Câncer colo-retal hereditário não polipose - Diagnóstico e surgimento de famílias de alto risco

Hereditary nonpolyposis colorectal cancer is an autosomal dominant condition caused by highly penetrant gene mutations. It is characterized by increased susceptibility for a specific group of cancer, mainly colorectal cancer. The syndrome originates from the inheritance of mutations in DNA mismatch repair genes. The most commonly affected genes in hereditary nonpolyposis colorectal cancer are hMLH1 and hMSH2. Their deficient expression renders the cell susceptible to the accumulation of many molecular defects, a condition which can be evaluated by the instability in sections of base repeats in the genoma known as microsatellite instability. The molecular detection of hereditary nonpolyposis colorectal cancer is possible in most of the highly suspicious cases. Genetic tests for hereditary nonpolyposis colorectal cancer also allow characterization of the individual that bears the mutation within a family. The high cost and restricted availability of these tests hamper their use for every person presenting colorectal cancer. Due to this fact, some clinical criteria have been developed by a hereditary nonpolyposis colorectal cancer international organization to select families with a high probability of carrying the mutation. Once families at risk are identified, they are encouraged to join a screening program that aims at early detection of hereditary nonpolyposis colorectal cancer-related cancers, increasing the possibility of its prevention and early detection.O câncer colo-retal hereditário não polipose é uma síndrome genética caracterizada por uma susceptilidade aumentada para certos tipos específicos de câncer, especialmente o câncer colo-retal. Ao nível molecular, a síndrome caracteriza-se pela herança autossômica dominante de mutações em genes envolvidos em um mecanismo de reparo do DNA dirigido para defeitos em trocas, ganhos ou perdas de um número de pequeno de bases, chamado de sistema de reparo de erros de pareamento. Os genes mais comumente afetados em câncer colo-retal hereditário não polipose são hMLH1 e hMSH2, e sua inativação destina a célula portadora à acumulação de mutações, uma condição conhecida como fenótipo de erro de replicação. Estas mutações múltiplas serão transmitidas e amplificadas em células-filhas e sua identificação pode ser feita por meio da identificação de distúrbios em seqüências repetidas de DNA chamadas de microssatélites. Células portadoras de defeitos deste tipo em seus microssatélites apresentam um fenótipo denominado de instabilidade de microssatélites (também denominado fenótipo MSI). Por meio da detecção destes defeitos genéticos é possível, presentemente, a realização de um diagnóstico preciso de câncer colo-retal hereditário não polipose, permitindo a atuação preventiva em portadores da síndrome que ainda não desenvolveram câncer. Contudo, limitações financeiras e de acesso aos exames inviabilizam sua realização em todos os indivíduos que apresentam câncer colo-retal. Por isso, foram estabelecidos pela comunidade internacional alguns critérios que selecionam as famílias com alta probabilidade de possuírem a mutação e que, portanto, podem beneficiar-se com estes exames. Este artigo procura abordar as estratégias recomendadas para identificação de casos de alto risco de câncer colo-retal hereditário não polipose, os testes genéticos disponíveis para estes casos e as recomendações para prevenção e seguimento destas famílias

Zebrafish Tric-b is required for skeletal development and bone cells differentiation

IntroductionTrimeric intracellular potassium channels TRIC-A and -B are endoplasmic reticulum (ER) integral membrane proteins, involved in the regulation of calcium release mediated by ryanodine (RyRs) and inositol 1,4,5-trisphosphate (IP3Rs) receptors, respectively. While TRIC-A is mainly expressed in excitable cells, TRIC-B is ubiquitously distributed at moderate level. TRIC-B deficiency causes a dysregulation of calcium flux from the ER, which impacts on multiple collagen specific chaperones and modifying enzymatic activity, leading to a rare form of osteogenesis imperfecta (OI Type XIV). The relevance of TRIC-B on cell homeostasis and the molecular mechanism behind the disease are still unknown.ResultsIn this study, we exploited zebrafish to elucidate the role of TRIC-B in skeletal tissue. We demonstrated, for the first time, that tmem38a and tmem38b genes encoding Tric-a and -b, respectively are expressed at early developmental stages in zebrafish, but only the latter has a maternal expression. Two zebrafish mutants for tmem38b were generated by CRISPR/Cas9, one carrying an out of frame mutation introducing a premature stop codon (tmem38b-/-) and one with an in frame deletion that removes the highly conserved KEV domain (tmem38bΔ120-7/Δ120-7). In both models collagen type I is under-modified and partially intracellularly retained in the endoplasmic reticulum, as described in individuals affected by OI type XIV. Tmem38b-/- showed a mild skeletal phenotype at the late larval and juvenile stages of development whereas tmem38bΔ120-7/Δ120-7 bone outcome was limited to a reduced vertebral length at 21 dpf. A caudal fin regeneration study pointed towards impaired activity of osteoblasts and osteoclasts associated with mineralization impairment.DiscussionOur data support the requirement of Tric-b during early development and for bone cell differentiation

Hereditary nonpolyposis colorectal cancer identification and surveillance of high-risk families Câncer colo-retal hereditário não polipose - Diagnóstico e surgimento de famílias de alto risco

