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1.
Hautarzt ; 72(4): 288-294, 2021 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-33661338

RESUMO

Hereditary tumor syndromes are characterized by a familial occurrence of tumors/cancer. A hereditary tumor syndrome should be suspected if a familial occurrence of cancer is seen and/or persons at younger age are affected. Some of the currently known tumor syndromes are associated with specific skin symptoms that can aid the physician in establishing the correct diagnosis. Examples are fibrofolliculoma in Birt-Hogg-Dubé syndrome, epidermal cysts, sebaceous cysts, neurofibroma in Gardner syndrome and sebaceous neoplasms or keratoacanthoma in Muir-Torre syndrome. If a genetic tumor syndrome is suspected, genetic testing and counselling should be performed in the index patient and is also recommended for family members. Affected patients should be offered regular clinical surveillance by the appropriate medical disciplines. Since curative therapy does not exist so far, preventive screening is of great importance.


Assuntos
Síndrome de Birt-Hogg-Dubé , Síndromes Neoplásicas Hereditárias , Neoplasias das Glândulas Sebáceas , Dermatopatias , Neoplasias Cutâneas , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia
2.
Rev Fac Cien Med Univ Nac Cordoba ; 77(4): 385-386, 2020 12 21.
Artigo em Espanhol | MEDLINE | ID: mdl-33351390

RESUMO

Mr. Editor, The National Comprehensive Cancer Network (NCCN) has determined that when a syndrome of predisposition to cancer is suspected, it is necessary to refer the patient for genetic evaluation because of the implications for diagnosis and management, as well as follow-up in the family (1). The genetic evaluation includes the description of the personal/family history and the request for the corresponding genetic study.


Assuntos
Neoplasias Gastrointestinais , Síndromes Neoplásicas Hereditárias , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética
3.
PLoS Genet ; 16(12): e1009231, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33332384

RESUMO

PURPOSE: Historically, cancer predisposition syndromes (CPSs) were rarely established for children with cancer. This nationwide, population-based study investigated how frequently children with cancer had or were likely to have a CPS. METHODS: Children (0-17 years) in Denmark with newly diagnosed cancer were invited to participate in whole-genome sequencing of germline DNA. Suspicion of CPS was assessed according to Jongmans'/McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) criteria and familial cancer diagnoses were verified using population-based registries. RESULTS: 198 of 235 (84.3%) eligible patients participated, of whom 94/198 (47.5%) carried pathogenic variants (PVs) in a CPS gene or had clinical features indicating CPS. Twenty-nine of 198 (14.6%) patients harbored a CPS, of whom 21/198 (10.6%) harbored a childhood-onset and 9/198 (4.5%) an adult-onset CPS. In addition, 23/198 (11.6%) patients carried a PV associated with biallelic CPS. Seven of the 54 (12.9%) patients carried two or more variants in different CPS genes. Seventy of 198 (35.4%) patients fulfilled the Jongmans' and/or MIPOGG criteria indicating an underlying CPS, including two of the 9 (22.2%) patients with an adult-onset CPS versus 18 of the 21 (85.7%) patients with a childhood-onset CPS (p = 0.0022), eight of the additional 23 (34.8%) patients with a heterozygous PV associated with biallelic CPS, and 42 patients without PVs. Children with a central nervous system (CNS) tumor had family members with CNS tumors more frequently than patients with other cancers (11/44, p = 0.04), but 42 of 44 (95.5%) cases did not have a PV in a CPS gene. CONCLUSION: These results demonstrate the value of systematically screening pediatric cancer patients for CPSs and indicate that a higher proportion of childhood cancers may be linked to predisposing germline variants than previously supposed.


Assuntos
Testes Genéticos/estatística & dados numéricos , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias/epidemiologia , Sequenciamento Completo do Genoma/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Taxa de Mutação , Síndromes Neoplásicas Hereditárias/genética
4.
BMJ Case Rep ; 13(12)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33370972

RESUMO

Juvenile polyposis syndrome (JPS) and hereditary haemorrhagic telangiectasia (HHT) are rare autosomal dominant diseases, where symptoms manifest at childhood. A 32-year-old man with no family history of JPS or HHT with SMAD4 gene mutation who developed signs and symptoms only at the age of 32, when he was an adult. In this article, we highlight the steps taken to diagnose this rare pathology, explain its pathophysiology and management.


