RESUMO
BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Instabilidade de Microssatélites , Neoplasias Encefálicas , Neoplasias Colorretais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Mutação , Síndromes Neoplásicas HereditáriasRESUMO
BACKGROUND & AIMS: Approximately half of the families that fulfill Amsterdam criteria for Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) do not have evidence of the germline mismatch repair gene mutations that define this syndrome and result in microsatellite instability (MSI). The carcinogenic pathways and the best diagnostic approaches to detect microsatellite stable (MSS) HNPCC tumors are unclear. We investigated the contribution of epigenetic alterations to the development of MSS HNPCC tumors. METHODS: Colorectal cancers were divided into 4 groups: (1) microsatellite stable, Amsterdam-positive (MSS HNPCC) (N = 22); (2) Lynch syndrome cancers (identified mismatch repair mutations) (N = 21); (3) sporadic MSS (N = 92); and (4) sporadic MSI (N = 46). Methylation status was evaluated for CACNAG1, SOCS1, RUNX3, NEUROG1, MLH1, and long interspersed nucleotide element-1 (LINE-1). KRAS and BRAF mutation status was analyzed. RESULTS: MSS HNPCC tumors displayed a significantly lower degree of LINE-1 methylation, a marker for global methylation, than any other group. Although most MSS HNPCC tumors had some degree of CpG island methylation, none presented a high index of methylation. MSS HNPCC tumors had KRAS mutations exclusively in codon 12, but none harbored V600E BRAF mutations. CONCLUSIONS: Tumors from Amsterdam-positive patients without mismatch repair deficiency (MSS HNPCC) have certain molecular features, including global hypomethylation, that distinguish them from all other colorectal cancers. These characteristics could have an important impact on tumor behavior or treatment response. Studies are underway to further assess the cause and effects of these features.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Repetições de Microssatélites , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Feminino , Predisposição Genética para Doença , Instabilidade Genômica , Humanos , Elementos Nucleotídeos Longos e Dispersos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteína 1 Homóloga a MutL , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Linhagem , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Espanha , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/genética , Estados Unidos , Proteínas ras/genéticaRESUMO
BACKGROUND: Persimmon phytobezoar, although an infrequent entity, is not rare in some countries. Because of their particular features, management of diospyrobezoars is difficult. A number of surgical, endoscopic, and pharmacologic treatments have been proposed with variable success. This is a description of our experience with 10 patients with a new combination therapy. METHODS: Ten patients (7 men, 3 women; mean age 46.4 years) were treated with a new fragmentation technique consisting of a saw-like effect with a large polypectomy snare followed by administration of cellulase, cysteine, and metoclopramide. RESULTS: Resolution was achieved in 8 patients. Complications (intestinal obstruction) developed in 2 patients. CONCLUSIONS: Our combined therapy is safe and highly efficacious but caution must be exercised because intestinal obstruction can occur if large fragments pass through the pylorus. A more extensive study is required to assess these clinical observations.