Hereditary nonpolyposis colorectal cancer is an autosomal dominant condition caused by highly penetrant gene mutations. It is characterized by increased susceptibility for a specific group of cancer, mainly colorectal cancer. The syndrome originates from the inheritance of mutations in DNA mismatch repair genes. The most commonly affected genes in hereditary nonpolyposis colorectal cancer are hMLH1 and hMSH2. Their deficient expression renders the cell susceptible to the accumulation of many molecular defects, a condition which can be evaluated by the instability in sections of base repeats in the genoma known as microsatellite instability. The molecular detection of hereditary nonpolyposis colorectal cancer is possible in most of the highly suspicious cases. Genetic tests for hereditary nonpolyposis colorectal cancer also allow characterization of the individual that bears the mutation within a family. The high cost and restricted availability of these tests hamper their use for every person presenting colorectal cancer. Due to this fact, some clinical criteria have been developed by a hereditary nonpolyposis colorectal cancer international organization to select families with a high probability of carrying the mutation. Once families at risk are identified, they are encouraged to join a screening program that aims at early detection of hereditary nonpolyposis colorectal cancer-related cancers, increasing the possibility of its prevention and early detection.<br>O câncer colo-retal hereditário não polipose é uma síndrome genética caracterizada por uma susceptilidade aumentada para certos tipos específicos de câncer, especialmente o câncer colo-retal. Ao nível molecular, a síndrome caracteriza-se pela herança autossômica dominante de mutações em genes envolvidos em um mecanismo de reparo do DNA dirigido para defeitos em trocas, ganhos ou perdas de um número de pequeno de bases, chamado de sistema de reparo de erros de pareamento. Os genes mais comumente afetados em câncer colo-retal hereditário não polipose são hMLH1 e hMSH2, e sua inativação destina a célula portadora à acumulação de mutações, uma condição conhecida como fenótipo de erro de replicação. Estas mutações múltiplas serão transmitidas e amplificadas em células-filhas e sua identificação pode ser feita por meio da identificação de distúrbios em seqüências repetidas de DNA chamadas de microssatélites. Células portadoras de defeitos deste tipo em seus microssatélites apresentam um fenótipo denominado de instabilidade de microssatélites (também denominado fenótipo MSI). Por meio da detecção destes defeitos genéticos é possível, presentemente, a realização de um diagnóstico preciso de câncer colo-retal hereditário não polipose, permitindo a atuação preventiva em portadores da síndrome que ainda não desenvolveram câncer. Contudo, limitações financeiras e de acesso aos exames inviabilizam sua realização em todos os indivíduos que apresentam câncer colo-retal. Por isso, foram estabelecidos pela comunidade internacional alguns critérios que selecionam as famílias com alta probabilidade de possuírem a mutação e que, portanto, podem beneficiar-se com estes exames. Este artigo procura abordar as estratégias recomendadas para identificação de casos de alto risco de câncer colo-retal hereditário não polipose, os testes genéticos disponíveis para estes casos e as recomendações para prevenção e seguimento destas famílias

Zebrafish Tric-b is required for skeletal development and bone cells differentiation

IntroductionTrimeric intracellular potassium channels TRIC-A and -B are endoplasmic reticulum (ER) integral membrane proteins, involved in the regulation of calcium release mediated by ryanodine (RyRs) and inositol 1,4,5-trisphosphate (IP3Rs) receptors, respectively. While TRIC-A is mainly expressed in excitable cells, TRIC-B is ubiquitously distributed at moderate level. TRIC-B deficiency causes a dysregulation of calcium flux from the ER, which impacts on multiple collagen specific chaperones and modifying enzymatic activity, leading to a rare form of osteogenesis imperfecta (OI Type XIV). The relevance of TRIC-B on cell homeostasis and the molecular mechanism behind the disease are still unknown.ResultsIn this study, we exploited zebrafish to elucidate the role of TRIC-B in skeletal tissue. We demonstrated, for the first time, that tmem38a and tmem38b genes encoding Tric-a and -b, respectively are expressed at early developmental stages in zebrafish, but only the latter has a maternal expression. Two zebrafish mutants for tmem38b were generated by CRISPR/Cas9, one carrying an out of frame mutation introducing a premature stop codon (tmem38b-/-) and one with an in frame deletion that removes the highly conserved KEV domain (tmem38bΔ120-7/Δ120-7). In both models collagen type I is under-modified and partially intracellularly retained in the endoplasmic reticulum, as described in individuals affected by OI type XIV. Tmem38b-/- showed a mild skeletal phenotype at the late larval and juvenile stages of development whereas tmem38bΔ120-7/Δ120-7 bone outcome was limited to a reduced vertebral length at 21 dpf. A caudal fin regeneration study pointed towards impaired activity of osteoblasts and osteoclasts associated with mineralization impairment.DiscussionOur data support the requirement of Tric-b during early development and for bone cell differentiation.</jats:sec

Implications of an Underlying Beckwith–Wiedemann Syndrome for Wilms Tumor Treatment Strategies

Beckwith–Wiedemann Syndrome (BWS) is a pediatric overgrowth disorder involving a predisposition to embryonal tumors. Most of the tumors associated with BWS occur in the first 8–10 years of life, and the most common is Wilms tumor (WT). BWS clinical heterogeneity includes subtle overgrowth features or even silent phenotypes, and WT may be the presenting symptom of BWS. WT in BWS individuals exhibit distinct characteristics from those of sporadic WT, and the management of these patients needs a peculiar approach. The most important feature is a higher risk of developing bilateral disease at some time in the course of the illness (synchronous bilateral disease at diagnosis or metachronous recurrence after initial presentation with unilateral disease). Accordingly, neoadjuvant chemotherapy is the recommended approach also for BWS patients with unilateral WT to facilitate nephron-sparing surgical approaches. This review emphasizes the importance of early BWS recognition, particularly if a WT has already occurred, as this will result in an urgent consideration of first-line cancer therapy