Assuntos
Anemia Ferropriva/diagnóstico , Gastrite/diagnóstico , Polipose Intestinal/congênito , Pólipos Intestinais/diagnóstico , Síndromes Neoplásicas Hereditárias/diagnóstico , Telangiectasia Hemorrágica Hereditária/diagnóstico , Adulto , Idade de Início , Anemia Ferropriva/sangue , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/genética , Colo/diagnóstico por imagem , Colo/patologia , Endoscopia Gastrointestinal , Gastrectomia , Mucosa Gástrica/diagnóstico por imagem , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastrite/microbiologia , Gastrite/patologia , Gastrite/cirurgia , Helicobacter heilmannii/isolamento & purificação , Hematínicos/administração & dosagem , Humanos , Hiperplasia , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Polipose Intestinal/complicações , Polipose Intestinal/diagnóstico , Polipose Intestinal/genética , Pólipos Intestinais/genética , Masculino , Mutação , Síndromes Neoplásicas Hereditárias/complicações , Síndromes Neoplásicas Hereditárias/genética , Índice de Gravidade de Doença , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/genética , Tomografia Computadorizada por Raios X
5.
BMC Med Genet ; 21(1): 196, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032550

RESUMO

BACKGROUND: Juvenile polyposis syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple distinct juvenile polyps in the gastrointestinal tract with an increased risk of colorectal cancer. Germline mutations in two genes, SMAD4 and BMPR1A, have been identified to cause JPS. CASE PRESENTATION: Here, we report a germline heterozygous missense variant (c.299G > A) in exon 3 BMPR1A gene in a family with juvenile polyposis. This variant was absent from the population database, and concluded as de novo compared with the parental sequencing. Further sequencing of the proband's children confirmed the segregation of this variant with the disease, while the variant was also predicted to have damaging effect based on online prediction tools. Therefore, this variant was classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. CONCLUSIONS: Germline genetic testing revealed a de novo germline missense variant in BMPR1A gene in a family with juvenile polyposis. Identification of the pathogenic variant facilitates the cancer risk management of at-risk family members, and endoscopic surveillance is recommended for mutation carriers.


Assuntos
Polipose Adenomatosa do Colo/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Mutação em Linhagem Germinativa , Polipose Intestinal/congênito , Mutação de Sentido Incorreto , Síndromes Neoplásicas Hereditárias/genética , Polipose Adenomatosa do Colo/diagnóstico , Adulto , Saúde da Família , Feminino , Testes Genéticos , Heterozigoto , Humanos , Polipose Intestinal/diagnóstico , Polipose Intestinal/genética , Masculino , Síndromes Neoplásicas Hereditárias/diagnóstico , Linhagem , Proteína Smad4/genética
6.
Clin Dermatol ; 38(4): 432-454, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972602

RESUMO

The hereditary nature of some forms of cancer was recognized long ago. Over time, recognition of associated findings led to the delineation of numerous hereditary cancer syndromes. Many of these syndromes also have cutaneous manifestations, the recognition of which can lead to their early identification. Recognition of these syndromes allows vigilant surveillance and preemptive treatment, which can dramatically impact the risks of morbidity and mortality for affected patients. The rise of rapid and accurate genetic testing now allows the early identification of asymptomatic at risk family members so that monitoring can be initiated as early as possible. The dermatologist plays a critical role in early identification of these syndromes and, in many cases, their treatment. This review summarizes many known hereditary cancer syndromes with cutaneous findings, their etiology, identification, evaluation, and management. Importantly, this is an ever evolving topic and new findings and syndromes will continue to be recognized. The dermatologist must be always alert to ensure they are detected.


