Analysis of phenotype and FH gene variation in a pedigree affected with hereditary leiomyomatosis and renal cell carcinoma syndrome / 中华医学遗传学杂志

OBJECTIVE@#To analyze clinical phenotype and genetic variants in a Chinese pedigree of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.@*METHODS@#Whole exome sequencing was carried out for the proband from the pedigree. Suspected FH gene variants were validated by Sanger sequencing. Clinical manifestation and histopathological examination were used to analyze the pedigree comprehensively.@*RESULTS@#The pedigree met the clinical diagnostic criteria for HLRCC syndrome. The whole exome sequencing showed that the FH gene of the proband had a heterozygous missense variant of c.1490T>C (p.F497S), which was consistent with the Sanger sequencing. The mother, daughter and son of the proband all had the heterozygous missense variant of c.1490T>C (p.F497S). According to the American Society of Medical Genetics and Genomics Classification Standards and Guidelines for Genetic Variations, c.1490T>C (p.F497S) (PM2+PP1-M+PP3+PP4) was a possible pathogenic variant. Based on our literature search, this variant was a new variant that had not been reported.@*CONCLUSION@#The FH gene missense variant of c.1490T>C (p.F497S) may be the cause of the HLRCC syndrome pedigree, which provides a basis for the genetic diagnosis and genetic counseling of the HLRCC syndrome.

Importancia del síndrome de Li-Fraumeni, un síndrome genético de predisposición al cáncer / The importance of Li-Fraumeni syndrome, a hereditary cancer predisposition disorder

El cáncer en pediatría es una entidad infrecuente. Se estima que más de un 10-15 % de los tumores son secundarios a una variante patogénica en un gen de predisposición al cáncer.Se conocen más de 100 genes de predisposición al cáncer y su asociación con síndromes o tumores aislados. Uno de los más descritos es el síndrome de Li-Fraumeni.Los pacientes con este síndrome tienen alto riesgo de desarrollar uno o más tumores. Su conocimiento permite realizar un protocolo de seguimiento del paciente y de sus familiares afectos, con el que detectar precozmente nuevos tumores y disminuir la morbimortalidad del tumor y de su tratamiento.Esta revisión pretende ser una guía útil para el pediatra. Utilizando como caso guía a una familia, se revisarán los motivos de sospecha de un síndrome de Li-Fraumeni, su diagnóstico clínico y genético, y el protocolo de seguimiento de los familiares portadores de la misma mutación

Pediatric cancer is rare. It is estimated that more than 10-15 % of tumors are secondary to a pathogenic variant in a cancer predisposition gene.More than 100 cancer predisposition genes and their association with syndromes or isolated tumors have been identified. Li-Fraumeni syndrome is one of those who have been most widely described.Patients with this syndrome present a high risk of developing one or more tumors. Its knowledge allows to establish a follow-up protocol for the patient and affected family members, so as to detect new tumors in an early manner and reduce tumor- and treatment-related morbidity and mortality.The objective of this review is to offer useful guidelines for pediatricians. Based on a family case, reasons for Li-Fraumeni syndrome suspicion, clinical and genetic diagnosis, and the follow-up protocol of family members who carry the same mutation will be reviewed.

Estudios clínicos y genéticos en tres miembros de una familia afectados con adenomas hipofisarios aislados con prolactinomas homogéneos / Clinical and genetic studies of a three-member familial isolated pituitary adenoma with homogeneous prolactinomas

