RESUMO
The identification of Lynch syndrome has been greatly assisted by the advent of tumour immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and by the recognition of the role of acquired somatic BRAF mutation in sporadic MMR-deficient colorectal cancer (CRC). However, somatic BRAF mutation may also be present in the tumours in families with a predisposition to develop serrated polyps in the colorectum. In a subgroup of affected members in these families, CRCs emerge which demonstrate clear evidence of MMR deficiency with absent MLH1 staining and high-level microsatellite instability (MSI). This may result in these families being erroneously classified as Lynch syndrome, or conversely, an individual is considered "sporadic" due to the presence of a somatic BRAF mutation in a tumour. In this report, we describe two Lynch syndrome families who demonstrated several such inconsistencies. In one family, IHC deficiency of both MSH2 and MLH1 was demonstrated in tumours from different affected family members, presenting a confusing diagnostic picture. In the second family, MLH1 loss was observed in the lesions of both MLH1 mutation carriers and those who showed normal MLH1 germline sequence. Both families had Lynch syndrome complicated by an independently segregating serrated neoplasia phenotype, suggesting that in families such as these, tumour and germline studies of several key members, rather than of a single proband, are indicated to clarify the spectrum of risk.
Assuntos
Pólipos do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenoma/genética , Adenoma/patologia , Adulto , Idoso , Pólipos do Colo/patologia , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Linhagem , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Health services research is important to ensure continued best quality of care, but often uses data obtained without explicit consent for this purpose. Obtaining consent may be difficult for many reasons, but excluding individuals may introduce biases that alter the significance of studies. Approval by ethics committees of a waiver of the need for consent allowed our study to proceed and provide evidence that has led to the implementation of a population-based screening policy for the prospective detection of hereditary non-polyposis colorectal cancer. This screening policy has resulted in more cases being detected routinely with better management for affected patients and their at-risk families. A need for consent would have prohibited this study, and the development of a more efficient screening policy could have been delayed for several more years. Ethics committees can effectively manage the need to uphold basic ethical principles without unnecessarily impeding socially useful research. Committees need to be familiar with the guidelines approved under sections 95 and 95A of the Privacy Act 1988 (Cwlth) in addition to the National Health and Medical Research Council National statement on ethical conduct in research involving humans.
