RESUMEN
Lynch syndrome accounts for 3-5% of colorectal cancers and is due to a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Somatic hypermethylation of the MLH1 promoter is commonly associated to sporadic cases. Strategies have been developed to identify patients with Lynch Syndrome based on clinical findings, tumoral phenotype, family history and immunohistochemistry analysis. However, there still are some pitfalls in this strategy, possibly responsible for an underdiagnosis of Lynch syndrome. Here we report the case of a 37 years-old man presenting with two concomitant tumors located in the rectosigmoid and in the ileocecal angle. Both tumors were microsatellites instability-high (MSI-H) and showed a loss of MLH1 and PMS2 protein expression, but only one had MLH1 promoter hypermethylation. Constitutional analysis of mismatch repair genes could not be performed from a blood sample, because of the early death of the patient. However, tumoral tissue analyses revealed in both tumors a pathogenic variant in the MLH1 gene. Further analysis of the surrounding tumor-free tissue also showed the presence of this alteration of the MHL1 gene. Finally, the same pathogenic variant was present constitutionally in one of the siblings of the patient, confirming its hereditary nature. This new case of concomitant presence of MLH1 promoter hypermethylation and MLH1 germline mutation demonstrates that the presence of MLH1 promoter hypermethylation should not rule out the diagnosis of Lynch Syndrome.
Asunto(s)
Adenocarcinoma Mucinoso/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Mutación de Línea Germinal , Inestabilidad de Microsatélites , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Homólogo 1 de la Proteína MutL/genética , Adenocarcinoma Mucinoso/patología , Adulto , Carcinoma de Células en Anillo de Sello/genética , Carcinoma de Células en Anillo de Sello/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Proteínas de Unión al ADN/genética , Resultado Fatal , Humanos , Masculino , Madres , HermanosRESUMEN
BACKGROUND: The tumor spectrum in the Lynch syndrome is well defined, comprising an increased risk of developing colonic and extracolonic malignancies. Muir-Torre syndrome is a variant with a higher risk of skin disease. Patients have been described carrying mutations in the mismatch repair genes and presenting tumors with unusual histology or affected organ not part of the Lynch syndrome spectrum. Hence, the real link between Lynch syndrome, or Muir-Torre syndrome, and these tumors remains difficult to assess. CASE PRESENTATION: We present the case of a 45-year-old-woman, diagnosed with breast cancer at 39 years of age and skin squamous cell carcinoma (SCC) at 41 years of age, without personal history of colorectal cancer. The microsatellite instability analysis performed on the skin SCC showed a low-level of microsatellite instability (MSI-Low). The immunohistochemical expression analysis of the four DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 showed a partial loss of the expression of MSH2 and MSH6 proteins. Germline deletion was found in MSH2 gene (c.1277-? _1661 + ?del), exon 8 to 10. Then, at 45 years of age, she presented hyperplastic polyps of the colon and a sebaceous adenoma. CONCLUSION: Squamous cell carcinomas have been described in Lynch syndrome and Muir-Torre syndrome in two studies and two case reports. This new case further supports a possible relationship between Lynch syndrome and squamous cell carcinoma.
RESUMEN
BACKGROUND: Diffuse H3 K27M-mutant gliomas occur primarily in children but can also be encountered in adults. The aim of this study was to describe the characteristics of H3 K27M-mutant gliomas in adults. METHODS: We analyzed the characteristics of 21 adult H3 K27M-mutant gliomas and compared them with those of 135 adult diffuse gliomas without histone H3 and without isocitrate dehydrogenase (IDH) mutation (IDH/H3 wild type). RESULTS: The median age at diagnosis in H3 K27M-mutant gliomas was 32 years (range: 18-82 y). All tumors had a midline location (spinal cord n = 6, thalamus n = 5, brainstem n = 5, cerebellum n = 3, hypothalamus n = 1, and pineal region n = 1) and were IDH and BRAF-V600E wild type. The identification of an H3 K27M mutation significantly impacted the diagnosis in 3 patients (14%) for whom the histological aspect initially suggested a diffuse low-grade glioma and in 7 patients (33%) for whom pathological analysis hesitated between a diffuse glioma, ganglioglioma, or pilocytic astrocytoma. Compared with IDH/H3 wild-type gliomas, H3 K27M-mutant gliomas were diagnosed at an earlier age (32 vs 64 y, P < .001), always had a midline location (21/21 vs 21/130, P < .001), less frequently had a methylated MGMT promoter (1/21 vs 52/129, P = .002), and lacked EGFR amplification (0/21 vs 26/128, P = .02). The median survival was 19.6 months in H3 K27M-mutant gliomas and 17 months in IDH/H3 wild-type gliomas (P = .3). CONCLUSION: In adults, as in children, H3 K27M mutations define a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis.
Asunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , Histonas/genética , Mutación/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Astrocitoma/genética , Neoplasias Encefálicas/patología , Niño , Femenino , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Adulto JovenRESUMEN
BACKGROUND: The goal of this prospective multicentric trial was to validate a technique that allowed for MGMT promoter methylation analysis in routine clinical practice. METHODS: The MGMT status of 139 glioblastoma patients, whom had received standard first line treatment, was determined using pyrosequencing (PSQ) and a semi-quantitative Methylation-specific PCR (sqMS-PCR) method, using both frozen and formalin-fixed paraffin-embedded FFPE samples. Eight participating centers locally performed the analysis, including external quality controls. RESULTS: There was a strong correlation between results from FFPE and frozen samples. With cut-offs of 12% and 13%, 98% and 91% of samples were identically classified with PSQ and sqMS-PCR respectively. In 12% of cases frozen samples were excluded because they had a low percentage of tumor cells. In 5-6% of cases the analysis was not feasible on FFPE samples. The optimized risk cut-offs were higher in both techniques when using FFPE samples, in comparison to frozen samples. For sqMS-PCR, we validated a cut-off between 13-15% to dichotomize patients. For PSQ, patients with a low level of methylation (<= 8%) had a median progression-free survival under 9 months, as compared with more than 15.5 months for those with a level above 12%. For intermediate values (9-12%), more discordant results between FFPE and frozen samples were observed and there was not a clear benefit of temozolomide treatment, which indicated a "grey zone". CONCLUSIONS: MGMT status can reliably be investigated in local laboratories. PSQ is the ideal choice as proven by strong interlaboratory reproducibility, along with threshold agreements across independent studies.
Asunto(s)
Neoplasias Encefálicas/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Glioblastoma/genética , Análisis de Secuencia de ADN , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Metilación de ADN , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Estudios Prospectivos , Reproducibilidad de los Resultados , Temozolomida , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Carcinoma Neuroendocrino/mortalidad , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Dacarbazina/administración & dosificación , Fluorouracilo/administración & dosificación , Humanos , Mutación , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/mortalidad , Resultado del Tratamiento , Proteínas Supresoras de Tumor/genéticaRESUMEN
AIM: The aim of this article is to clarify the epidemiologic, clinical, endoscopic, biological and genetic characteristics of type 1 serrated polyposis patients. PATIENTS AND METHODS: Consecutive patients responding to the WHO definition of type 1 serrated polyposis in one reference center for polyposis patients accepted genetic counseling. Detailed data on previous endoscopies, histology, and life habits were recorded, after informed consent, germline analysis of MUTYH, APC, and PTEN germline mutations. Molecular biology was tested on available fixed tissue from different lesion types. RESULTS: We included 29 patients (mean age 53.5 years, 21 women (72.4%)), four with a personal history of colorectal cancer (CRC), with a mean of 11.6 SSAs, with associated hyperplastic polyps in 93.1% and adenomas in 82.8%. SSAs showed no dysplasia in 46.9% of lesions (three of 29 patients), LGD in 51.9% (22/29 patients), and HGD in 1.2% (four of 29 patients). Dysplasia was more frequent in proximal SSAs and in women. Colectomy 15 patients (51.7%), upper digestive neoplasms: eight patients (27.5%); smokers: 24 patients (82.8%); family history of CRC: 16 patients (55.2%). Biology: MSI-H phenotype in one SSA, V600E BRAF mutation in 95% of SSAs; MGMT hypermethylation in three of 17 SSAs. No germline mutation was detected in MYH, APC or PTEN genes. CONCLUSION: Type 1 serrated polyposis corresponds to a majority of women, with a high prevalence of smokers, a high prevalence of dysplastic serrated adenomas, particularly in females, without identified germline mutation in targeted predisposing genes.
