The impact of the genetic background in a patient with papillary thyroid cancer and familial adenomatous polyposis

SUMMARY Thyroid cancer is the most common endocrine malignancy, and papillary thyroid carcinoma (PTC) is the main subtype. The cribriform morular variant is a histological phenotype of PTC characterized by its relationship with familial adenomatous polyposis (FAP). Description of the case: We report the genetic assessment of a 20-year-old female patient diagnosed with a cribriform-morular variant of PTC and FAP. We aimed to assess the genetic background of the reported patient, looking for variants that would help us explain the predisposition to tumorigenesis. Genomic DNA was extracted from peripheral blood lymphocytes, and whole exome sequencing was performed. We applied an overrepresentation and gene-set enrichment analysis to look for an accumulation of effects of variants in multiple genes at the genome. We found an overrepresentation of single nucleotide variants (SNVs) in extracellular matrix interactions and cell adhesion genes. Underrepresentation of SNVs in genes related to the regulation of autophagy and cell cycle control was also observed. We hypothesize that the package of alterations of our patient may help to explain why she presented colonic manifestations and thyroid cancer. Our findings suggest that multiple variants with minor impact, when considered together, may be helpful to characterize one particular clinical condition.

Analysis of APC gene variants in a pedigree affected with familial adenomatous polyposis / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pedigree affected with familial adenomatous polyposis (FAP).@*METHODS@#The proband, with recurrence of blood in the stool, was diagnosed with FAP by endoscopy, pathological examination and a family history. She was subjected to next generation sequencing to detect genetic variant. Suspected variant was verified by Sanger sequencing of members from her pedigree.@*RESULTS@#The proband, her mother and brother were found to carry a heterozygous c.532-1G>A variant of the APC gene, which may lead to aberrant splicing of mRNA resulting in a truncated protein, which may lose its normal function and promote the tumorigenesis. Based on the American College of Medical Genetics and Genomics standards and guidelines, c.532-1G>A variant of APC gene was predicted to be pathogenic(PVS1+PP1+PP4+PP5).@*CONCLUSION@#The c.532-1G>A variant of the APC gene probably underlay the pathogenesis of FAP in this pedigree.

Síndrome de Turcot / Turcotꞌs syndrome

RESUMEN Se presenta a una paciente de 27 años de edad, con varios ingresos en el Hospital Provincial Clínico Quirúrgico Docente “José Ramón López Tabrane”, de Matanzas. Por presentar clínica compatible con pólipos de colon, corroborados por videocolonoscopia, diagnosticados en marzo de 2015. Posteriormente reingresa a los 14 meses por convulsiones, al inicio generalizado y luego limitado al hemicuerpo derecho, cefalea universal y vómitos. Falleció a los 23 días de su ingreso, en los antecedentes patológicos familiares destaca madre fallecida a los 52 años por cáncer de colon y hermana a los 21 años por neoplasia maligna colorectal (AU).

ABSTRACT The case of a female patient, aged 27 years is presented. She was in-patient in the Teaching Clinical Surgical Provincial Hospital “José Ramón López Tabrane”, of Matanzas for several times presenting clinical characteristics compatible polyps in the colon, corroborated by video colonoscopy, and diagnosed in March 2015. She was readmitted 14 months later because of convulsions, generalized firstly and lately limited to the right side of the body, universal headache and vomits. She died 23 days after the admittance. The family history shows that her mother died when she was 52, due to colon cancer and her sister died at twenty one due to colorectal malignant neoplasia (AU).

Adenomatous polyposis coli gene large deletions in Iranian patients with familial adenomatous polyposis.