Assuntos
Síndromes Neoplásicas Hereditárias , Dermatopatias Genéticas , Síndrome do Nevo Basocelular , Síndrome de Birt-Hogg-Dubé , Complexo de Carney , Neoplasias Colorretais Hereditárias sem Polipose , Diagnóstico Precoce , Feminino , Síndrome de Gardner , Testes Genéticos , Síndrome do Hamartoma Múltiplo , Humanos , Masculino , Neoplasia Endócrina Múltipla , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Síndromes Neoplásicas Hereditárias/terapia , Neurofibromatoses , Pele/patologia , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia , Dermatopatias Genéticas/terapia
7.
Clin Dermatol ; 38(4): 467-476, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972605

RESUMO

Basal cell nevus syndrome, also known as Gorlin syndrome, is a hereditary cancer syndrome associated with multiple basal cell carcinomas, congenital defects, and nondermatologic tumors. This disease is autosomal dominant with variable expressivity and is caused by abnormalities in the sonic hedgehog signaling pathway. Management requires a multidisciplinary approach and should include the biopsychosocial needs of patients and their families. Genetic testing is necessary to confirm an unclear diagnosis, evaluate at-risk relatives, and assist with family planning.


Assuntos
Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/terapia , Terapia de Alvo Molecular , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Adulto , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/patologia , Feminino , Testes Genéticos , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Comunicação Interdisciplinar , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/patologia , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Receptor Patched-2/genética , Receptor Patched-2/metabolismo , Equipe de Assistência ao Paciente , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais/genética , Pele/patologia , Adulto Jovem
8.
Rev. senol. patol. mamar. (Ed. impr.) ; 33(3): 81-87, jul.-sept. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-197290

RESUMO

OBJETIVO: Analizar la incidencia de cáncer de mama y de ovario, y las características de dichos tumores en pacientes portadoras de mutaciones BRCA1-2. PACIENTES Y MÉTODOS: Estudio observacional retrospectivo que incluye un total de 111 pacientes con diagnóstico molecular de mutación en genes BRCA1 (56) o BRCA2 (55). RESULTADOS: En el 69,4% de los casos el test genético se realizó tras el diagnóstico oncológico. La incidencia objetivada de cáncer de mama y ovario fue, respectivamente, del 62,2 y el 20,7%. El tipo histológico más frecuente de cáncer de mama fue el ductal infiltrante (89,7%). El 67,7% de los tumores mamarios BRCA1 presentaron un fenotipo triple negativo y el 80% de los BRCA2 mostraron un fenotipo luminal, siendo la diferencia estadísticamente significativa. El 87% de los cánceres de ovario fueron carcinomas serosos de alto grado. El 41,4% de las pacientes se realizó mastectomía profiláctica encontrándose de forma casual lesiones patológicas en el 19,5% de las piezas quirúrgicas. El 41,4% se realizó salpingooforectomía bilateral profiláctica, en cuyas piezas quirúrgicas objetivaron un 6,5% de lesiones patológicas. CONCLUSIONES: La incidencia de cáncer de mama/ovario en las pacientes portadoras de BRCA 1-2 estudiadas es superior a la descrita en la población general, desarrollándose a edades más tempranas. No obstante, el diagnóstico genético de la mutación es, en la mayoría de los casos, secundario al del evento oncológico. Se debe incidir en el diagnóstico precoz de la mutación basado en los antecedentes familiares para instaurar precozmente medidas de cribado y de reducción de riesgo