RESUMEN
Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs.SEMA3F expression was detected in normal neuroendocrine cells but was lost in most of human primary tumors and all their metastases. SEMA3F loss of expression was associated with promoter gene methylation. After increasing endogenous SEMA3F levels through stable transfection, enteroendocrine cell lines STC-1 and GluTag showed a reduced proliferation rate in vitro. In two different xenograft mouse models, SEMA3F-overexpressing cells exhibited a reduced ability to form tumors and a hampered liver dissemination potential in vivo. This resulted, at least in part, from the inhibition of mTOR and MAPK signaling pathways.This study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy.
Asunto(s)
Orientación del Axón/fisiología , Neoplasias del Íleon/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Tumores Neuroendocrinos/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Femenino , Xenoinjertos , Humanos , Neoplasias del Íleon/genética , Neoplasias del Íleon/patología , Proteínas de la Membrana/genética , Ratones , Proteínas del Tejido Nervioso/genética , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Transducción de SeñalRESUMEN
BACKGROUND: The alkylating agents (ALKYs) streptozotocin, dacarbazine, and temozolomide currently are the main drugs used in systemic chemotherapy for neuroendocrine tumors (NETs). The promising activity shown by gemcitabine and oxaliplatin (GEMOX) in previous studies prompted this study 1) to confirm the use of GEMOX in a larger population of NET patients, 2) to compare its efficacy with that of ALKYs, and 3) to explore whether the O(6) -methylguanine-DNA methyltransferase (MGMT) status could help in selecting the chemotherapy regimen. METHODS: One hundred four patients with metastatic NETs (37 pancreatic NETs, 33 gastrointestinal NETs, 23 bronchial NETs, and 11 NETs of other/unknown origin) were treated with GEMOX between 2004 and 2014. Among these patients, 63 also received ALKYs. MGMT promoter gene methylation was assessed via pyrosequencing in 42 patients. RESULTS: Patients received a median of 6 courses of GEMOX. Twenty-four (23%) had an objective response (OR). The median progression-free survival (PFS) and overall survival were 7.8 and 31.6 months, respectively. In the 63 patients treated with both ALKYs and GEMOX, the ORs (22% and 22%) and the PFSs (7.5 and 7.3 months) were similar. The response was concordant in 53% of the patients. Promoter gene methylation of MGMT was associated with better outcomes with ALKYs (P = .03 for OR and P = .04 for PFS) but not GEMOX. CONCLUSIONS: GEMOX is effective against NETs; its activity is comparable to that of ALKYs, and it is not influenced by the MGMT status. Our data suggest that GEMOX might be preferred for patients with unmethylated MGMT tumors. Cancer 2015;121:3435-43. © 2015 American Cancer Society.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Tumores Neuroendocrinos/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Alquilantes , Antimetabolitos Antineoplásicos/administración & dosificación , Antineoplásicos Alquilantes/uso terapéutico , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Estudios Retrospectivos , Resultado del Tratamiento , GemcitabinaRESUMEN
Sebaceous neoplasms are a major clinical feature of Muir-Torre syndrome (MTS) associated with visceral malignancies, especially colorectal and endometrial tumors. The diagnosis of MTS relies largely on the microsatellite instability (MSI) phenotype in tumors, suggesting germline mutations in DNA mismatch repair (MMR) genes responsible for the inherited disease. We hypothesized that in some MSI-H sebaceous tumors, acquired rather than inherited mutations in MMR genes could be involved. Using next-generation sequencing, we screened MMR gene mutations in 18 MSI-H sebaceous tumors. We found mutations in 17 samples (94%). Indeed, 12/17 (71%) were shown to carry acquired somatic mutations and among 12 samples, seven were shown to be associated with additional somatic alterations like loss of heterozygosity or multiple mutations, suggesting somatic second hits. Our findings strongly suggest that somatic MMR deficiency is responsible for a proportion of MSI-H sebaceous tumors.
