miR-383-5p suppresses the proliferation and invasion of medulloblastoma by down-regulating MSH6 / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the effect of miR-383-5p on the proliferation and invasion of medulloblastoma (MB) by targeting DNA mismatch repair MSH6 gene. Methods: A total of 15 pairs of tumor tissues and corresponding adjacent tissues from MB patients, who were surgically treated and pathologically confirmed in the Department of Oncology of the Second Affiliated Hospital of Hainan Medical College from July 2014 to May 2017, were collected for this study. qPCR was applied to detect the expression of miR-383-5p in MB tissues and cell lines. The experimental cells were divided into control group (NC group), miR-383-3p overexpression group (miR-383-5p group), MSH6 knockdown group (si-MSH6 group) and miR-383-5p inhibitor+si-MSH6 group. CCK-8 assay was used to detect the proliferation of UW473 cells. Transwell assay was used to examine the invasion and migration of UW473 cells, the targeting relationship between miR-383-5p and MSH6 was verified by Dual-luciferase reporter gene assay, and Western blotting (WB) was performed to detect the protein expression of MSH6. Results: The expression level of miR-383-5p was significantly down-regulated in MB tissues and cell lines compared with para-cancer tissues (all P<0.05 or P<0.01). Overexpression of miR-383-5p significantly inhibited the proliferation, migration and invasion of UW473 cells (all P<0.05 or P<0.01), and down-regulated the expression level of MSH6 (all P<0.01). Dual-luciferase reporter gene assay demonstrated that miR-383-5p could targetedly bind to the 3'UTR of MSH6. Knockdown of MSH6 could inhibit the proliferation, invasion and migration of UW473 cells (all P<0.01). Further experiments showed that simultaneous knockdown of miR-383-5p and MSH6 could attenuate the inhibition of MSH6 silence on the proliferation, invasion and migration of UW473 cells. Conclusion: miR-383-5p expression is down-regulated in MB tissues and cell lines, and miR-383-5p suppresses the proliferation, migration and invasion of UW473 cells via targetedly down-regulating MSH6.

Alterações germinativas em pacientes com câncer de reto em idade jovem / Germline alterations in patients with rectal cancer at a young age

O câncer colorretal (CCR) é o terceiro tipo de câncer mais comum no mundo e a segunda causa de morte por câncer. Dados atuais apontam que o câncer de reto (CaRe) contribui para a maior incidência de CCR observada em pacientes jovens e é responsável por um aumento destes tumores em cerca de 75% nos últimos 40 anos. As variantes germinativas são reportadas em 14 a 16% dos indivíduos jovens com CCR, independente de história familiar de câncer. Ainda assim, a causa do desenvolvimento de CCR na maioria dos casos de indivíduos jovens ou famílias com múltiplos indivíduos afetados permanece desconhecida. Neste estudo, foram investigadas variantes germinativas em 76 pacientes com CaRe incluindo 29 classificados pelos critérios de Amsterdam I/II para a Síndrome de Lynch (Grupo 1) e 47 pacientes com idade igual ou inferior 40 anos (Grupo 2). O objetivo principal foi identificar variantes em 93 genes relacionados ao câncer que possam contribuir para o risco de desenvolvimento da doença usando sequenciamento de alto desempenho. Quinze variantes foram selecionadas e avaliadas em membros de oito famílias. Foram identificadas 153 variantes envolvendo 65 genes. Pacientes com câncer de reto apresentaram alta frequência de variantes germinativas em ATM (19%), APC (10%) e BRCA2 (9%). Variantes patogênicas ou likely-patogênicas foram identificadas em genes de alta (MSH2, MSH6, MLH1, MUTYH e BRCA2), moderada (ATM) e baixa (MTHFR e NOTCH1) penetrância, em 18% (14/76) dos pacientes, concordante com dados da literatura. Variantes características da Síndrome de Lynch foram identificadas em seis pacientes (6/76) e variantes associadas à polipose no gene MUTYH, em dois pacientes (2/76). Variantes patogênicas ou likely-patogênicas foram identificadas em 17% (8/47) dos pacientes jovens, especialmente em MUTYH (3/47), MTHFR (2/47), ATM, MSH6 e MLH1 (1/47 cada). Dentre estes, dois de 14 pacientes não reportaram câncer na família e seis tiveram pelo menos um caso de câncer na família, mas não preencheram os critérios clínicos para síndrome de predisposição hereditária ao câncer. Este estudo revelou 25 variantes novas (não identificadas em bancos de dados públicos ou reportadas em literatura). Em adição, foram observadas variantes germinativas em diferentes genes das vias MMR e de recombinação homóloga, incluindo ATM, BRCA2 e POLD1. Foram identificadas 15 variantes candidatas e ou associadas ao fenótipo nos genes ATM, APC, MSH2, MTHFR, CDKN2A, MUTYH e POLD1. Essas variantes foram avaliadas em 20 indivíduos de 8 famílias, sendo confirmadas nos probandos e identificadas em mais de um membro das famílias investigadas. A identificação de genes associados à predisposição ao CaRe tem potencial importância para o delineamento de estratégias mais eficientes de diagnóstico e aconselhamento genético em famílias com um alto risco de desenvolver este tumor (AU)

