RESUMO
BACKGROUND: Lynch syndrome (LS) is an autosomal dominant familial condition caused by a pathogenic variant (PV) in a DNA mismatch repair gene, which then predisposes carriers to various cancers. AIM: To review the pathogenesis, clinical presentation, differential diagnosis and clinical strategies for detection and management of LS. METHODS: A narrative review synthesising knowledge from published literature, as well as current National Comprehensive Cancer Network guidelines for management of LS was conducted. RESULTS: LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance. LS is one of the most common hereditary causes of cancer, and about 1 in 279 individuals carry a PV in an LS gene that predisposes to associated cancers. Individuals with LS have increased risks for colorectal, endometrial and other cancers, with significant variation in lifetime risk by LS-associated gene. CONCLUSIONS: As genetic testing becomes more widespread, the number of individuals identified with LS is expected to increase in the population. Understanding the pathogenesis of LS informs current strategies for detection and clinical management, and also guides future areas for clinical innovation. Unravelling the mechanisms by which these tumours evolve may help to more precisely tailor management by the gene involved.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Reparo de Erro de Pareamento de DNA/genética , Testes Genéticos/métodos , Humanos , Instabilidade de MicrossatélitesRESUMO
The present case report describes a 65-year-old man with Lynch syndrome and hypercalcaemia associated with hyperparathyroidism. Parathyroid surgery confirmed the diagnosis of parathyroid carcinoma. Serum calcium and parathyroid hormone (PTH) concentrations serially increased after initial surgery. Imaging study and subsequent biopsy confirmed lung metastases with mismatch repair deficiency. Pembrolizumab was initiated achieving 60% reduction in tumour burden.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Pulmonares/tratamento farmacológico , Instabilidade de Microssatélites , Neoplasias das Paratireoides/terapia , Idoso , Biomarcadores Tumorais/genética , Biópsia , Cálcio/sangue , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais Hereditárias sem Polipose/sangue , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Análise Mutacional de DNA , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/genética , Hipercalcemia/terapia , Hiperparatireoidismo/diagnóstico , Hiperparatireoidismo/genética , Hiperparatireoidismo/terapia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Glândulas Paratireoides/diagnóstico por imagem , Glândulas Paratireoides/patologia , Glândulas Paratireoides/cirurgia , Hormônio Paratireóideo/sangue , Neoplasias das Paratireoides/diagnóstico , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/patologia , Paratireoidectomia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento , Sequenciamento do ExomaRESUMO
The National Comprehensive Cancer Network now recommends BRCA1/2 genetic testing in men with metastatic prostate cancer. The purpose of this article is to provide a review of principles of genetic testing in prostate cancer and highlight the significance of clinical genetic testing of BRCA1/2 and other genes (CHEK2, HOXB13, PALB2), including Lynch syndrome genes (MLH1, MSH2, MSH6, and PMS2) in men with metastatic prostate cancer. The potential impact of genetic testing on systemic treatments and the significance of the pathogenic results for at-risk family members is discussed.
Assuntos
Proteína BRCA1/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Metástase Neoplásica/genética , Metástase Neoplásica/terapia , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Microsatellite instability (MSI) is a key biomarker in colorectal cancer (CRC), with crucial diagnostic, prognostic, and predictive implications. Testing for mismatch repair deficiency (MMR-D)/MSI is recommended during screening for Lynch syndrome, an autosomal-dominant hereditary disease that is characterized by germline mutations in the MMR genes and associated with an increased risk for several types of cancer. Additionally, MSI-high (MSI-H) status is associated with a better prognosis in early-stage CRC and a lack of benefit from adjuvant treatment with 5-fluorouracil in stage II disease. More recently, MSI has emerged as a predictor of sensitivity to immunotherapy-based treatments. The groundbreaking success of checkpoint inhibitors in MMR-D metastatic CRC has opened a new therapeutic scenario for patients with these tumors. MSI-H CRC, in both the sporadic and hereditary settings, is characterized by distinctive molecular and clinicopathologic features and represents a unique subset of CRC that is the object of growing interest and fervent research efforts. This article, an overview of the expanding role of MSI in CRC, covers its clinical significance, the available data on molecular profiling, novel perspectives on MSI testing, biomarkers in MSI-H CRC, immunotherapy resistance, and novel immunotherapy strategies.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Reparo de Erro de Pareamento de DNA , Fluoruracila/uso terapêutico , Imunoterapia/métodos , Instabilidade de Microssatélites , Quimioterapia Adjuvante , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Humanos , Metástase Neoplásica , Estadiamento de NeoplasiasRESUMO
Gastrointestinal carcinoid tumors are often associated with other tumors, particularly colon adenocarcinomas; but the association between carcinoid tumors and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome has not yet been explored. We report an unusual case of a 28-year-old woman with HNPCC who underwent surgery for a transverse colon adenocarcinoma in whom an appendix carcinoid tumor was incidentally found. To assess whether the carcinoid tumor displayed the characteristic molecular features of HNPCC tumors, we investigated the expression of mismatch-repair (MMR) proteins and microsatellite instability (MSI) status in both tumors. Both tumors demonstrated normal expression of the MMR proteins hMLH1, hMSH2, hMSH6, and hPMS2. Interestingly, the adenocarcinoma exhibited an MSI phenotype but the carcinoid tumor did not, indicating that these 2 tumors arose through different molecular pathways.
Assuntos
Neoplasias do Apêndice/patologia , Tumor Carcinoide/patologia , Neoplasias do Colo/patologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias do Apêndice/genética , Neoplasias do Apêndice/terapia , Tumor Carcinoide/genética , Tumor Carcinoide/terapia , Quimioterapia Adjuvante , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , DNA de Neoplasias/análise , Proteínas de Ligação a DNA/análise , Quimioterapia Combinada , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Repetições de Microssatélites/genética , Proteína 3 Homóloga a MutS , Resultado do TratamentoRESUMO
We have implemented a randomized controlled dietary intervention in patients polypectomized for tumors of the colorectum to elucidate potential beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) on the development of colorectal tumors. Those individuals in the experimental group were advised not only to decrease their consumption of fats/oils as a whole and foods supplying n-6 PUFAs but also to increase intake of foods and supplements containing n-3 PUFAs, while those in the comparison group were cautioned to reduce intake of fats/oils as a whole. Patients' compliance/adherence was monitored with a semi-quantitative food frequency questionnaire and by assessment of fatty acid concentrations in plasma, membranes of red blood cells and sigmoid colon samples. As for endpoints to assess tumor suppressive effects of n-3 PUFAs, the number/multiplicity, sizes and incidence rates of colorectal tumors were compared between the experimental and comparison groups after 12 and 24 months of the dietary intervention. On the specified assumption, the number of pairs needed for achieving statistical significance was calculated to be approximately 60-80. A randomized controlled trial is under way to secure enough patients, sustain compliance/adherence and minimize dropouts.