Síndrome de Lynch

Epidemiologia

• Prevalência: 1 em cada 279 pessoas são portadoras de genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure defeituosos de reparação mismatch ( MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome, pela sigla em inglês).
  • É a síndrome de carcinoma do cólon hereditário mais MAIS Androgen Insensitivity Syndrome comum
  • Representa 2 – 4% dos carcinomas colorretais
  • Aumento do risco de carcinoma do endométrio e muitos outros carcinomas
• As neoplasias ocorrem mais MAIS Androgen Insensitivity Syndrome cedo do que na população geral (5.ª década).
• Riscos gerais de carcinoma ao longo da vida na síndrome de Lynch (SL) (pontos médios aproximados de amplas faixas):
  • Cancro colorretal: 50% (cólon direito > cólon esquerdo)
  • Cancro do endométrio: 38%
  • Cancro do ovário: 19%
  • Cancro do estômago: 7%
• Rácio sexo: mulheres = homens

Etiologia

Os doentes com síndrome de Lynch herdam um ou mais MAIS Androgen Insensitivity Syndrome genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome mutantes e os respetivos alelos/alelos normais; o 2.º alelo sofre mutação ou perde a função por silenciamento epigenético com tanta frequência que o padrão de transmissão é autossómico dominante.

• Genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome que podem sofrer mutação: MLH1 , MSH2 (mutação do gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics EpCAM EPCAM A cell adhesion molecule that is expressed on the membranes of nearly all epithelial cells, especially at the junctions between intestinal epithelial cells and intraepithelial lymphocytes. It also is expressed on the surface of adenocarcinoma and epithelial tumor cells. It may function in the mucosa through homophilic interactions to provide a barrier against infection. It also regulates the proliferation and differentiation of embryonic stem cells. Lynch syndrome (molécula de adesão celular epitelial) também pode causar perda de função), MSH6 e PMS2
• As mutações ocorrem em taxas até 1.000 vezes maiores que o normal, principalmente em regiões de sequências repetitivas chamadas microssatélites.
• Os produtos proteicos dos genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure de reparação mismatch ( MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome) são importantes na “verificação ortográfica” do DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure durante a duplicação, detetando e reparando defeitos no DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure.
• A perda de atividade de MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome causa uma acumulação de erros de replicação de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure, particularmente em sequências repetitivas (“tandem repeats”).
  • O teste de microssatélites que mostra mutações em 30% ou mais MAIS Androgen Insensitivity Syndrome dos microssatélites é chamado alta instabilidade de microssatélites (MSI-H, pela sigla em inglês) e é o hallmark dos MMRs defeituosos.
  • É eventualmente criada uma mutação causadora de carcinoma por um dos erros não corrigidos cometidos durante a replicação do DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure.
• As mutações MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome também podem ocorrer como mutações somáticas esporádicas.

Patogénese e Patologia

Patogénese

• Algumas sequências de microssatélites mutantes estão associadas a genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure de crescimento celular, levando à formação de um pólipo/carcinoma neoplásico benigno que pode posteriormente ser maligno.
• A via MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome de carcinogénese do cólon é a segunda via mais MAIS Androgen Insensitivity Syndrome comum de carcinoma colorretal (CCR), após a via adenoma-carcinoma de carcinogénese do cólon.

Patologia

• Características dos CCRs que surgem através da via MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome (MSI-H): tendem a mostrar características mais MAIS Androgen Insensitivity Syndrome mucinosas e linfócitos infiltrantes de tumor Tumor Inflammation reativos
• Características dos carcinomas endometriais no SL: aumento da frequência de histologias de carcinoma não endometrioide
• Número ligeiramente maior de pólipos adenomatosos do que a população geral, mas uma maior taxa de progressão para CCR do que pólipos típicos.

Apresentação Clínica e Diagnóstico

Apresentação clínica

• Os doentes estão assintomáticos até desenvolverem malignidade.
• Adenocarcinomas colorretais:
  • A SL manifesta-se apenas com um número baixo ou ligeiramente superior ao normal de pólipos.
  • Carcinomas do lado direito ( mais MAIS Androgen Insensitivity Syndrome comuns): anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types por défice de ferro devido a hemorragia
  • Carcinomas do lado esquerdo: alterações nos hábitos intestinais ou no tamanho das fezes
• Carcinomas endometriais: hemorragia endometrial anormal