Context: Familial adenomatous polyposis (FAP) is one type of hereditary colon cancer with a large number of precancerous polyps that initiation to growth in childhood and adolescent. Mutation in adenomatous polyposis coli (APC) gene is the cause of FAP. Aims: The aim of the current study was to standardize multiplex ligation probe amplification (MLPA) method in screening of APC large deletions for the first time in Iranian patients with FAP. Subjects and Methods: Deoxyribonucleic acid was extracted from 34 FAP patients by saluting out method. All patients were screened for APC large deletions whit MLPA and for the positive results, respective region was investigated by polymerase chain reaction sequencing. All genetic alterations were doubled checked in two separated rounds of MLPA. Results: The detection rate of large fragment deletions in APC was 5.8% (2/34). Both of the Iranian patients had deletion in the middle and the end of exon 15, however, comparing of clinical features between patient with the large deletion and patients without deletion did not show any significant difference in each variable including, age at diagnosis, signs of disease and poly type. Conclusions: It seems that exon 15 of APC gene is probably the hotspot region in Iranian FAP patients. Association of genotype/phenotype is well known in FAP patients, but in this study statistical analyses did not show a significant difference in each considerable factor between patients with and without large deletions. It seems better to consider MLPA as an initial step to screening APC mutations.

unique profile of adenomatous polyposis coli gene mutations in iranian patients suffering sporadic colorectal cancer

Colorectal cancer [CRC] is one of the most common and aggressive cancers worldwide. The majority of CRC cases are sporadic that caused by somatic mutations. The Adenomatous Polyposis Coli [APC; OMIM 611731] is a tumor suppressor gene of Wnt pathway and is frequently mutated in CRC cases. This study was designed to investigate the spectrum of APC gene mutations in Iranian patients with sporadic colorectal cancer. In this descriptive study, Tumor and normal tissue samples were obtained from thirty randomly selected and unrelated sporadic CRC patients. We examined the hotspot region of the APC gene in all patients. Our mutation detection method was direct DNA sequencing. We found a total of 8 different APC mutations, including two nonsense mutations [c.4099C>T and c.4348C>T], two missense mutations [c.3236C>G and c.3527C>T] and four frame shift mutations [c.2804dupA, c.4317delT, c.4464_4471delATTACATT and c.4468_4469dupCA]. The c.3236C>G and c.4468_4469dupCA are novel mutations. The overall frequency of APC mutation was 26.7% [8 of 30 patients]. This mutation rate is lower in comparison with previous studies from other countries. The findings of present study demonstrate a different APC mutation spectrum in CRC patients of Iranian origin compared with other populations

Mutación homocigota en la línea germinal del gen MUTYH en una paciente chilena con poliposis adenomatosa familiar / Homozygous germline mutation in MUTYH gene in familial adenomatous polyposis

Recently, MUTYH mutations have been reported to predispose to the development of polyposis. However, polyposis caused by mutations in MUTYH has been characterized as an autosomal recessive hereditary disease, different from the autosomal dominant pattern observed in polyposis caused by APC mutations. We report a 41-year-old female consulting for anemia. Colonoscopy detected multiple sessile polyps and a cecal carcinoma. The patient was operated and in the surgical piece, the tumor invaded serosa and there was lymph node involvement. Approximately 100 polyps were found. The patient received 5-fluorouracil, as adjuvant therapy. The patient had a sister (of a total of 12 brothers) with a colorectal carcinoma. The genetic study identified a homozygous mutation of the MUTYH gene, called c.340T > C, that produces an amino acid change of tyrosine for histidine called p.Y114H. The sister with colorectal cancer was a heterozygous carrier of this mutation.

Síndrome de Turcot: relato de caso e achados da imunoistoquímica / Turcot's syndrome: case report and immunohistochemical findings

A síndrome da polipose intestinal associada a tumor cerebral também é conhecida como síndrome de Turcot. Relata-se o caso de um paciente de 65 anos portador de polipose colônica hereditária e que desenvolveu sinais e sintomas neurológicos devido a glioblastoma multiforme cerebral. Destacam-se os achados imunoistoquímicos da lesão cerebral.

Intestinal polyposis syndrome associated with brain tumor, also known as Turcot's syndrome. We report a patient of 65 years old with hereditary colonic polyposis and developed neurological signs and symptoms due glioblastoma multiforme. We highlight the immunohistochemical findings of brain injury.