OBJECTIVE: To analyse the incidence of breast and ovarian cancer, and the characteristics of these tumours, in patients with BRCA1-2 mutations. PATIENTS AND METHODS: Retrospective observational study that included a total of 111 patients with a molecular diagnosis of mutation in BRCA1 (56) and / or BRCA2 (55) genes. RESULTS: In 69.4% of the cases, genetic testing was performed after oncological diagnosis. The incidence of breast and ovarian cancer was 62.2% and 20.7%, respectively. The most frequent histological type of breast cancer was infiltrating ductal (89.7%). A total of 67.7% of breast tumours in BRCA1 patients had a triple negative phenotype and 80% of BRCA2 patients showed a luminal phenotype. Most (87%) ovarian cancers were high grade serous carcinomas. In 41.4% of the patients, prophylactic mastectomy was performed, with a coincidental pathological finding in 19.5% of the surgical specimens. In 41.4% of the patients, prophylactic bilateral salpingo-oophorectomy was performed, with 6.5% of surgical specimens showing pathological lesions. CONCLUSIONS: The incidence of breast/ovarian cancer in patients harbouring BRCA 1-2 mutations is higher than in the general population, and the cancer develops in younger patients. However, the genetic diagnosis of the mutation is usually secondary to that of the oncological event. The early diagnosis of the mutation based on family history should be emphasised in order to initiate early screening and risk-reduction measures


Assuntos
Humanos , Feminino , Genes BRCA1 , Genes BRCA2 , Neoplasias dos Genitais Femininos/epidemiologia , Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Patologia Molecular/métodos , Mutação/genética , Biomarcadores Tumorais/análise , Síndromes Neoplásicas Hereditárias/genética , Estudos Retrospectivos , Epidemiologia Molecular/métodos
9.
Pathologe ; 41(5): 535-549, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32780213

RESUMO

BACKGROUND: Monogenic hereditary tumor syndromes or tumor disposition syndromes (TDS) are based on germline/constitutional mutations in key genes of carcinogenesis. Early onset and a clustering of tumors belonging to a typical spectrum in the personal or family history are indicators for a hereditary form. In particular, rare specific tumors occur relatively frequently in the context of TDS. METHODS: Based on a literature search the current article presents information on which TDS should be considered for differential diagnosis (DD) in the presence of a rare tumor. RESULTS: The identification of a causal germline mutation in the index patient is important for the DD, the evaluation of recurrence risks, and predictive testing of asymptomatic at-risk family members. In TDS with autosomal dominant inheritance, it is often possible to identify several high-risk individuals in the affected families. CONCLUSION: Early detection and correct classification are of high clinical relevance as the patients and persons at risk can often be offered effective preventive procedures (surveillance, prophylactic operations), and in some cases, special therapeutic options exist. TDS are paradigmatic for an extremely successful concept of preventive oncology and personalized medicine. The introduction of new methods of high-throughput sequencing (next generation sequencing) enables a more effective genetic diagnosis, but also poses a challenge for the interpretation of findings and counseling. Referral to multidisciplinary expert centers is useful for care of the families.


Assuntos
Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias , Predisposição Genética para Doença/genética , Testes Genéticos , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética
10.
BMC Med Genet ; 21(1): 141, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611331

RESUMO

BACKGROUND: Lynch syndrome (LS), which is known as a hereditary cancer syndrome, is distinguished by microsatellite instability, represented by the altered number of repetitive sequences in the coding and/or non-coding region. Immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins (e.g., MLH1, MSH2, MSH6, and PMS2) has been recognized as an useful technique for screening of LS. Previous study has shown that the assessment of IHC, however, requires specific caution due to variable staining patterns even without germline mutations in MMR genes. CASE PRESENTATION: A 48-year-old man, who had been treated for anaplastic astrocytoma, was referred to our department for the precise examination of progressing anemia. Whole-body examination revealed two advanced carcinomas in descending colon and stomach. A hypo-vascular mass lesion was detected in liver as well. Pathological diagnosis (on surgical specimens) was poorly differentiated adenocarcinoma in descending colon, moderately differentiated tubular adenocarcinoma in stomach, and liver metastasis, which is possibly from colon. It was suspected that this case would be Turcot's syndrome-type-1 due to its specific family history having two cases of colon cancer within the second relatives. Pathogenic frameshift mutations in codon 618 of MLH1 gene was identified. Immunohistochemical analyses (IHC) demonstrated complete loss of MLH1 immuno-expression as well as of PMS2 except for those in brain tumor. Although frameshift mutation was not found in MSH6 gene, histological expression of MSH6 was patchy in primary colon carcinoma and was completely lost in the metastatic site in liver. MSH6 expression in gastric carcinoma, a coincidental cancer in this case, was intact. An abnormal (C)8 region was identified by the cloned PCR of colon and liver tumors but not from gastric cancer. Frameshift mutation in a (C)8 tract in exon 5 of the MSH6 gene was also detected in liver metastasis. CONCLUSION: This case supports a plausible mechanism, proposed by a previous literature, for the reduced expression of MSH6 in a somatic mutation manner, which might preferentially happen in colon cancer rather than in stomach carcinoma in MLH1/PMS2-deficient type of Turcot's syndrome type 1.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/imunologia , Predisposição Genética para Doença , Neoplasias Hepáticas/secundário , Mutação/genética , Síndromes Neoplásicas Hereditárias/genética , Adulto , Sequência de Bases , Reparo de Erro de Pareamento de DNA/genética , Feminino , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Linhagem
12.
Am J Surg Pathol ; 44(9): 1204-1212, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32520759