La mayoría de los adenomas hipofisarios son esporádicos, pero un 3-5% puede ocurrir en un contexto familiar y hereditario. Este es el caso de la neoplasia endocrina múltiple de tipo 1 (NEM1), complejo de Carney (CNC) y adenomas hipofisarios aislados familiares (FIPA). El FIPA es una condición infrecuente, que ocurre en un contexto familiar, no asociada a NEM t ipo1 ni CNC. Los FIPA pueden ser homogéneos (todos los adenomas tienen el mismo fenotipo) o heterogéneos (diferente fenotipo tumoral). Describimos una familia congolesa en la que dos hermanas y una prima fueron diagnosticadas a los 29, 32 y 40 años, respectivamente, con un prolactinoma (FIPA homogéneo). Las pacientes presentaron macroadenomas no invasivos al momento del diagnóstico, con buena respuesta biológica y tumoral al tratamiento con cabergolina hasta una dosis máxima de 1.5 mg/semanal. De las dos hermanas, una cursó un embarazo sin complicaciones. Durante el seguimiento de 12 años, ninguna de ellas presentó elementos clínicos o biológicos compatibles con NEM1 o CNC, por lo que dichos genes no se estudiaron. El análisis genético en dos de las pacientes permitió descartar la posibilidad de una mutación germinal del gen aryl hydrocarbon receptor interacting protein (AIP). Se considera que el 80% de los pacientes con FIPA no presentan mutación del gen AIP, por lo que se requieren futuros estudios en este tipo de familias, para poder determinar otros genes afectados involucrados en su fisiopatología.

Most pituitary adenomas are sporadic, but 3-5% can occur in a family and hereditary context. This is the case of multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC) and familial isolated pituitary adenomas (FIPA). FIPA is an infrequent condition that occurs in a family context, not associated with MEN type1 or CNC. FIPA kindred can be homogeneous (all adenomas affected in the family having the same tumor phenotype) or heterogeneous (different tumor phenotypes in the affected members). We describe a Congolese family in which two sisters and a cousin were diagnosed with a prolactinoma (homogenous FIPA) at the ages of 29, 32 and 40 years, respectively. The patients presented with macroadenomas at the time of diagnosis, non-invasive tumors and good biological response to cabergoline treatment (maximum dose of 1.5 mg/weekly). Of these two sisters, one went through a pregnancy without complications. Because no MEN1 and CNC clinical and biochemical features were detected during the 12-year follow-up, these genes were not investigated. The genetic analysis of the aryl hydrocarbon receptor interacting protein (AIP) was normal. As nearly 80% of patients with FIPA do not have a mutation in the AIP gene, future studies in these families are required to identify other affected genes involved in their physiopathology.

Rastreio de câncer na prática clínica: recomendações para a população de risco habitual / Cancer screening in clinical practice: recommendations for average risk population

Objetivo: Compilar as evidências da literatura e as recomendações das principais sociedades médicas mundiais para o rastreamento populacional de câncer, contextualizando com a relevância epidemiológica de cada subtipo da doença. Métodos: Trata-se de revisão narrativa da literatura, realizada por levantamento na base de dados PubMed® e consulta aos posicionamentos de instituições governamentais e sociedades médicas nas áreas específicas. Resultados: O rastreamento populacional sistemático foi recomendado apenas para as neoplasias de mama, colo do útero e colorretal, utilizando-se métodos, idade e periodicidade específicos. O rastreio do câncer de próstata mostrou-se controverso, e o pulmonar e o hepático recomendados apenas em tabagistas com alta carga tabágica e cirróticos, respectivamente. Não houve evidência para se recomendar atualmente o rastreamento sistemático da população geral para as neoplasias de pele, tireoide, esôfago, estômago, pâncreas, ovário, endométrio, bexiga, rins, dentre outras. Conclusão: O exame periódico de saúde do paciente saudável abrangeu a prevenção e o rastreamento do câncer para redução de morbidade e mortalidade pela doença, e a estratificação das evidências atuais teve o potencial de melhorar o direcionamento dos esforços, aumentando a cobertura, havendo maior benefício e reduzindo riscos e custos de exames desnecessários.

Objective: To gather evidence from the literature, and recommendations of the main medical societies worldwide for the population screening of cancer, contextualizing with the epidemiological relevance of each subtype of the disease. Methods: This is a narrative review of the literature, carried out through research on PubMed® database, and consultation to the governmental institutions and medical societies' opinions in specific areas. Results: Systematic population screening was recommended only for breast, cervix and colorectal cancers, using specific methods, age and periodicity. Prostate cancer screening showed to be controversial, and pulmonary and hepatic screening are recommended only in heavy smokers and cirrhotic patients, respectively. Currently, there is no evidence to recommend the screening of the general population for neoplasms of skin, thyroid, esophagus, stomach, pancreas, ovary, endometrium, bladder, and kidneys. Conclusion: The periodic health screening of the healthy patient covered the prevention and screening for cancer to reduce morbidity and mortality from the disease; the stratification of current evidence has the potential to improve the direction of efforts, broadening coverage, with more benefit, and reducing risks and costs of unnecessary tests.