Asunto(s)
Reparación de la Incompatibilidad de ADN , Proteínas de Unión al ADN/genética , Síndrome de Muir-Torre/genética , Mutación , Neoplasias de las Glándulas Sebáceas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia de ADNRESUMEN
CONTEXT: Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant inherited syndrome, related to mutations in the MEN1 gene. Controversial data suggest that the nonsynonymous p.Ala541Thr variant, usually considered as a non-pathogenic polymorphism, may be associated with an increased risk of MEN1-related lesions in carriers. OBJECTIVE: The aim of this study was to evaluate the pathogenic influence of the p.Ala541Thr variant on clinical and functional outcomes. PATIENTS AND METHODS: We analysed a series of 55 index patients carrying the p.Ala541Thr variant. Their clinical profile was compared to that of 117 MEN1 patients. The biological impact of the p.Ala541Thr variant on cell growth was additionally investigated on menin-deficient Leydig cell tumour (LCT)10 cells generated from Men1+/Men1- heterozygous knock-out mice, and compared with wild type (WT). RESULTS: The mean age at first appearance of endocrine lesions was similar in both p.Ala541Thr carriers and MEN1 patients, but no p.Ala541Thr patient had more than one cardinal MEN1 lesion at initial diagnosis. A second MEN1 lesion was diagnosed in 13% of MEN1 patients and in 7% of p.Ala541Thr carriers in the year following preliminary diagnosis. Functional studies on LCT10 cells showed that overexpression of the p.Ala541Thr variant did not inhibit cell growth, which is in direct contrast to results obtained from investigation of WT menin protein. CONCLUSION: Taken together, these data raise the question of a potential pathogenicity of the p.Ala541Thr missense variant of menin that commonly occurs within the general population. Additional studies are required to investigate whether it may be involved in a low-penetrance MEN1 phenotype.
Asunto(s)
Neoplasia Endocrina Múltiple Tipo 1/genética , Mutación , Polimorfismo Genético/genética , Proteínas Proto-Oncogénicas/genética , Adenoma/genética , Adulto , Animales , Línea Celular Tumoral , Femenino , Heterocigoto , Humanos , Hiperparatiroidismo/genética , Tumor de Células de Leydig/genética , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Fenotipo , Neoplasias Hipofisarias/genética , Proteínas Proto-Oncogénicas/deficiencia , TransfecciónRESUMEN
Ten percent of paragangliomas are malignant and one-third occurs in a genetic background. We report a case of succinate dehydrogenase subunit B (SDHB)-related malignant paraganglioma with dramatic response to temozolomide and capecitabine regimen (decrease in tumor size of 70% with RECIST criteria). Tumor cells harbored a new mutation in SDHB gene and showed aberrant hypermethylation of O6-methylguanine-DNA-methyltransferase promoter. Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. This observation points to a possible genotype response to treatment relationships, which could help to design tailor-made treatments in the future.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Paraganglioma/tratamiento farmacológico , Paraganglioma/enzimología , Neoplasias Retroperitoneales/tratamiento farmacológico , Neoplasias Retroperitoneales/enzimología , Succinato Deshidrogenasa/genética , Adulto , Biomarcadores de Tumor/metabolismo , Capecitabina , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Sinergismo Farmacológico , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Inmunohistoquímica , Masculino , Paraganglioma/genética , Paraganglioma/metabolismo , Paraganglioma/cirugía , Neoplasias Retroperitoneales/genética , Neoplasias Retroperitoneales/metabolismo , Neoplasias Retroperitoneales/cirugía , Temozolomida , Resultado del TratamientoRESUMEN
Constitutional epimutation is one of the causes for MLH1 gene inactivation associated with hereditary non-polyposis colon cancer (HNPCC) syndrome. Here we investigate MLH1 promoter hypermethylation in 110 sporadic early-onset colorectal cancer patients. Variable levels of hypermethylation were detected in 55 patients (50%). Importantly a reduced MLH1 gene expression was found in patients with high-level methylation, with the association of microsatellite instability (MSI) in their tumor cells. Such high-level methylation accounts for 7.4% of all patients included in this study. Furthermore, we found that in one case constitutional methylation affected both alleles, indicating a post-zygotic methylation dysregulation. Our findings suggest that constitutional epimutation is a mechanism underlying early-onset colorectal cancer, although it is involved in only a small proportion of patients, who require appropriate surveillance. Our findings provide further insight into the role of aberrant constitutional methylation in colon carcinogenesis and raise the question of whether prevalent low-level methylation constitutes a potential risk factor for cancer development.