Caracterización clínica y genética de las poliposis intestinales hereditarias / Clinics and genetic characteristics in hereditary colon polyposis

Se denomina pólipo intestinal a una lesión visible elevada o tumor que se proyecta desde la superficie epitelial al lumen visceral. En relación al número, presencia de antecedentes familiares, manifestaciones extraintestinales y estudios genéticos es que se constituyen diversas poliposis intestinales. Si bien, las poliposis intestinales se manifiestan en general en la edad adulta, existen manifestaciones que pueden hacer sospechar la presencia de un síndrome poliposico hereditario en la infancia. Además en una proporción considerable estas poliposis presentan manifestaciones extraintestinales, tanto benignas como tumores en otros órganos. Es por esto, que una alta tasa de sospecha, en particular frente a pacientes con antecedentes familiares, puede conducir a un diagnóstico y tratamiento oportuno, además de considerar a la familia como potenciales pacientes e ingresar al grupo familiar a un registro de tumores hereditarios. Diversas técnicas de biología molecular han permitido la identificación de las mutaciones que son heredadas en estas enfermedades, permitiendo realizar conductas preventivas al saber el riesgo de cada persona en una familia afectada. El objetivo de esta revisión, es caracterizar las distintas poliposis intestinales, en cuanto a sus manifestaciones clínicas, clasificaciones, estudio genético y enfrentamiento multidisciplinario.

Polyps are solid or tumoral elevated lesions that arise from the intestinal epithelium so that they become visible in the intestinal epithelium so that they become visible in the intestinal lumen. Information regarding familial history, number, extraintestinal manifestations and genetic studies of polyps, assemble different types of intestinal polyposis. Generally, clinical manifestations occur in adult patients, although in children there are several signs that should make the physician suspect a hereditary polyposis syndrome. In addition it is important to know extraintestinal manifestations which are mostly benign but tumors may be present in other organs too. Bearing in mind that high clínical suspicion of hereditary polyposis syndrome especially if familial history is present, provides early diagnosis and appropriate treatment for the patient and eventually for the family members that could be affected, entering that family in a registry of hereditary tumors. Molecular biology has created different techniques to identify the presence of hereditary mutations that are specific for intestinal polyposis. Acknowledgment of these mutations establishes risks groups allowing adequate prevention strategies. The objective of this revision is to characterize and different types of intestinal polyposis, according to clinical manifestations, classification, genetic study and multidisciplinary approach.

Poliposis adenomatosa familiar: presentación de un caso y revisión de la literatura / Familial adenomatous polyposis: case report and literature review

Colorectal cancer (CRC) is a genetic and epigenetic disease. Approximately one third of the CRC has an hereditary component. Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition that has its origins in the line of APC gene mutation, which occurs with a frequency of approximately 1:10,000 live births. We report a case of a patient of 25 years with FAP. This review provides current knowledge on the broad clinical spectrum of this disease, also referring to the optimal method of diagnosis, differential diagnosis and management.

El cáncer colorrectal (CCR) es una enfermedad genética y epigenética. Aproximadamente un tercio del CCR tiene un componente hereditario. La poliposis adenomatosa familiar (PAF) es una condición hereditaria autosómica dominante que tiene su origen en la línea de mutación del gen APC, el cual ocurre con una frecuencia aproximada de 1:10.000 nacidos vivos. Se reporta el caso de una paciente de 25 años con PAF. La presente revisión proporciona los conocimientos actuales sobre el amplio espectro clínico de esta enfermedad, refiriéndose también al método óptimo de diagnóstico, diagnóstico diferencial y su manejo.

