Genetic Features of Metachronous Esophageal Cancer Developed in Hodgkin's Lymphoma or Breast Cancer Long-Term Survivors: An Exploratory Study.

Background Development of novel therapeutic drugs and regimens for cancer treatment has led to improvements in patient long-term survival. This success has, however, been accompanied by the increased occurrence of second primary cancers. Indeed, patients who received regional radiotherapy for Hodgkin's Lymphoma (HL) or breast cancer may develop, many years later, a solid metachronous tumor in the irradiated field. Despite extensive epidemiological studies, little information is available on the genetic changes involved in the pathogenesis of these solid therapy-related neoplasms. Methods Using microsatellite markers located in 7 chromosomal regions frequently deleted in sporadic esophageal cancer, we investigated loss of heterozygosity (LOH) and microsatellite instability (MSI) in 46 paired (normal and tumor) samples. Twenty samples were of esophageal carcinoma developed in HL or breast cancer long-term survivors: 14 squamous cell carcinomas (ESCC) and 6 adenocarcinomas (EADC), while 26 samples, used as control, were of sporadic esophageal cancer (15 ESCC and 11 EADC). Results We found that, though the overall LOH frequency at the studied chromosomal regions was similar among metachronous and sporadic tumors, the latter exhibited a statistically different higher LOH frequency at 17q21.31 (p = 0.018). By stratifying for tumor histotype we observed that LOH at 3p24.1, 5q11.2 and 9p21.3 were more frequent in ESCC than in EADC suggesting a different role of the genetic determinants located nearby these regions in the development of the two esophageal cancer histotypes. Conclusions Altogether, our results strengthen the genetic diversity among ESCC and EADC whether they occurred spontaneously or after therapeutic treatments. The presence of histotype-specific alterations in esophageal carcinoma arisen in HL or breast cancer long-term survivors suggests that their transformation process, though the putative different etiological origin, may retrace sporadic ESCC and EADC carcinogenesis

Transcribed ultraconserved noncoding RNAs (T-UCR) are involved in Barrett's esophagus carcinogenesis.

Barretts esophagus (BE) involves a metaplastic replacement of native esophageal squamous epithelium (Sq) by columnar-intestinalized mucosa, and it is the main risk factor for Barrett-related adenocarcinoma (BAc). Ultra-conserved regions (UCRs) are a class non-coding sequences that are conserved in humans, mice and rats. More than 90% of UCRs are transcribed (T-UCRs) in normal tissues, and are altered at transcriptional level in tumorigenesis. To identify the T-UCR profiles that are dysregulated in Barretts mucosa transformation, microarray analysis was performed on a discovery set of 51 macro-dissected samples obtained from 14 long-segment BE patients. Results were validated in an independent series of esophageal biopsy/surgery specimens and in two murine models of Barretts esophagus (i.e. esophagogastric-duodenal anastomosis). Progression from normal to BE to adenocarcinoma was each associated with specific and mutually exclusive T-UCR signatures that included up-regulation of uc.58-, uc.202-, uc.207-, and uc.223- and down-regulation of uc.214+. A 9 T-UCR signature characterized BE versus Sq (with the down-regulation of uc.161-, uc.165-, and uc.327-, and the up-regulation of uc.153-, uc.158-, uc.206-, uc.274-, uc.472-, and uc.473-). Analogous BE-specific T-UCR profiles were shared by human and murine lesions. This study is the first demonstration of a role for T-UCRs in the transformation of Barretts mucosa

Neuroendocrine neoplasms of the esophagus and stomach.

Esophageal neuroendocrine neoplasms (E-NENs) are much rarer than other gastro-entero-pancreatic neuroendocrine neoplasms, the majority showing aggressive behavior with early dissemination and poor prognosis. Among E-NENs, exceptionally rare well differentiated neuroendocrine tumors (E-NET) and more frequent esophageal poorly differentiated neuroendocrine carcinomas (E-NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNEN) can be recognized. E-NECs usually exhibit a small cell morphology or mixed small and large cells. Esophageal MiNEN are composed of NEC component admixed with adenocarcinoma or squamous cell carcinoma. Gastric (G) NENs encompass a wide spectrum of entities ranging from indolent G-NETs to highly aggressive G-NECs and MiNENs. Among G-NETs, ECL-cell NETs are the most common and, although composed of histamine-producing cells, are a heterogeneous group of neoplastic proliferations showing different clinical and prognostic features depending on the patient's clinico-pathological background including the morphology of the peri-tumoral mucosa, gastrin serum levels, presence or absence of antral G-cell hyperplasia, and presence or absence of MEN1 syndrome. In general, NET associated with hypergastrinemia show a better outcome than NET not associated with hypergastrinemia. G-NECs and MiNENs are aggressive neoplasms more frequently observed in males and associated with a dismal prognosis