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Alelos , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Metilación de ADN/genética , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Edad de Inicio , Secuencia de Bases , Estudios de Casos y Controles , Regulación Neoplásica de la Expresión Génica , Humanos , Inestabilidad de Microsatélites , Persona de Mediana Edad , Datos de Secuencia Molecular , Homólogo 1 de la Proteína MutL , Proteínas Nucleares/genéticaRESUMEN
Since the first report by our group in 1999, more than 20 unrelated biallelic mutations in DNA mismatch repair genes (MMR) have been identified. In the present report, we describe two novel cases: one carrying compound heterozygous mutations in the MSH6 gene; and the other, compound heterozygous mutations in the PMS2 gene. Interestingly, the inactivation of one PMS2 allele was likely caused by gene conversion. Although gene conversion has been suggested to be a mutation mechanism underlying PMS2 inactivation, this is the first report of its involvement in a pathogenic mutation. The clinical features of biallelic mutation carriers were similar to other previously described patients, with the presence of café-au-lait spots (CALS), early onset of brain tumors, and colorectal neoplasia. Our data provide further evidence of the existence, although rare, of a distinct recessively inherited syndrome on the basis of MMR constitutional inactivation. The identification of this syndrome should be useful for genetic counseling, especially in families with atypical hereditary nonpolyposis colon cancer (HNPCC) associated with childhood cancers, and for the clinical surveillance of these mutation carriers.
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Adenosina Trifosfatasas/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Conversión Génica , Silenciador del Gen , Mutación , Adulto , Disparidad de Par Base , Secuencia de Bases , Neoplasias Encefálicas/genética , Neoplasias Colorrectales/genética , Cartilla de ADN , Reparación del ADN/genética , Femenino , Tamización de Portadores Genéticos , Humanos , Masculino , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Linaje , Trastornos de la Pigmentación/genéticaAsunto(s)
Carcinoma de Células de Merkel/virología , Trasplante de Órganos , Neoplasias Cutáneas/virología , Antígenos Virales/sangre , Carcinoma de Células de Merkel/sangre , Sondas de ADN de HPV , Humanos , Inmunocompetencia , Papillomaviridae/inmunología , Estudios Retrospectivos , Neoplasias Cutáneas/sangreRESUMEN
The three mammalian receptors UNC5H1, UNC5H2, and UNC5H3 (also named UNC5A, UNC5B, and UNC5C in human) that belong to the family of the netrin-1 receptors, UNC5H, were initially proposed as mediators of the chemorepulsive effect of netrin-1 on specific axons. However, they were also recently shown to act as dependence receptors. Such receptors induce apoptosis when unbound to their ligand. We show here that the expression of the human UNC5A, UNC5B, or UNC5C is down-regulated in multiple cancers including colorectal, breast, ovary, uterus, stomach, lung, or kidney cancers. In colorectal tumors, this down-regulation is associated with loss of heterozygosity occurring within UNC5A, UNC5B, and UNC5C genes but may also be partially related to epigenetic processes because histone deacetylase inhibitor increased UNC5C expression in various cancer cell lines. Moreover, sequencing of UNC5C gene in patients with colorectal tumors revealed the presence of missense mutations. The lossreduction of expression may be a crucial mechanism for tumorigenicity because the expression of UNC5H1, UNC5H2, or UNC5H3 inhibits tumor cell anchorage-independent growth and invasion. Moreover, these hallmarks of malignant transformation can be restored by netrin-1 addition or apoptosis inhibition. Hence, UNC5H1, UNC5H2, and UNC5H3 receptors may represent tumor suppressors that inhibit tumor extension outside the region of netrin-1 availability by inducing apoptosis.