Cáncer gástrico hereditario: indicaciones de estudio genético ¿cuando y a quiénes? / Hereditary gastric cancer: indications of genetic study: when and to whom?

Resumen El objetivo de esta revisión es realizar una actualización de los conocimientos actuales en cáncer gástrico hereditario, especialmente enfocado a que pacientes tienen indicación de estudio genético y su manejo clínico. En un 5-10% de los cánceres gástricos existe un patrón familiar. Los cánceres hereditarios, a diferencia de los esporádicos, se asocian a mutaciones germinales en un gen específico. En cáncer gástrico hereditario difuso (HDGC), se han identificado mutaciones en genes específicos asociados a la enfermedad (CDH1 y CTNNA1). El síndrome clínico de HDGC se asocia a la aparición a temprana edad, típicamente alrededor de los 40 años de múltiples focos de cáncer gástrico (CG) de tipo difuso, frecuentemente con células en anillo de sello y la aparición de cáncer de mama de tipo lobulillar. De los pacientes que cumplen los criterios clínicos de HDGC, el 20-50% presenta una mutación del gen CDH1. La presencia de una mutación confiere un riesgo de aparición de CG difuso de 67-70% para hombres y de 56-83% para mujeres; y un riesgo de 42% de cáncer de mama a lo largo de la vida del paciente. Se consideran actualmente como indicaciones para asesoría y estudio genético; la presencia de 2 o más familiares con CG, uno confirmado difuso, independiente de la edad; y en segundo lugar individuos con CG menores de 40 años de edad, sin historia familiar previa. Dentro del manejo de es estos pacientes es clave un equipo multidisciplinario y las principales alternativas de manejo son el seguimiento endoscópico y la gastrectomía profiláctica. Así como se ha avanzado en definir el mejor manejo clínico de estos pacientes, esta patología también representa una área de importante interés en investigación.

The aim is to update the current knowledge in hereditary gastric cancer, especially the current indications for genetic testing and its clinical management. In 5-10% of gastric cancers there is a familiar pattern. Hereditary cancers, unlike sporadic cancers, are associated with germline mutations in a specific gene. In hereditary diffuse gastric cancer (HDGC), mutations have been identified in specific genes associated with the disease (CDH1 y CTNNA1). The clinical syndrome of HDGC is associated with the appearance at an early age, typically around 40 years, of multiple foci of diffuse gastric cancer (GC), frequently with signet ring cells and the appearance of lobular type breast cancer. Twenty to fifty percent of patients who meet the clinical criteria for HDGC have a mutation in the CDH1 gene. The presence of a mutation confers a risk of diffuse CG of 67-70% for men and 56-83% for women; and a 42% risk of breast cancer throughout the life of the patient. The main current indications for genetic counseling and study are the presence of 2 or more relatives with CG, one confirmed diffuse, regardless of age; and individuals with CG less than 40 years of age, without previous family history. A multidisciplinary team is key and the main management alternatives are endoscopic follow-up and prophylactic gastrectomy. Just as there has been progress in defining the best clinical management of these patients, this pathology also represents an area of important research interest.

Tricoepitelioma múltiple familiar: a propósito de un caso / Familial multiple trichoepithelioma: a case report

El Tricoepitelioma Múltiple Familiar (TMF) constituye una rara enfermedad autosómica dominante, se caracteriza por la aparición de múltiples pápulas color piel, monomorfas, simétricas, ubicadas en la región central de la cara. El diagnóstico es histopatológico, donde se encuentran tricoepiteliomas, los cuales son neoplasias anexiales benignas que se originan en los folículos pilosos. La condición es de comportamiento indolente, pero con una importante repercusión estética y de difícil manejo. Al ser esta una entidad poco frecuente, el objetivo de este artículo es actualizar los aspectos más relevantes de esta enfermedad. Se presenta el caso de una paciente de 23 años con lesiones faciales típicas en quien se confirmó el diagnostico de TMF