Diagnóstico

• São necessárias 1 ou mais MAIS Androgen Insensitivity Syndrome mutações germinativas nos genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure de reparação mismatch ( MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome) ou no gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics EPCAM EPCAM A cell adhesion molecule that is expressed on the membranes of nearly all epithelial cells, especially at the junctions between intestinal epithelial cells and intraepithelial lymphocytes. It also is expressed on the surface of adenocarcinoma and epithelial tumor cells. It may function in the mucosa through homophilic interactions to provide a barrier against infection. It also regulates the proliferation and differentiation of embryonic stem cells. Lynch syndrome para um diagnóstico definitivo da síndrome de Lynch.
• São utilizadas 2 vias para estabelecer o diagnóstico: avaliar o tumor Tumor Inflammation primeiro ou rastreio na presença de histsória familiar.
• Deve-se suspeitar de síndrome de Lynch em qualquer doente que tenha:
  • CCR antes dos 50 anos de idade, ou se mais MAIS Androgen Insensitivity Syndrome de 1 CCR
  • Carcinoma endometrial <60 anos
  • Um familiar de 1º grau com SL conhecido
  • Cumpre os critérios para SL (critérios de Amesterdão ou guidelines da Bethesda)
• Critérios Amesterdão II (baixa sensibilidade, suspeita de SL se cumprir os seguintes critérios):
  • 3 ou mais MAIS Androgen Insensitivity Syndrome familiares (pelo menos 1 de primeiro grau) com carcinoma associado ao SL; com exclusão da polipose adenomatosa familiar (PAF).
  • Carcinomas associados ao SL que envolvem pelo menos 2 gerações
  • 1 ou mais MAIS Androgen Insensitivity Syndrome carcinomas diagnosticados antes dos 50 anos
• Guidelines de Bethesda, revistas (melhor sensibilidade e especificidade do que os critérios de Amesterdão):
  • CCR diagnosticado <50 anos de idade
  • 2 ou mais MAIS Androgen Insensitivity Syndrome carcinomas associados ao SL
  • CCR com histologia semelhante a MSI-H em doentes <60 anos
  • CCR em doente com familiar de 1º grau com carcinoma associado ao SL com idade <50 anos
  • CCR em doente com 2 familiares de 1º grau com carcinoma associado ao SL, em qualquer idade

Tratamento

Testes Testes Gonadal Hormones de rastreio e vigilância

• Para CCR: colonoscopia anual com início aos 20 – 25 anos de idade, ou 2 – 5 anos antes da idade mais MAIS Androgen Insensitivity Syndrome jovem do diagnóstico de CCR na família
• Para carcinoma do endométrio: biópsia endometrial anual, a partir dos 30 anos de idade
• Exames anuais da pele para detetar: tumores sebáceos (benignos e malignos) e queratoacantomas cutâneos associados à síndrome de Muir-Torre (uma variante da SL)
• Aconselhamento reprodutivo: doentes com SL em idade reprodutiva devem realizar rastreio para detetar estado de portador.

Tratamento cirúrgico

Para o CCR:

• Colectomia total em vez de resseção segmentar para CCR
• Se carcinoma do reto: proctocolectomia total

Para o carcinoma do endométrio:

• Histerectomia total e salpingo-ooforectomia bilateral caso seja diagnosticado tumor Tumor Inflammation
• Histerectomia total e salpingo-ooforectomia bilateral profilática quando a fertilidade está completa

Tratamento médico

Quimioprevenção:

• Anticoncecionais de estrogénio-progesterona reduzem o risco de carcinoma do endométrio e ovário
• Aspirina: pode reduzir o risco de CCR

Imunoterapia:

• Pembrolizumab Pembrolizumab Squamous Cell Carcinoma (SCC) ou nivolumab Nivolumab A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma. Melanoma
• Usada em tumores com ausência de MSI-H–/ MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome

Diagnóstico Diferencial

• PAF: doença que se apresenta com centenas de pólipos adenomatosos e tipicamente resulta em CCR do cólon distal. A síndrome de Lynch manifesta-se geralmente com CCR no cólon proximal e apenas um baixo número de pólipos. O teste genético pode ser usado para distinguir as 2 doenças.
• Carcinoma colorretal familiar tipo X (FCCTX, pela sigla em inglês): são cumpridos os critérios de Amesterdão I, mas os tumores não apresentam o MSI MSI The occurrence of highly polymorphic mono- and dinucleotide microsatellite repeats in somatic cells. It is a form of genome instability associated with defects in DNA mismatch repair. Colorectal Cancer observado no SL. Sem outro risco aumentado de outros carcinomas associados ao SL.