Cáncer hereditario de colon: Aportes del diagnóstico genético molecular / Molecular and genetic studies for hereditary colon cancer in two patients and their families

Background: About 30 percent of cases of colon cancer (CC) have a family history of CC, and only 5 percent are hereditary forms. Hereditary forms have an increased risk of CC and other tumors. Aim: To report the molecular and genetic study in two families with hereditary CC. Material and Methods: Molecular analysis of the adenomatous polyposis coli (APC) gene of familial adenomatous polyposis (FAP), was done in a patient with multiple benign polyps and his children. Molecular analysis was performed for MLH1 gene mutation of hereditary non-polyposis colon cancer (HNPCC) in an asymptomatic patient with family history of multiple cancers and his mother with a confrmed mutation in the MLH1 gene. Results: The patient with FAP had an insertion of 17 base pairs in exon 9 of the APC gene and two of his children had the same mutation. The patient with history of HNPCC did not have the family mutation on MLH1. Conclusions: In the case of FAP, molecular study was performed in his children since manifestations in carriers of the mutation may begin in childhood. If the second patient would have had the mutation, the study of his children could have been postponed until the age of 18, when the risk for CC is increased.

[ study on mutations in hotspot sites of exon 15 of apc gene in familial adenomatous polyposis patients and their relatives in Iran Khuzestan province]

The aim of this study was to estimate mutation frequency in exon 15 of APC gene in Khuzestan FAP patients and their relatives. We have analyzed 12 patients and 11 individual among their relatives. DNA extraction from EDTA treated whole blood was performed by routine salting out method. Three hotspot regions of axon 15 from APC gene were amplified separately with three primer pairs by PCR and the fragments have been analyzed for putative mutations by single stranded conformation polymorphism [SSCP] according to standard protocols and subsequent sequencing. We found aberrant bands by SSCP method in seven patients and two related members, that compared with data from sequence analysis yield following five patients [24 to 35 years old] carried novel frame shift mutation [3195-3196insT] leading to premature protein. In two patients whose SSCP were positive, no mutations in their two relatives were identified. In this report we have used SSCP as pre-screening method for mutation analysis of our samples and found putative mutations in nine of them. After sequencing, only in five samples "true mutation" could be confirmed It is intersting that approximately 50% of Khuzestan FAP patients carry mutation in axon 15 of APC gene. Noteworthly, in this work only a small region of the APC gene was subject of the investigation and interestingly, all patients showed the same new mutation. Studies with large number of samples can help us to know, whether this new mutation is predominant or even exclusive within Khuzestan FAP patients.

Bases genéticas del cáncer colorrectal hereditario / Genetic basis of hereditary colorectal cancer

Las variantes hereditarias representan aproximadamente el 5 por ciento de los casos de cáncer colorrectal. Las formas más frecuentes son la Poliposis Adenomatosa Familiar (PAF) y el Cáncer Colorrectal Hereditario No Polipósico (HNPCC) o Síndrome de Lynch. Esta revisión analiza los genes relacionados, sus mecanismos moleculares y la importancia de los estudios genéticos en el manejo de los pacientes y las familias comprometidas. En la PAl; diferentes mutaciones del gen APC son responsables del desarrollo de cientos de pólipos en colon y recto, y sus manifestaciones extracolónicas como tumores desmoides, pólipos gástricos y duodenales. En el HNPCC, mutaciones principalmente en los genes MLH1, MSH2 Y MSH6 son la causa de tumores en el colon, endometrio, ovario, estómago, urotelio e intestino delgado.

Hereditary variants account for approximately 5 percent of colorectal cancers. Within them, Familiar Adenomatous Polyposis (FAP) and Hereditary Non Polyposis Colorectal Cancer (HNPCC) or Lynch's syndrome are the most frequent. The underlyinggenes and their molecular pathways are reviewed, and the importance of genetic testing for the clinical management of patients and their families is analyzed. In FARmutations on the APC gene are responsible for the development of hundreds of colorectal polyps and extracolonic manifestations such as desmoid tumors, gastric and duodenal polyps. In HNPCC, mutations on MLH1, MSH2 and MSH6 genes are the most frequent causes of colonic, endometrial, ovarian, gastric, urothelial and small bowel tumors.

