Pedro Pérez Segura

Prevalence of germline mutations of MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer families from Spain

HNPCC is an autosomal dominantly inherited cancer‐susceptibility syndrome that confers an increased risk for colorectal cancer and endometrial cancer at a young age. It also entails an increased risk of a variety of other tumors, such as ovarian, gastric, uroepithelial and biliary tract cancers. The underlying pathogenic mutation lies in 1 of the 5 known DNA MMR genes (MSH2, MLH1, PMS1, PMS2 and MSH6). We screened a total of 140 individuals from 56 Spanish families with suspected HNPCC for mutations in the DNA mismatch repair genes MLH1 and MSH2, using DGGE and direct DNA sequencing. Families were selected on the basis of a history of HNPCC‐related tumors or the occurrence of other associated tumors in members besides the index case affected with colorectal cancer. We detected 14 definite pathogenic germline mutations, 9 in MLH1 and 5 in MSH2 in 13 unrelated families selected by the Amsterdam criteria and Bethesda guidelines (1 family carries 2 mutations) and 3 missense mutations in 3 unrelated families selected by the Amsterdam criteria. Among the 17 germline mutations noted in the Spanish cohort, 10 are novel, 7 in MLH1 and 3 in MSH2, perhaps demonstrating different mutational spectra in the Spanish population, where no founder mutation has been identified. Based on our results, we suggest that in the Spanish population not only HNPCC families fulfilling the Amsterdam criteria but also those following Bethesda guidelines should undergo genetic testing for MSH2 and MLH1 mutations.

Analysis of PALB2 Gene in BRCA1/BRCA2 Negative Spanish Hereditary Breast/Ovarian Cancer Families with Pancreatic Cancer Cases

Background The PALB2 gene, also known as FANCN, forms a bond and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer and 3–4% of familial pancreatic cancer. The goal of this study was to determine the prevalence of PALB2 mutations in a population of BRCA1/BRCA2 negative breast cancer patients selected from either a personal or family history of pancreatic cancer. Methods 132 non-BRCA1/BRCA2 breast/ovarian cancer families with at least one pancreatic cancer case were included in the study. PALB2 mutational analysis was performed by direct sequencing of all coding exons and intron/exon boundaries, as well as multiplex ligation-dependent probe amplification. Results Two PALB2 truncating mutations, the c.1653T>A (p.Tyr551Stop) previously reported, and c.3362del (p.Gly1121ValfsX3) which is a novel frameshift mutation, were identified. Moreover, several PALB2 variants were detected; some of them were predicted as pathological by bioinformatic analysis. Considering truncating mutations, the prevalence rate of our population of BRCA1/2-negative breast cancer patients with pancreatic cancer is 1.5%. Conclusions The prevalence rate of PALB2 mutations in non-BRCA1/BRCA2 breast/ovarian cancer families, selected from either a personal or family pancreatic cancer history, is similar to that previously described for unselected breast/ovarian cancer families. Future research directed towards identifying other gene(s) involved in the development of breast/pancreatic cancer families is required.

Role of flow cytometry immunophenotyping in the diagnosis of leptomeningeal carcinomatosis

PURPOSE To explore the contribution of flow cytometry immunophenotyping (FCI) in detecting leptomeningeal disease in patients with solid tumors. EXPERIMENTAL DESIGN Cerebrospinal fluid (CSF) samples from 78 patients who received a diagnosis of epithelial-cell solid tumors and had clinical data suggestive of leptomeningeal carcinomatosis (LC) were studied. A novel FCI protocol was used to identify cells expressing the epithelial cell antigen EpCAM and their DNA content. Accompanying inflammatory cells were also described. FCI results (positive or negative for malignancy) were compared with those from CSF cytology and with the diagnosis established by the clinicians: patients with LC (n = 49), without LC (n = 26), and undetermined (n = 3). RESULTS FCI described a wide range of EpCAM-positive cells with a hyperdiploid DNA content in the CSF of patients with LC. Compared with cytology, FCI showed higher sensitivity (75.5 vs 65.3) and negative predictive value (67.6 vs 60.5), and similar specificity (96.1 vs 100) and positive predictive value (97.4 vs 100). Concordance between cytology and FCI was high (Kp = 0.83), although misdiagnosis of LC did not show differences between evaluating the CSF with 1 or 2 techniques (P = .06). Receiver-operator characteristic curve analyses showed that lymphocytes and monocytes had a different distribution between patients with and without LC. CONCLUSION FCI seems to be a promising new tool for improving the diagnostic examination of patients with suspicion of LC. Detection of epithelial cells with a higher DNA content is highly specific of LC, but evaluation of the nonepithelial cell compartment of the CSF might also be useful for supporting this diagnosis.