Familial Multiple Trichoepithelioma (FMT) is a rare autosomal dominant disease, characte-rized by the appearance of multiple papules of skin color, monomorphic, symmetrical and located in the central region of the face. The diagnosis is based on histopathological features of trichoepitheliomas, which are benign adnexal neoplasms that originate in the hair follicles. The condition has an indolent behavior but it has an important aesthetic repercussion and it's difficult to treat. As this is a rare entity, the objective of this article is to update the most relevant aspects of this disease. We present the case of a 23 year old patient with typical facial lesions in whom the diagnosis of FMT was confirmed.

Large desmoid tumors in familial adenomatous polyposis: a successful outcome

Desmoid tumors develop from connective tissue, fasciae, and aponeuroses, and may occur in the context of familial adenomatous polyposis or may arise sporadically; also, they may be extra-abdominal, intra-abdominal, or located in the abdominal wall. These benign tumors have a great aggressiveness with a high rate of local recurrence. Familial adenomatous polyposis is an inherited condition with autosomal dominant transmission, and is characterized by the development of multiple colonic and rectal adenomatous polyps, as well as desmoid tumors. We present the case of a 54-year-old woman with germline APC gene mutation, who underwent a total colectomy, subsequently developing two large infiltrative solid intra-abdominal lesions consistent with desmoid tumors. Medical treatment with Cox-2 inhibitors was initiated without result. She was submitted to resection for intestinal obstruction, but developed local recurrence. The lesions were also unresponsive to tamoxifen, and chemotherapy was initiated with dacarbazine plus doxorubicin, switching to vinorelbine plus methotrexate, achieving a good response in all lesions after 12 months. The approach to these intra-abdominal lesions should be progressive, beginning with observation, then a medical approach with non-steroidal anti-inflammatory drugs or with an anti-hormonal agent. Afterwards, if progression is still evident, chemotherapy should be started. Surgery should be reserved for resistance to medical treatment, in palliative situations, or for extra-abdominal or abdominal wall desmoids tumors.

Síndrome de Lynch: aspectos genéticos, clínicos y diagnósticos / Lynch syndrome: genetic, clinical and diagnostic aspects

Esta revisión tiene como objetivo dar a conocer los aspectos genéticos, clínicos y diagnósticos del síndrome de Lynch, además de brindar la información más relevante acerca de la asesoría genética en estos pacientes y las recomendaciones actuales para su seguimiento.

This review aims to present the genetic, clinical and diagnostic aspects of Lynch syndrome, as well as providing the most relevant information about genetic counseling in these patients and the current recommendations for their surveillance.

Carcinoma de ovario en paciente con mutación del gen BRCA1. Diagnóstico tras biopsia de adenopatía cervical, en el contexto de un síndrome paraneoplásico cutáneo / Ovarian carcinoma in a patient with a BRCA1 gene mutation. Diagnosis after biopsy of cervical adenopathy, in the context of a cutaneous paraneoplastic syndrome

RESUMEN El cáncer epitelial de ovario representa uno de los tumores ginecológicos más letales ya que más del 75% de las pacientes son diagnosticadas en estadío avanzado. Aún no se ha demostrado que la realización de pruebas y exámenes pélvicos rutinarios haya reducido la mortalidad, no existiendo actualmente, un cribado eficaz para su diagnóstico precoz. Aunque la sintomatología metastásica extraperitoneal más común es el derrame pleural, las linfadenopatías neoplásicas a nivel supraclavicular aparecen hasta en el 4% de casos, generalmente asociándose a un mal pronóstico. La identificación de una adenopatía supraclavicular se relaciona hasta en un 58-83% de los casos, con el hallazgo de una tumoración maligna. Por otro lado, la dermatomiositis del adulto puede tener un origen paraneoplásico en un 15-25% de las ocasiones, siendo el cáncer de mama y de ovario la etiología más frecuente en la población femenina. Las pacientes portadoras de mutaciones en los genes BRCA 1 y 2 tienen un aumento del riesgo de padecer neoplasias de mama y ovario. En aquellas afectas de un cáncer de ovario y portadoras de una mutación en los genes BRCA, no se debería plantear una cirugía profiláctica de rutina sobre la mama, al menos en los primeros 5 años tras el diagnóstico de la neoplasia ovárica. Presentamos el caso de una paciente portadora de una mutación germinal del gen BRCA 1, que debuta con un cáncer de ovario, tras el estudio de una adenopatía neoplásica de cuello, biopsiada en el contexto de un síndrome paraneoplásico cutáneo.