Cáncer colorrectal hereditario: análisis molecular de los genes APC y MLH1 / Hereditary colorectal cancer: Molecular analysis of APC and MLH1 genes

Background: Among colorectal cancer hereditary variants, two syndromes show a predisposition to the disease based on germline mutations: Familial Adenomatous Polyposis (FAP) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Aim: To screen mutations in FAP and HNPCC families in Chile. Materials and Methods: Two FAP and one HNPCC families were studied. The APC gene (for FAP patients) and the MLH1 gene (for HNPCC patients), were screened for mutations on genomic DNA. The molecular analysis was performed through polymerase chain reaction, Single Strand Conformer Polymorphism (SSCP) and DNA sequencing. Mutations were defined as changes in the DNA sequence leading into a stop codon and a truncated protein. Results: In the two FAP families the analysis revealed a mutation consisting in the deletion of five nucleotides named c.3927_3931delAAAGA. The genetic study of the HNPCC family demonstrated the insertion of one adenine in codon 168 of exon 6, named c.504insA. Discussion: Germ-line mutations were identified in the three families. The relevance of these studies in a better knowledge of cancer susceptibility, and the possibility of identifying in relatives in risk by molecular diagnosis.

Cáncer colorrectal no polipóideo (Síndrome de Lynch) / Non poliposys colorectal cancer (Lynch syndrome)

Cancer of the large intestine (colon and rectum) is the most frequent neoplasm of the GL tract. The clinical importance of this disease is based both on its frequent occurrence and the fact that its early detection may lead to a substantial imporvement in autcome. The step wise progression from normal mucosa to cancer is better understood in the colon than in any other GI organ. Adenomas which begin in flat mucosa, are the earliest histologically identifiable neoplastic lesions. patients with adenomatous polyps are at greater risk for subsequent development of cancer...The early detection of this complaint, including genetic tests and diagnostic features, treatment and postoperative follow-ups, are described in the article.

Poliposis familiar: Alternativas terapéuticas y estudio de los familiares / Treatment of familial adenomatous polyposis and family screening

Background: To reduce the mortality associated to Familial Adenomatous Polyposis (FAP), screening of close relatives of patients with the disease is crucial. Aim: To analyze the results of the surgical treatment of patients with FAP, and to evaluate the family screening. Patients and Methods: Clinical records of patients operated in our institution since 1977, were reviewed analyzing surgical and pathological results, and follow up. In their family members, we evaluated and analyzed the performance of screening tests, former surgeries, history of disease-related cancer and mortality, all due to FAP. Results: Between January 1977 and August 2002, 15 patients were operated on. Of these, only 33 percent consulted on the setting of a familial screening. A proctocolectomy and terminal ileostomy was performed in 27 percent of patients; 20 percent had a proctocolectomy and ileal pouch, and 53 percent underwent a total colectomy with ileo-rectal anastomosis. Morbidity and mortality were 7 percent and 0 percent, respectively. Twenty percent had a colorectal cancer. During a median of 68 months follow-up, the disease-related survival was 92 percent; no cancer of the rectal stump was detected. Of the 122 family members identified, only 33 percent with clear indication of screening underwent a colonoscopy. Twenty-nine percent had a confirmed FAP and were operated: in 61 percent of them a colorectal cancer was found, and 91 percent of these died. Conclusions: The results of the surgical treatment of FAP are satisfactory. Nevertheless, family screening should be improved to reduce the high rates of mortality revealed in the study of other family members (Rev Méd Chile 2005; 133: 1043-50).