Spanish Society of Medical Oncology consensus for the use of haematopoietic colony-stimulating factors in cancer patients

Neutropenia is a common complication of cancer chemotherapy. Colony-stimulating factors (CSF) may be used to avoid neutropenia-associated complications. The Spanish Society of Medical Oncology (SEOM) recently constituted a working group to review the main issues concerning the use of CSF and carried out a consensus process about the use of CSF in cancer patients, held in Madrid on 26 May 2006. The group concluded the following recommendations: prophylactic use of CSF is recommended when a rate of febrile neutropenia (FN) higher than 20% is expected without the use of CSF or when additional risk factors for neutropenia exist; therapeutic use of CSF is recommended in order to treat FN episodes but not to treat afebrile neutropenic episodes. In addition, the use of CSF is considered effective when used to mobilise stem cells before high-dose chemotherapy and when used for chemotherapy schedule optimisation in dose-dense and in dose-intense regimens.

Necesidad de una atención coordinada y multidisciplinaria en la población española con riesgo elevado de desarrollar cáncer colorrectal

El cáncer colorrectal (CCR) constituye la segunda causa de muerte por cáncer en la mayoría de los países desarrollados, así como la neoplasia más prevalente cuando se consideran hombres y mujeres conjuntamente1. España ocupa una posición intermedia en cuanto a incidencia y mortalidad, con más de 25.000 nuevos casos/año y casi 14.000 muertes anuales por esta neoplasia. La mayoría de casos acontecen en individuos sin antecedentes familiares de este tumor (70-80%), mientras que una pequeña proporción de ellos corresponde a formas hereditarias, ya sea síndromes polipósicos (1%), síndrome de Lynch (2-5%) o el CCR asociado al gen MUTYH (<1%)2--5. Sin embargo, se estima que en un 20-25% adicional de casos puede existir un componente hereditario asociado aun no bien establecido, lo que se conoce como CCR familiar (fig. 1). La elevada prevalencia y mortalidad por CCR contrasta con el hecho de ser uno de los tumores que más se pueden beneficiar de medidas preventivas. Así, el conocimiento de la historia natural, los factores patogénicos implicados en su aparición, y la disponibilidad de herramientas para su detección precoz y tratamiento han permitido desarrollar diferentes estrategias de prevención6. Las estrategias de cribado o screening tienen como objetivo identificar individuos

SEOM guideline for the treatment of malignant glioma

High-grade gliomas are an infrequent disease diagnosed usually in the fifth or sixth decade. Careful histopathological diagnosis is essential because tumour grade and type condition the treatment. Magnetic resonance with gadolinium is considered the standard radiologic exploration and should be followed by tissue sampling. Treatment of these patients should be decided in a multidisciplinary committee. Surgery, radiotherapy and chemotherapy are the basis of patients’ treatment, with the best results obtained when the three of them can be used.

Need to implement a coordinated and multidisciplinary care in the Spanish population at increased risk for colorectal cancer

Colorectal cancer (CRC) is the second leading cause of cancer death in most developed countries and the most prevalent malignancy when considering men and women together. From a practical standpoint, the individual probability of developing CRC is divided in average risk, which corresponds to individuals aged ≥50 years without additional risk factors (susceptible to population-based screening measures), and high risk, which corresponds to those individuals with any risk factor (hereditary syndromes, personal history and/or family history of adenomas or CRC). This group requires a specific, specialized, and multidisciplinary evaluation in high-risk units. Despite the evidence that screening and surveillance in high-risk forms of CRC is highly effective preventing CRC-deaths, underdiagnosis and lack of application of preventive measures in this population remain the main challenges. The Alliance for Colon Cancer Prevention, an organization that brings together the majority of scientific societies and associations involved in the prevention of this disease in Spain, has gathered a group of experts in various fields involved in the management of patients with CRC. These experts have integrated a discussion forum evaluating the current status and needs in relation to the care of people with an increased risk of CRC in Spain. This document is intended to bring consensus of all involved professionals with the only hope of improving the care of population at risk for CRC.

Impacto psicológico del consejo genético valorado por el cuestionario de evaluación multidimensional del impacto de riesgo de cáncer (micra). estudio de las propiedades psicométricas del micra

Objetivos: a) valorar el impacto psicosocial de la realización del test genético. b) Comprobar el efecto de las variables: sexo, diagnóstico oncológico, estar recibiendo tratamiento, ser el primer probando, el tipo de síndrome hereditario: cáncer de mama/ovario (SHCMO) o cáncer de colon (SHCC), resultado del test genético; y tiempo desde la comunicación de resultados. c) Estudiar las propiedades psicométricas y replicar la estructura factorial de la versión castellana del MICRA Método: se evaluó a 122 sujetos que habían realizado test genético en un intervalo de 1 mes a 5 años, mediante el cuestionario de evaluación multidimensional del impacto de riesgo de cáncer (MICRA). Datos de la muestra: 95 mujeres y 27 hombres; media de edad: 50,48 años; con nivel educativo alto; 93 (72,2%) fueron diagnosticados de cáncer; 45 (36,9%) recibían tratamiento oncológico; 89 (73%) consultaban por SHCMO y 33 (27%) por SHCC; 50 (41%) eran negativos para la mutación, 37 (30,3%) positivos y 35 (28,7%) no informativos. La media del tiempo que ha transcurrido desde la comunicación de los resultados: 401 días. Se calculó la consistencia interna del MICRA, se llevó a cabo un análisis de la validez convergente y discriminante de los ítems de Abstract