RESUMO

Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an increased risk of developing Laurén's diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet-ring cell carcinoma (SRCC) in situ (SRCC-pTis) has been reported as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant), and a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been sufficiently clarified. Here, we examined gastrectomy samples from 6 Japanese HDGC patients with CDH1 germline mutation, belonging to 4 families, and analyzed SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the 6 samples, SRCC-pT1a accounted for 225 lesions (range: 8 to 107, mean 45.7 lesions per patient), while 46 foci were of SRCC-pTis (range: 1 to 15, mean 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. Histologically, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. Immunohistochemically, E-cadherin expression was lost in SRCC-pTis (27/28, 96.4%) more frequently than in SRCC-pT1a (95/197, 48.2%; P<0.001). To elucidate the specificity of SRCC-pTis for HDGC, 60 samples (range: 0.12 to 1.49 m, total 28.8 m of mucosal length) from gastric cancer cases were analyzed as controls, in which no SRCC-pTis were identified. Our results indicate that SRCC-pTis is a distinct histologic feature with high specificity for HDGC cases with CDH1 germline mutations.


Assuntos
Carcinoma de Células em Anel de Sinete/patologia , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Gástricas/patologia , Adulto , Antígenos CD/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Caderinas/genética , Carcinoma de Células em Anel de Sinete/química , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/cirurgia , Análise Mutacional de DNA , Feminino , Gastrectomia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Hereditariedade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/cirurgia , Fenótipo , Estudos Retrospectivos , Neoplasias Gástricas/química , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirurgia
15.
Jpn J Clin Oncol ; 50(7): 826-829, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32378721

RESUMO

Hereditary mixed polyposis syndrome (HMPS) is a rare autosomal dominant disorder characterized by a mixture of typical and/or atypical juvenile polyps, adenomas and hyperplastic polyps, resulting in an increased risk of colorectal cancer. In HMPS, four different germline BMPR1A variants from five unrelated families have been reported. This study is the first to report HMPS within a Japanese family. The proband underwent repeated colonoscopic polypectomies over a 5-year period, since the age of 67. Histological examination of these resected polyps revealed adenomas, juvenile-like polyps and hyperplastic changes. Genetic testing was conducted to identify the causative genes for hereditary gastrointestinal cancer syndromes, including BMPR1A. We detected a germline variant, c.72_73delGA, in BMPR1A. The proband's elder brother, younger sister and nephew have also undergone repeated colonoscopic polypectomies at other clinics. His sister and nephew underwent genetic testing, and the same BMPR1A variant was identified.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Células Germinativas/fisiologia , Síndromes Neoplásicas Hereditárias/genética , Proteína Smad4/genética , Idoso , Feminino , Humanos , Japão , Masculino , Proteína Smad4/metabolismo
16.
Breast Cancer Res ; 22(1): 43, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393398