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. Recent studies suggest that rectal cancer (ReCa) contributes to the higher CRC incidence observed in young patients, and it is responsible for 75% of the increased incidence in colorectal tumors over the last 40 years. Germline variants have been reported in 14-16% of patients with early-onset CRC, regardless of family history of cancer. Nonetheless, the causes of CRC onset in most young patients or families with multiple affected cases remain unknown. We investigated germline variants in 76 ReCa patients, including 29 cases classified by the Amsterdam I/II criteria for Lynch Syndrome (Group 1) and 47 early-onset ReCa patients (≤40 years old, Group 2). The main objective was to identify variants in 93 cancer-related genes that can contribute to increased risk of the disease development using next-generation sequencing. Fifteen candidate variants were evaluated in eight selected families. Next-generation sequencing revealed 153 variants involving 65 genes. ReCa patients showed high frequency of germline variants in ATM (19%), APC (10%) and BRCA2 (9%). Pathogenic or likely-pathogenic variants were observed in high (MSH2, MSH6, MLH1, MUTYH, and BRCA2), moderate (ATM) and low (MTHFR and NOTCH1) penetrance genes, in 18% (14/76) of the patients, consistent with the literature data. Variants associated with Lynch Syndrome were identified in six patients (6/76), and variants involved in MUTYH-associated polyposis in two patients (2/76). Pathogenic or likely-pathogenic variants were identified in 17% (8/47) of early-onset patients, especially in the MUTYH (3/47), MTHFR (2/47), ATM, MSH6, and MLH1 (1/47 each) genes. Among these, two of fourteen patients had no family history of cancer and six reported at least one case of cancer in the family, but none of them met clinical criteria for the hereditary cancer syndrome. This study revealed 25 new variants (not reported in public databases or previous studies). In addition, germline variants were observed in several genes involved in MMR and homologous recombination (HR) pathways, including ATM, BRCA2 and POLD1. Fifteen candidates and associated to the phenotype variants were identified in the ATM, APC, MSH2, MTHFR, CDKN2A, MUTYH, and POLD1 genes. These variants were evaluated in 20 individuals (8 families), being confirmed in the index cases and identified in more than one relative of the evaluated families. The identification of genes associated with ReCa predisposition is crucial for outlining more efficient diagnostic strategies and for improving genetic counseling for families with high risk to develop this tumor type (AU)

Mismatch repair protein deficient endometrioid adenocarcinomas, metastasizing to adrenal gland and lymph nodes: Unusual cases with diagnostic implications.

Recently, certain endometrial carcinomas have been found to be associated with mismatch repair (MMR) protein defects/deficiency. A 39-year-old female presented with cough, decreased appetite and significant weight loss since 2 months. Earlier, she had undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) for endometrioid adenocarcinoma. Imaging disclosed an 8 cm-sized adrenal mass that was surgically excised. Histopathology of the adrenal tumor, endocervical tumor, and endometrial biopsy revealed Federation of Gynecology and Obstetrics (FIGO) Grade II to III endometrioid adenocarcinoma. By immunohistochemistry, tumor cells were positive for cytokeratin 7, epithelial membrane antigen, PAX8, MLH1 and PMS2 while negative for estrogen receptor (ER), progesterone receptor (PR), MSH2 and MSH6. She underwent adjuvant radiotherapy and chemotherapy. A 34-year-old lady presented with vaginal bleeding since 9 months. She underwent TAH-BSO, reported as FIGO Grade III endometrioid adenocarcinoma. By immunohistochemistry, tumor cells were negative for ER, PR, MLH1, and PMS2 while positive for MSH2 and MSH6. She underwent adjuvant radiotherapy and chemotherapy. However, she developed multiple nodal and pericardial metastases and succumbed to the disease within a year post-diagnosis. Certain high-grade endometrioid adenocarcinomas occurring in younger women are MMR protein deficient and display an aggressive clinical course. Adrenal metastasis in endometrial carcinomas is rare.