RESUMO
The POLD1 gene is involved in DNA proofreading to ensure accurate DNA replication. Some germline alterations in its exonuclease domain are associated with predisposition to cancers and colonic polyps. Only a few pathogenic variants have been clearly identified so far. Here we report a novel variant: c.1458G>T p.(Lys486Asn) that we classified as pathogenic, detected in two putatively unrelated families. The cancer spectrum was very similar to Lynch syndrome, implying an overlapped tissue susceptibility. The common presence of colonic polyps in carriers and the MMR proficient phenotype in tumors were distinctive features suggesting POLD1 implication. Some clinical characteristics observed in the carriers of this variant differed from those reported previously, suggesting a potential genotype/phenotype correlation, and very likely in relation to the functional importance of affected residues. Our findings provide further insight into understanding the role of POLD1 in cancer-related risk.
Assuntos
Pólipos do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Polimerase III/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Pólipos do Colo/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Diagnóstico Diferencial , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , FenótipoRESUMO
Lynch syndrome accounts for 3-5% of colorectal cancers and is due to a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Somatic hypermethylation of the MLH1 promoter is commonly associated to sporadic cases. Strategies have been developed to identify patients with Lynch Syndrome based on clinical findings, tumoral phenotype, family history and immunohistochemistry analysis. However, there still are some pitfalls in this strategy, possibly responsible for an underdiagnosis of Lynch syndrome. Here we report the case of a 37 years-old man presenting with two concomitant tumors located in the rectosigmoid and in the ileocecal angle. Both tumors were microsatellites instability-high (MSI-H) and showed a loss of MLH1 and PMS2 protein expression, but only one had MLH1 promoter hypermethylation. Constitutional analysis of mismatch repair genes could not be performed from a blood sample, because of the early death of the patient. However, tumoral tissue analyses revealed in both tumors a pathogenic variant in the MLH1 gene. Further analysis of the surrounding tumor-free tissue also showed the presence of this alteration of the MHL1 gene. Finally, the same pathogenic variant was present constitutionally in one of the siblings of the patient, confirming its hereditary nature. This new case of concomitant presence of MLH1 promoter hypermethylation and MLH1 germline mutation demonstrates that the presence of MLH1 promoter hypermethylation should not rule out the diagnosis of Lynch Syndrome.
Assuntos
Adenocarcinoma Mucinoso/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação em Linhagem Germinativa , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Adenocarcinoma Mucinoso/patologia , Adulto , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/patologia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Proteínas de Ligação a DNA/genética , Evolução Fatal , Humanos , Masculino , Mães , IrmãosRESUMO
BACKGROUND: The tumor spectrum in the Lynch syndrome is well defined, comprising an increased risk of developing colonic and extracolonic malignancies. Muir-Torre syndrome is a variant with a higher risk of skin disease. Patients have been described carrying mutations in the mismatch repair genes and presenting tumors with unusual histology or affected organ not part of the Lynch syndrome spectrum. Hence, the real link between Lynch syndrome, or Muir-Torre syndrome, and these tumors remains difficult to assess. CASE PRESENTATION: We present the case of a 45-year-old-woman, diagnosed with breast cancer at 39 years of age and skin squamous cell carcinoma (SCC) at 41 years of age, without personal history of colorectal cancer. The microsatellite instability analysis performed on the skin SCC showed a low-level of microsatellite instability (MSI-Low). The immunohistochemical expression analysis of the four DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 showed a partial loss of the expression of MSH2 and MSH6 proteins. Germline deletion was found in MSH2 gene (c.1277-? _1661 + ?del), exon 8 to 10. Then, at 45 years of age, she presented hyperplastic polyps of the colon and a sebaceous adenoma. CONCLUSION: Squamous cell carcinomas have been described in Lynch syndrome and Muir-Torre syndrome in two studies and two case reports. This new case further supports a possible relationship between Lynch syndrome and squamous cell carcinoma.