ABSTRACT Epithelial ovarian cancer represents one of the most lethal gynecological tumors, since more than 75% of affected women are diagnosed at an advanced stage. However, studies have not demonstrated yet that performing routine pelvic exams and tests had reduced mortality in ovarian cancer, and currently there is no effective screening for early diagnosis. The most common extraperitoneal metastatic symptomatology of ovarian cancer is pleural effusion, but there are other, like neoplastic lymphadenopathies at supraclavicular level, described in up to 4% of cases and generally related to a poor prognosis. The identification of a supraclavicular adenopathy is associated with the finding of a malignant tumor in 58-83% of the cases. On the other hand, adult dermatomyositis can have a paraneoplastic origin in 15-25% of patients, being breast and ovarian cancer the most frequent etiology in the female population. Patients with BRCA 1 and 2 genes mutations have an increased risk of breast and ovarian malignancies. In those affected by an ovarian cancer and carriers of a mutation in the BRCA genes, routine prophylactic surgery should not be considered on the breast, at least in the first 5 years after the diagnosis of ovarian neoplasia. We present the case of a patient with a germinal mutation of the BRCA 1 gene, who debuts with an ovarian cancer, after the study of a neoplastic adenopathy of neck, biopsied in the context of a cutaneous paraneoplastic syndrome.

Alterações genômicas no carcinoma adrenocortical de pacientes portadores da Síndrome de Li-Fraumeni / Genomic alterations profile in adrenocortical carcinoma of Li-Fraumeni Syndrome patients

A Síndrome de Li Fraumeni (LFS) tem caráter autossômico dominante associada ao risco aumentado de câncer hereditário. Embora rara no mundo, no Brasil é frequente devido à ocorrência de uma mutação fundadora, a p.R337H TP53. A ocorrência de câncer e a idade de acometimento são variáveis mesmo em portadores da mesma mutação. Pacientes com mutações no gene TP53 podem desenvolver um amplo espectro de tumores, incluindo o carcinoma adrenocortical (ADR). Os mecanismos moleculares envolvidos na carcinogênese adrenocortical assim como os dados epidemiológicos associados a estes tumores são pouco explorados em literatura. Neste estudo, foram coletados e analisados os dados epidemiológicos dos ADR incluindo os efeitos de idade, período e coorte utilizando o banco de dados SEER, o qual reúne dados de 18 registros de câncer de base populacional dos EUA. Foi avaliado o perfil de alterações genômicas (CytoScan HD Array, Affymetrix) em ADR de pacientes com e sem a mutação p.R337H. Foi também comparado o perfil mutacional (sequenciamento do genoma) de três pacientes (tumor e tecido normal de 2 adultos e 1 criança) com ADR portadores da mutação TP53 p.R337H. Entre os casos de ADR diagnosticados nos EUA, aproximadamente 80% ocorreram após a quarta década de vida. Nas análises de sobrevida, houve diferença estatística (p<0,05) para gênero, com uma melhor sobrevida para as mulheres. Pacientes diagnosticados até os 19 anos e com doença localizada apresentaram uma sobrevida maior. A análise genômica em sete casos revelou 644 alterações. Os três casos positivos para a mutação p.R337H apresentaram 175 alterações genômicas (127 ganhos, 27 cnLOH e 21 perdas). Os quatros casos negativos para a mutação apresentaram 469 alterações (326 ganhos, 63 cnLOH e 80 perdas). Apesar do pequeno número amostral, os casos ADR positivos para a mutação TP53 p.R337H apresentaram um baixo nível de instabilidade genômica quando comparados com os casos não mutados. A análise de sequenciamento do genoma revelou alterações em genes previamente associados o ADR (como TP53, CTNNB1 e ATRX). Foram identificadas alterações em cinco genes com potencial associação ao desenvolvimento do ADR: HBB, MSR1, SH3TC2, LSS e ABCA4. Apesar do pequeno número amostral, foram identificados novos genes que podem estar associados ao ADR, no entanto esses achados deverão ser confirmados em estudos conduzidos em um grupo amostral maior (AU)