Hereditary Colorectal Cancer / 대한소화기학회지

Hereditary syndromes cause approximately 5 to 15% of overall colorectal cancer (CRC) cases. Hereditary CRC is conventionally divided into two major categories: hereditary non-polyposis colorectal cancer (HNPCC) and those related to polyposis syndromes including familial adenomatous polyposis (FAP), Peutz-Jegher syndrome (PJS), and juvenile polyposis (JP). The screening for the cancer and methods of treatment applied to patients with hereditary CRC are quite different from those applied to the general population. The genes responsible for these syndromes has recently identified, as a result, genetic testing has become the most important determining factor in clinical decisions. Germ-line mutation of the APC gene induces FAP, an autosomal dominant disorder, characterized by the development of hundreds to thousands of colonic adenomas. CRC appears in almost all affected individuals by the time they are 50 years of age. An affected individual should undergo colectomy by his/her late teens. Furthermore, according to the findings of genetic testing, at-risk family members also need endoscopic surveillance and surgery. Recently, a mutation on the MYH gene is increasingly being investigated in patients with multiple polyps, and autosomal recessive MYH polyposis is considered to be a new category of polyposis. More common than FAP, HNPCC is caused by germ-line mutations in DNA mismatch repair genes, mainly MLH1 and MSH2. Although there is no polyposis, polyps seem to be more villous and dysplastic and appear to grow rapidly into CRCs. The aggregate lifetime risk of CRC is about 80% for mutation carriers. The risk for other types of cancer, such as endometrial, ovarian, small bowel, and transitional cell cancer, is also increased. The Amsterdam criteria and Bethesda guidelines are the best-known tools for diagnosis and genetic testing, and colectomy followed by endoscopic follow-up is the standard treatment. PJS and JP are reported to be characterized by hamartomatous polyps throughout the GI tract and germ-line mutations in the STK11 gene (PJS) and the DPC4/BMPR1A gene (JP).

Poliposis adenomatosa familiar: presentación de un caso clínico: Hospital Universitario de Caracas / Famylial adenomatous polyposis: presentation of a case clinical: Hospital Universitario of Caracas

Se presenta caso de un paciente masculino de 20 años de edad, que ingrersó al Hospital Universitario de Caracas con diarrea crónica de 3 años de evolución, en quien la colonoscopia evidenció colon tapizado de cientos de pólipos de superficie lisa, diferentes tamaños. Se realizó endoscopia digestiva superior encontrando pólipos a nivel de segunda porción de duodeno no en la papila y en la enteroscopia, pólipos en duodeno y yeyuno. Tenía antecedente de madre con diagnóstico de adenomatosis familiar y Cáncer de Colon diagnosticado en el año 2002. La póliposis adenomatosa familiar es un desórden hereditario autosómico dominante caracterizado por la presencia de cientos y miles de pólipos en el colon. Todos los pacientes desarrollan cáncer de colon si no son tratados. Más del 90 por ciento de los casos presentan pólipos gastro-duodenales y el carcinoma de papila es una de las manifestaciones malignas más común en este síndrome

Contribuição à campanha nacional de conscientização sobre o câncer do intestino grosso: a questão da prevenção e do diagnóstico precoce / Contribution to the national campaign of awareness on the cancer of the large bowel: the question of the prevention and the early diagnosis

A interpretação dos resultados decorrentes dos novos conhecimentos médicos, as experiências acumuladas nas últimas seis décadas e suas aplicações práticas em relação ao tratamento e à cura do câncer nos deixaram, como saldos positivos e como maiores prioridades na abordagem daquela doença, em primeiro lugar, a prevenção e, em segundo lugar, o diagnóstico precoce. Se, para algumas neoplasias malignas, o tratamento cirúrgico e as terapêuticas adjuvantes evoluíram como meios para que pudéssemos modificar o perfil do câncer e evitar maior número de mortes, para outros tipos, tais como o câncer do intestino grosso e o câncer de mama, entre outros, o mesmo não ocorreu. Assim, os movimentos atuais, baseados nos conhecimentos adquiridos, são motivo para que enderecemos atenção mais para a prevenção do que exclusivamente para a terapêutica. Delinear métodos, definir meios propedêuticos para a população geral e classificar a população de risco para rastreamentos efetivos têm sido considerados prioridades maiores como forma de diminuir o número de pessoas com câncer do intestino grosso e de antecipar o tratamento para os momentos mais iniciais da doença, quando a probabilidade de cura se aproxima de 100por cento.