Stage IV perihilar cholangiocarcinoma with loss of expression of MSH2 and MSH6: hereditary cancer syndrome?

We present the case of a 69-year-old male diagnosed with stage IV perihilar cholangiocarcinoma with loss of expression of MSH2 and MSH6 proteins, but somatic wild type MSH2 and MSH6 genes with Oncomine Comprehensive Assay (OCA) genomic sequencing panel. In his cancer family history, there was a maternal aunt with sigmoid colon adenocarcinoma also missing MSH2 and MSH6 protein expression. Subsequently, we will discuss whether or not we are facing a hereditary cancer syndrome. (AU)

Stage IV perihilar cholangiocarcinoma with loss of expression of MSH2 and MSH6: hereditary cancer syndrome?

We present the case of a 69-year-old male diagnosed with stage IV perihilar cholangiocarcinoma with loss of expression of MSH2 and MSH6 proteins, but somatic wild type MSH2 and MSH6 genes with Oncomine Comprehensive Assay (OCA) genomic sequencing panel. In his cancer family history, there was a maternal aunt with sigmoid colon adenocarcinoma also missing MSH2 and MSH6 protein expression. Subsequently, we will discuss whether or not we are facing a hereditary cancer syndrome.

Chronic intestinal pseudo-obstruction: diagnostic and prognostic utility of ANNA-1/Anti-Hu onconeural antibodies.

We propose an algorithm for the early detection of cancer from a case of paraneoplastic syndrome.

Chronic intestinal pseudo-obstruction: diagnostic and prognostic utility of ANNA-1/Anti-Hu onconeural antibodies.

A 65-year-old woman who, in the context of dyspepsia and dismotility, was diagnosed with chronic intestinal pseudo-obstruction (CIPO) in small cell lung carcinoma (SCLC). In spite of a remarkable tumor response after the combination of chemotherapy and immunotherapy, an intestinal sepsis led to the patient's sudden death.

SEOM recommendations on the structure and operation of hereditary cancer genetic counseling units (HCGCUs).

INTRODUCTION: Approximately 5 % of all cancer cases are hereditary. Cancer genetic counseling assesses individual and family risks of cancer, conducts genetic studies, interprets results, and advises patients regarding strategies for prevention and risk reduction. Currently, many networks of hereditary cancer genetic counseling units (HCGCUs) are integrated in the medical oncology services of most Spanish hospitals, which are comprised of multidisciplinary teams and offer high-quality care for the treatment of hereditary cancer. MATERIALS AND METHODS: The Spanish Society of Medical Oncology (SEOM) analyzed key issues involving the integration of HCGCUs into the National Health Service. These included basic compliance issues by these units regarding their operation and organization, as well as prerequisites in quality control thereof. RESULTS: This document describes the specific roles and clinical processes performed in HCGCUs in addition to basic services provided by molecular diagnostic laboratories. It also provides a summary on the coordination of care across different levels for patients and families with hereditary cancers. Finally, this document describes the human and material resources needed for the organization of HCGCUs. CONCLUSIONS: SEOM has been a pioneer in the creation and development of HCGCUs. This paper seeks to ensure high-quality care to individuals and families with inherited susceptibility to cancer in Spain.

Characterization of new founder Alu-mediated rearrangements in MSH2 gene associated with a Lynch syndrome phenotype.

It has been reported that large genomic deletions in the MLH1 and MSH2 genes are a frequent cause of Lynch syndrome in certain populations. Here, a cohort has been screened and two new founder rearrangements have been found in the MSH2 gene. These mutations have been characterized by break point determination, haplotype analysis, and genotype-phenotype correlation. Mutations have been identified in the MLH1, MSH2, and MSH6 genes in 303 subjects from 160 suspected Lynch syndrome unrelated families. All subjects were tested using heteroduplex analysis by capillary array electrophoresis. Multiplex ligation-dependent probe amplification was used to detect rearrangements in mutation-negative index patients and confirmed by reverse transcriptase PCR. The break point of the deletions was further characterized by the array comparative genomic hybridization method. Immunohistochemical staining and microsatellite instability were studied in tumor samples. Hereditary nonpolyposis colorectal cancer-related phenotypes were evaluated. More than 16% (24 of 160) of the families had pathogenic mutations (8 MLH1, 15 MSH2, and 1 MSH6). Twelve of these families (50%) are carriers of a novel mutation. Seven of the 15 positive MSH2 families (47%) are carriers of a rearrangement. The exon 7 deletion and exon 4 to 8 deletion of MSH2 are new founder mutations. The segregation of a common haplotype, a similar phenotype, and anticipation effects were observed in these families. These findings will greatly simplify the diagnosis, counseling, and clinical care in suspected Lynch syndrome families and not just in specific geographic areas, so wide distribution may be explained by migration patterns.

Frequency of rearrangements in Lynch syndrome cases associated with MSH2: characterization of a new deletion involving both EPCAM and the 5' part of MSH2.

Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch repair genes and leads to a high risk of colorectal and endometrial cancer. It was recently shown that constitutional 3' end deletions of EPCAM could cause Lynch syndrome in tissues with MSH2 deficiency. We aim to establish the spectrum of mutations in MSH2-associated Lynch syndrome cases and their clinical implications. Probands from 159 families suspected of having Lynch syndrome were enrolled in the study. Immunohistochemistry and microsatellite instability (MSI) analyses were used on the probands of all families. Eighteen cases with MSH2 loss were identified: eight had point mutations in MSH2. In 10 Lynch syndrome families without MSH2 mutations, EPCAM-MSH2genomic rearrangement screening was carried out with the use of multiplex ligation-dependent probe amplification and reverse transcriptase PCR. We report that large germline deletions, encompassing one or more exons of the MSH2 gene, cosegregate with the Lynch syndrome phenotype in 23% (8 of 35) of MSI families tested. A new combined deletion EPCAM-MSH2 was identified and characterized by break point analysis, encompassing from the 3' end region of EPCAM to the 5' initial sequences of the MSH2 (c.859-1860_MSH2:646-254del). EPCAM-MSH2 fusion transcript was isolated. The tumors of the carriers show high-level MSI and MSH2 protein loss. The clinical correlation provided evidence that the type of mutation and the extension of the deletions involving the MSH2 gene could have different implications in cancer predisposition. Thus, the identification of EPCAM-MSH2 rearrangements and their comprehensive characterization should be included in the routine mutation screening protocols for Lynch syndrome.

[Molecular study of the BRCA1 and BRCA2 genes in 153 breast cancer families from Castilla and León (Spain): new nine unclassified variants identified]. / Estudio molecular de los genes BRCA1 y BRCA2 en 153 familias con cáncer de mama de Castilla y León (España): identificación de nueve variantes de efecto desconocido no descritas.

BACKGROUND: It is estimated that 5-10% of breast cancers have an hereditary origin, germline mutations of BRCA1 and BRCA2 genes causing a predisposition. In the present study we analyzed BRCA1 and BRCA2 mutations in moderate to high risk breast cancer patients in order to find out the types and frequency of these mutations in the Spanish regional community of Castilla y León. PATIENTS AND METHOD: We studied 207 moderate to high risk patients from 153 selected families. Genomic DNA was extracted from peripheral blood and analyzed by multiplex polymerase chain reaction-heteroduplexes-conformation sensitive gel electrophoresis (multiplex PCR-HA-CSGE). All variants detected were sequenced to further verify the mutation. RESULTS: 45 alterations (23 in BRCA1 and 22 in BRCA2) were identified in 74 families (48.4%), corresponding to 13 polymorphisms (29 families), 19 unclassified variants (26 families) of which 9 have not been previously described and 13 cancer-prone mutations (19 families; 12.42% of all families). Eight out of the 19 deleterious mutations (42.1%) were detected in the BRCA1 gene and 11 (57.9%) in the BRCA2 gene. The most prevalent mutation was 3036delACAA, which was detected in four unrelated families. CONCLUSIONS: The high proportion of mutations, polymorphisms and unclassified variants we have detected may be the result of the sensitive procedure and the risk selection criteria used in this study. There is a high proportion of unclassified variants. Their role in the disease must be clarified through more studies, including their typing in control samples.

Estudio molecular de los genes BRCA1 y BRCA2 en 153 familias con cáncer de mama de Castilla y León (España): identificación de nueve variantes de efecto desconocido no descritas / Molecular study of the BRCA1 and BRCA2 genes in 153 breast cancer families from Castilla y León (Spain): new nine unclassified variants identified

FUNDAMENTO: El cáncer de mama hereditario representa un 5-10 por ciento de todos los cánceres de mama. En la actualidad dos genes están asociados a la enfermedad, el BRCA1 y el BRCA2. Se sabe que mutaciones en estos genes aumentan el riesgo de padecer cáncer de mama hasta en un 80 por ciento en las portadoras. El objetivo de este estudio es la detección y caracterización de mutaciones en estos genes, en pacientes con cáncer de mama seleccionadas según criterios de moderado-alto riesgo pertenecientes a la Comunidad Autónoma de Castilla y León. PACIENTES Y MÉTODO: Se analizaron 207 muestras seleccionadas pertenecientes a 153 familias. Se realizó extracción de ADN de sangre periférica y para la detección de mutaciones se emplearon técnicas de PCR múltiplex-heterodúplex-CSGE y secuenciación. RESULTADOS: Se detectaron 45 cambios nucleotídicos distintos (23 en BRCA1 y 22 en BRCA2) en 74 familias (48,4 por ciento del total), que corresponden a 13 polimorfismos (29 familias), 19 variantes de efecto desconocido (26 familias), de las que 9 son descritas por primera vez en este trabajo, y 13 patológicas (19 familias; 12,42 por ciento de las familias). De las mutaciones patológicas, 8 (42,1 por ciento) afectan a BRCA1 y 11 (57,9 por ciento) a BRCA2. La mutación más frecuente es la 3036delACAA de BRCA2, presente en 4 familias no relacionadas. CONCLUSIONES: El alto porcentaje de mutaciones, polimorfismos y variantes de efecto desconocido detectado revela la alta resolución del método de análisis mutacional utilizado, así como la validez de los criterios de selección aplicados. Existe un gran número de variantes de significado desconocido cuyo papel en la enfermedad debe ser clarificado mediante diferentes tipos de estudios, entre los que se incluye su tipificación en poblaciones control. (AU)