatosis with a biopsy staining with Oil-Red-O. Results: Subjects with the B1B2/B2B2 genotype had higher percentage of degree of steatosis than those with B1B1 (11.95% vs. 2.19%, P = 0.008). The B1B2/B2B2 genotype (odds ratio [OR] 3.90 [confidence interval {CI} 95% 1.891-8.536], P = 0.04) and an elevated low-density lipoproteins (LDL)-cholesterol (OR 3.54 [CI 95% 1.042-2.058, P = 0.039) significantly increase the risk for NAFLD. Conclusions: This study provides evidence that the B1B2/B2B2 genotype of CETP and the elevated LDL-cholesterol serum levels increase the risk of NAFLD in women with GD.

Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women.

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher's exact tests and the OS by Kaplan-Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (≥60 years) (1.84) compared with younger (≤40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.

The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients.

Purposes: Most molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches. Patients and Methods: We collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes. Results: PAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors. Conclusions: This is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America. Clinical Trial Registration: ClinicalTrials.gov (Identifier: NCT02326857).

Renal Tissue Expression of BAFF and BAFF Receptors Is Associated with Proliferative Lupus Nephritis.

Background: The B-cell activating factor (BAFF) controls the maturation and survival of B cells. An imbalance in this cytokine has been associated with systemic autoimmunity in SLE and lupus nephritis (LN). However, few investigations have evaluated the tissular expression of BAFF in LN. This study aimed to associate BAFF system expression at the tissular level with the proliferative LN classes. Methods: The analysis included eighteen kidney tissues, with sixteen LN (class III = 5, class IV = 6, class III/IV+V = 4, and class V = 1), and two controls. The tissular expression was evaluated with an immunochemistry assay. A Cytation5 imaging reader and ImageJ software were used to analyze the quantitative expression. A p-value < 0.05 was considered significant. Results: The expressions of BAFF, A proliferation-inducing ligand (APRIL), and their receptors were observed in glomerular, tubular, and interstitial zones, with BAFF being the most strongly expressed in the overall analysis. BAFF-Receptor (BR3), transmembrane activator and CALM interactor (TACI), and B-Cell maturation antigen (BCMA) displayed higher expressions in LN class IV in all zones analyzed (p < 0.05). Additionally, a positive correlation was found between APRIL, TACI, and BCMA at the glomerular level; BCMA and APRIL in the interstitial zone; and BR3, TACI, and BCMA in the tubule (p < 0.05). Conclusions: The expression of BAFF and BAFF receptors is mainly associated with LN class IV, emphasizing the participation of these receptors as an essential pathogenic factor in kidney involvement in SLE patients.

The -174G>C and -596G>A Polymorphisms Are Not Associated with Circulating IL-6 Levels in Breast Cancer Patients from Jalisco, México.

Introduction: Interleukin-6 (IL-6) is a circulating proinflammatory cytokine that fulfills an important role in the survival and proliferation of cancer cells. Overexpression of IL-6, possibly due to the -174G>C and -596G>A polymorphisms in the IL6 gene, has been shown to be related to breast cancer (BC) and a more aggressive course of the disease. Aim: To determine the influence of the -174G>C and -596G>A polymorphisms of the IL6 gene on the circulating levels of IL-6 in BC patients from Jalisco, México. Methodology: Genotyping of the two polymorphisms was carried out on 208 BC patients and 219 healthy controls through polymerase chain reaction-restriction fragment length polymorphism analyses. In addition, the plasma IL-6 concentration levels were measured in the BC patients. Results: There was no significant association between BC and the IL-6 alleles and genotypes (-174G>C, p = 0.276; -596G>A, p = 0.762) under study. Similarly, there were no significant differences in the mean plasma IL-6 concentrations associated with the polymorphisms that were analyzed (-174G>C, p = 0.839; -596G>A, p = 0.848). Conclusions: No evidence was found that the analyzed polymorphisms are associated with the IL-6 expression or concentration in patients suffering from BC from Jalisco, Mexico.

Positive staining of the immunoligand B7-H6 in abnormal/transformed keratinocytes consistently accompanies the progression of cervical cancer.

BACKGROUND: B7-H6 has been revealed as an endogenous immunoligand expressed in a variety of tumors, but not expressed in healthy tissues. Heretofore, no studies have been reported describing B7-H6 in women with cervical cancer. To investigate this question, our present study was conducted. RESULTS: This retrospective study comprised a total of 62 paraffinized cervical biopsies, which were distributed in five groups: low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), squamous cervical carcinoma (SCC), uterine cervical adenocarcinoma (UCAC), and a group of cervicitis (as a control for non-abnormal/non-transformed cells). Cervical sections were stained by immunohistochemistry to explore the expression of B7-H6, which was reported according to the immunoreactive score (IRS) system. We observed a complete lack of B7-H6 in LSIL abnormal epithelial cells. Interestingly, B7-H6 began to be seen in HSIL abnormal epithelial cells; more than half of this group had B7-H6 positive cells, with staining characterized by a cytoplasmic and membranous pattern. B7-H6 in the SCC group was also seen in the majority of the sections, showing the same cytoplasmic and membranous pattern. Strong evidence of B7-H6 was notably found in UCAC tumor columnar cells (in 100% of the specimens, also with cytoplasmic and membranous pattern). Moreover, consistent B7-H6 staining was observed in infiltrating plasma cells in all groups. CONCLUSIONS: B7-H6 IRS positively correlated with disease stage in the development of cervical cancer; additionally, B7-H6 scores were found to be even higher in the more aggressive uterine cervical adenocarcinoma, suggesting a possible future therapeutic target for this cancer type.