Li-Fraumeni syndrome (LFS) is an autosomal dominant disease with high risk to develop hereditary tumors. Although LFS is a worldwide rare disorder, in Brazil its incidence is higher due to the occurrence of a founder mutation, TP53 p.R337H. The cancer occurrence and age of onset are variable even considering patients with the same mutation. Patients carrying TP53 mutations can develop a large spectrum of tumors, including the adrenocortical carcinoma (ADR). The main molecular mechanisms and the epidemiological factors associated with these tumors are poorly explored in literature. In this study, epidemiological data of ADR were collected and analyzed, including the effects of age, period and cohort. The SEER database, which collects and publishes cancer incidence and survival data from 18 cancer registries from the USA, was used for this analysis. The genomic profile (CytoScan HD Array, Affymetrix) of ADR positive or negative for TP53 p.R337H was also investigated. Furthermore, the mutational profile (Whole Genome Sequencing- WGS) of three ADR patients (normal and tumor samples - 2 adults and 1 pediatric case), all of them positive for TP53 p.R337H mutation, were analyzed. Approximately 80% of the ADR cases diagnosed in the USA developed after the fourth decade of life. In the survival analyses, a statistical difference (p <0.05) was observed for gender, with women showing better survival. Patients diagnosed up to the age of 19 and with localized disease presented better survival. The genomic analysis of seven cases revealed 644 genomic alterations. The three TP53 p.R337H positive cases showed 175 genomic alterations (127 gains, 27 cnLOH and 21 losses). The four negative mutated cases presented 469 alterations (369 gains, 63 cnLOH and 80 losses). Despite the small set of samples, mutated cases presented lower level of chromosome instability compared to cases not carrying this mutation. The WGS analysis identified alterations in genes previously associated with ADR (as TP53, CTNNB1 and ATRX). In addition, five genes (HBB, MSR1, SH3TC2, LSS and ABCA4) potentially associated with the development of ADR were identified. This study revealed new genes that might be associated with ADR. However, further analysis are necessary in a larger number of samples to confirm our findings (AU)

Urological cancer related to familial syndromes

ABSTRACT Cancer related to hereditary syndromes corresponds to approximately 5-10% of all tumors. Among those from the genitourinary system, many tumors had been identified to be related to genetic syndromes in the last years with the advent of new molecular genetic tests. New entities were described or better characterized, especially in kidney cancer such as hereditary leiomyomatosis renal cell carcinoma (HLRCC), succinate dehydrogenase kidney cancer (SDH-RCC), and more recently BAP1 germline mutation related RCC. Among tumors from the bladder or renal pelvis, some studies had reinforced the role of germline mutations in mismatch repair (MMR) genes, especially in young patients. In prostate adenocarcinoma, besides mutations in BRCA1 and BRCA2 genes that are known to increase the incidence of high-risk cancer in young patients, new studies have shown mutation in other gene such as HOXB13 and also polymorphisms in MYC, MSMB, KLK2 and KLK3 that can be related to hereditary prostate cancer. Finally, tumors from testis that showed an increased in 8 - 10-fold in siblings and 4 - 6-fold in sons of germ cell tumors (TGCT) patients, have been related to alteration in X chromosome. Also genome wide association studies GWAS pointed new genes that can also be related to increase of this susceptibility.