RESUMO

Next-generation sequencing of Sri Lankan families with inherited cancer syndromes resulted in the identification of five BRCA2 variants of unknown clinical significance. Interpreting such variants poses significant challenges for both clinicians and patients. Using a mouse embryonic stem cell-based functional assay, we found I785V, N830D, and K2077N to be functionally indistinguishable from wild-type BRCA2. Specific but mild sensitivity to olaparib and reduction in homologous recombination (HR) efficiency suggest partial loss of function of the A262T variant. This variant is located in the N-terminal DNA binding domain of BRCA2 that can facilitate HR by binding to dsDNA/ssDNA junctions. P3039P is clearly pathogenic because of premature protein truncation caused by exon 23 skipping. These findings highlight the value of mouse embryonic stem cell-based assays for determining the functional significance of variants of unknown clinical significance and provide valuable information regarding risk estimation and genetic counseling of families carrying these BRCA2 variants.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Células-Tronco Embrionárias Murinas/metabolismo , Mutação , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Animais , Proteína BRCA2/metabolismo , Bioensaio/métodos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Sobrevivência Celular , Estudos de Coortes , Feminino , Recombinação Homóloga , Humanos , Camundongos , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/metabolismo , Sri Lanka/epidemiologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Surg Clin North Am ; 100(3): 483-498, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32402295

RESUMO

For most individuals, cancer development is multifactorial; however, up to 10% of all cancers are related to an inherited genetic mutation. As health care shifts to having a greater emphasis on prevention, care providers, including general surgeons, will need to play a role in identifying patients at high risk for cancer development. Genetic testing provides a tool to determine those patients with a genetic mutation and to whom appropriate preventive care and treatment may be offered. It is imperative for general surgeons to understand the role genetics plays in the care of individual patients and their relatives.


Assuntos
Neoplasias/genética , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Análise Mutacional de DNA , Feminino , Aconselhamento Genético , Testes Genéticos , Humanos , Masculino , Neoplasias/diagnóstico , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Linhagem , Cuidado Pré-Concepcional , Medição de Risco , Neoplasias Gástricas/genética
18.
Medicina (B Aires) ; 80(2): 181-184, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-32282328

RESUMO

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.


Assuntos
Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Neoplasias Hipofisárias/genética , Adenoma/diagnóstico , Adulto , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Hipofisárias/diagnóstico
19.
Am J Surg Pathol ; 44(7): e47-e65, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32251007

RESUMO

Renal cell carcinoma (RCC) subtypes are increasingly being discerned via their molecular underpinnings. Frequently this can be correlated to histologic and immunohistochemical surrogates, such that only simple targeted molecular assays, or none at all, are needed for diagnostic confirmation. In clear cell RCC, VHL mutation and 3p loss are well known; however, other genes with emerging important roles include SETD2, BAP1, and PBRM1, among others. Papillary RCC type 2 is now known to include likely several different molecular entities, such as fumarate hydratase (FH) deficient RCC. In MIT family translocation RCC, an increasing number of gene fusions are now described. Some TFE3 fusion partners, such as NONO, GRIPAP1, RBMX, and RBM10 may show a deceptive fluorescence in situ hybridization result due to the proximity of the genes on the same chromosome. FH and succinate dehydrogenase deficient RCC have implications for patient counseling due to heritable syndromes and the aggressiveness of FH-deficient RCC. Immunohistochemistry is increasingly available and helpful for recognizing both. Emerging tumor types with strong evidence for distinct diagnostic entities include eosinophilic solid and cystic RCC and TFEB/VEGFA/6p21 amplified RCC. Other emerging entities that are less clearly understood include TCEB1 mutated RCC, RCC with ALK rearrangement, renal neoplasms with mutations of TSC2 or MTOR, and RCC with fibromuscular stroma. In metastatic RCC, the role of molecular studies is not entirely defined at present, although there may be an increasing role for genomic analysis related to specific therapy pathways, such as for tyrosine kinase or MTOR inhibitors.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Mutação , Metástase Neoplásica , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/patologia , Patologia Clínica , Patologia Molecular , Prognóstico , Sociedades Médicas , Urologia
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