Helicobacter pylori Dampens HLA-II Expression on Macrophages via the Up-Regulation of miRNAs Targeting CIITA

Macrophages have a major role in infectious and inflammatory diseases, and the available data suggest that Helicobacter pylori persistence can be explained in part by the failure of the bacterium to be killed by professional phagocytes. Macrophages are cells ready to kill the engulfed pathogen, through oxygen-dependent and -independent mechanisms; however, their killing potential can be further augmented by the intervention of T helper (Th) cells upon the specific recognition of human leukocyte antigen (HLA)-II\u2013peptide complexes on the surface of the phagocytic cells. As it pertains to H. pylori, the bacterium is engulfed by macrophages, but it interferes with the phagosome maturation process leading to phagosomes with an altered degradative capacity, and to megasomes, wherein H. pylori resists killing. We recently showed that macrophages infected with H. pylori strongly reduce the expression of HLA-II molecules on the plasma membrane and this compromises the bacterial antigen presentation to Th lymphocytes. In this work, we demonstrate that H. pylori hampers HLA-II expression in macrophages, activated or non-activated by IFN-\u3b3, by down-regulating the expression of the class II major histocompatibility complex transactivator (CIITA), the \u201cmaster control factor\u201d for the expression of HLA class II genes. We provided evidence that this effect relies on the up-regulation of let-7f-5p, let-7i-5p, miR-146b-5p, and -185-5p targeting CIITA. MiRNA expression analysis performed on biopsies from H. pylori-infected patients confirmed the up-regulation of let-7i-5p, miR-146b-5p, and -185-5p in gastritis, in pre-invasive lesions, and in gastric cancer. Taken together, our results suggest that specific miRNAs may be directly involved in the H. pylori infection persistence and may contribute to confer the risk of developing gastric neoplasia in infected patients

Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches

The inability to efficiently repair DNA double-strand breaks using the homologous recombination repair pathway is defined as homologous recombination deficiency (HRD). This molecular phenotype represents a positive predictive biomarker for the clinical use of poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors and platinum-based chemotherapy in ovarian cancers. However, HRD is a complex genomic signature, and different methods of analysis have been developed to introduce HRD testing in the clinical setting. This review describes the technical aspects and challenges related to HRD testing in ovarian cancer and outlines the potential pitfalls and challenges that can be encountered in HRD diagnostics

Mismatch-repair protein expression in high-grade gliomas: A large retrospective multicenter study

Background: DNA mismatch repair (MMR) is a system for repairing errors in DNA replication. Cancer cells with MMR deficiency can have immunohistochemical loss of MMR protein expression leading to a hypermutable phenotype that may correlate with anti-PD1 efficacy. Scant data exist about immunohistochemical loss of MMR protein expression in high-grade gliomas (HGG). Materials and Methods: We performed a large multicenter retrospective study to investigate the frequency and the prognostic role of immunohistochemical loss of MMR protein expression in HGG patients; we nevertheless evaluated the association between this status and clinical or molecular characteristics. Immunohistochemical loss of MMR protein expression was recorded as partial or complete loss of at least 1 MMR protein. Results: We analyzed the expression of MMR proteins in tumor tissue of 355 consecutive patients. Partial and complete immunohistochemical loss of MMR proteins was found in 43/355 samples (12.1%) and among these, 15 cases (4.2%) showed a complete loss of at the least one MMR protein. Alteration of MSH2 expression was found in 55.8%, MSH6 in 46.5%, PMS2 in 34.9%, and MLH1 in 30.2%. Alteration of MMR protein expression was statistically more frequent in anaplastic gliomas, in recurrent disease, in patients treated with temozolomide, and in IDH-mut gliomas. Immunohistochemical loss of MMR proteins was not associated with survival, adjusting for clinically relevant confounders. Conclusions: MMR protein expression status did not affect survival in HGG patients. We identified clinical and molecular characteristics correlating with immunohistochemical loss of MMR proteins expression. A large study should be performed to analyze its predictive role of immune checkpoint inhibitor efficacy in these subgroups of patients

mismatch repair deficiency mmrd in glioma patients pts frequency and correlation with clinical histological and molecular characteristics

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correlation between clinic pathological features msi pd l1 and survival in resectable gastric cancer looking for prognostic biomarkers

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