Muir-torre syndrome with different clinical presentations

The presence of sebaceous gland neoplasm and visceral malignancy is a very rare condition

We present two cases of Muir-Torre Syndrome [MTS] with different clinical presentations

The syndrome is associated with high incidence of multiple malignancies in various systems

One patient presented with a sebaceous cyst carcinoma and later with colonic neoplastic polyps while the other, after several colectomies for malignancy, developed a sebaceous cyst neoplasm

MTS is a hereditary disease; therefore, the family members may need to be counseled and screened, as early detection improves the overall prognosis and survival of the affected individual

Interpretation of the updates of NCCN 2017 version 1.0 guideline for colorectal cancer / 中华胃肠外科杂志

The NCCN has recently released its 2017 version 1.0 guideline for colorectal cancer. There are several updates from this new version guideline which are believed to change the current clinical practice. Update one, low-dose aspirin is recommended for patients with colorectal cancer after colectomy for secondary chemoprevention. Update two, biological agents are removed from the neoadjuvant treatment regimen for resectable metastatic colorectal cancer (mCRC). This update is based on lack of evidence to support benefits of biological agents including bevacizumab and cetuximab in the neoadjuvant setting. Both technical criteria and prognostic information should be considered for decision-making. Currently biological agents may not be excluded from the neoadjuvant setting for patients with resectable but poor prognostic disease. Update three, panitumumab and cetuximab combination therapy is only recommended for left-sided tumors in the first line therapy. The location of the primary tumor can be both prognostic and predictive in response to EGFR inhibitors in metastatic colorectal cancer. Cetuximab and panitumumab confer little benefit to patients with metastatic colorectal cancer in the primary tumor originated on the right side. On the other hand, EGFR inhibitors provide significant benefit compared with bevacizumab-containing therapy or chemotherapy alone for patients with left primary tumor. Update four, PD-1 immune checkpoint inhibitors including pembrolizumab or nivolumab are recommended as treatment options in patients with metastatic deficient mismatch repair (dMMR) colorectal cancer in second- or third-line therapy. dMMR tumors contain thousands of mutations, which can encode mutant proteins with the potential to be recognized and targeted by the immune system. It has therefore been hypothesized that dMMR tumors may be sensitive to PD-1 inhibitors.

Cáncer colorrectal hereditario no asociado a poliposis o síndrome de Lynch / Hereditary colorectal cancer not associated with polyposis or Lynch syndrome

El cáncer colorrectal hereditario no asociado a poliposis, también llamado síndrome de Lynch, es reconocido como un síndrome hereditario de patrón autosómico dominante de penetrancia incompleta, en el cual hay mutación en los genes reparadores del ADN. De 2 a 3 % de todos los tumores colorrectales se originan por este síndrome hereditario que predispone a su desarrollo. El síndrome Lynch, el más frecuente de los síndromes genéticos, incrementa, además del riesgo de desarrollar cáncer de colon, el de cáncer metacrónico y otros tipos de cáncer no colorrectal como los de endometrio, de intestino delgado, de uréter o de la pelvis renal. Por lo tanto, es indispensable reconocerlo e identificar a los individuos en riesgo de presentarlo para prevenir, diagnosticar y tratar de manera precoz la aparición de estas neoplasias, y poder disminuir las tasas de morbilidad y mortalidad asociadas

Hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome is recognized as an autosomal dominant hereditary syndrome of incomplete penetrance characterized by mutations in DNA repair genes. It is the most frequent of all the hereditary syndromes, and increases the likelihood of developing colorectal cancer, thus representing 2-3% of all colorectal cancers (CRC). This syndrome predisposes to metachronous (CRC) and other extracolonic cancers, as endometrium, small bowel, ureter and renal pelvis, among others. Therefore, it is necessary to recognize this syndrome and identify individuals with HNPCRC to prevent, diagnose and provide, if possible, early treatment in an effort to decrease its morbidity and mortality

Current applications of molecular pathology in colorectal carcinoma

Molecular pathology is playing an increasingly important role in the treatment and overall management of patients with colorectal carcinoma. Three distinct genetic pathways have been identified that play a role in carcinogenesis: the chromosomal instability pathway, the microsatellite instability pathway, and the CpG island methylator phenotype pathway. Certain genetic mutations, some of which overlap with the aforementioned pathways, can also indicate that a carcinoma patient has a genetic predisposition syndrome, such as familial adenomatous polyposis, Lynch syndrome, and hamartomatous polyposis syndromes. A variety of advanced methods, including next-generation sequencing, are available to test for these and other mutations, such as targetable mutations that may allow tailoring of a treatment regimen to a patient's specific cancer (e.g., KRAS and BRAF mutations). The possible future role of testing circulating tumor cells is also addressed. New mutations and syndromes continue to be discovered, ensuring that our knowledge of colorectal carcinoma and our ability to treat it will advance in the future (AU)

Hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report and implications of early onset

Abstract Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant manifestation of cutaneous and uterine leiomyomas together with renal cancer due to autosomal dominant germline mutations of fumarate hydratase gene. A twenty-year-old female patient presented with type-II segmental piloleiomyoma and increased menstruation due to uterine leiomyomas, with a history of bilateral nephrectomy performed at 13 and 16 years of age for type 2 papillary renal cell carcinoma. This case represents one of the very early onsets of hereditary leiomyomatosis and renal cell carcinoma syndrome. As genetic anticipation for renal cancer is a well-documented entity for HLRCC syndrome, early recognition is crucial for both the patient and her family in order to provide appropriate counseling and initiation of surveillance.

Síndrome de Li-Fraumeni / Li-Fraumeni syndrome

El síndrome de Li-Fraumeni se caracteriza por la aparición de tumores en múltiples órganos, generalmente a temprana edad. Esta condición hereditaria es causada por mutaciones germinales en el gen TP53 , que codifica el gen supresor tumoral p53 . Se presenta el caso de una paciente de 31 años con diagnóstico clínico y molecular de síndrome de Li-Fraumeni, que presentó dos tumores sincrónicos a los 31 años: un leiomiosarcoma de antebrazo y un tumor filoides de mama. Tenía el antecedente de un hijo con diagnóstico de carcinoma cortical suprarrenal a los tres años, que falleció a los cinco años debido a la enfermedad. Además, su abuela y su bisabuela maternas habían fallecido de cáncer gástrico a los 56 y 60 años, respectivamente, y la madre y una hermana de su abuelo materno presentaron cáncer de mama pasados los 60 y los 40 años de edad, respectivamente. Después de una asesoría genética, se ordenó hacer la secuenciación completa y el análisis de duplicaciones y deleciones en el gen TP53 . El estudio molecular en una muestra de ADN proveniente de linfocitos de sangre periférica reveló la mutación germinal c.527G>T (p.Cys176Phe) en el exón 5 del gen, mutación deletérea descrita anteriormente en tejidos tumorales. Hasta donde se sabe, este es el primer caso que se publica en Colombia de síndrome de Li-Fraumeni con diagnóstico molecular confirmado. El diagnóstico y el manejo del síndrome de Li-Fraumeni deben estar a cargo de un equipo multidisciplinario, y debe contarse con asesoría genética para el paciente y sus familiares.

The Li-Fraumeni syndrome is characterized clinically by the appearance of tumors in multiple organs generally at an early age. This hereditary condition is caused by germinal mutations in the TP53 gene, which codifies for the tumoural suppressor gene p53 . We present the case of a patient aged 31 with clinical and molecular diagnosis of Li-Fraumeni syndrome who presented two synchronous tumors: a leiomyosarcoma on the forearm and a phyllodes breast tumour. She had a family history of cancer, including a son diagnosed with a cortical adrenal carcinoma when he was three years old, who died at five from the disease. Furthermore, her maternal grandmother and great-grandmother died of stomach cancer at 56 and 60 years old, respectively, while her other great-grandmother and a great aunt presented with breast cancer at the ages of 60 and 40, respectively. After genetic counseling, complete sequencing and analysis of duplications and deletions in the TP53 gene were ordered prior to diagnosis. The molecular analysis of a DNA sample taken from peripheral blood lymphocytes revealed the germinal mutation c.527G>T (p.Cys176Phe) on exon 5 of the TP53 gene, a deleterious mutation described previously in tumoural tissues. To our knowledge, this is the first published case in Colombia of Li-Fraumeni syndrome with confirmed molecular diagnosis. The diagnosis and management of Li-Fraumeni syndrome should be performed by a multidisciplinary team, and genetic counselling should be offered to patients and their relatives.