Dados do Resumo

Título

Lynch-like syndrome: a case report

Introdução

Lynch Syndrome (LS) is a hereditary syndrome that causes predisposition to cancer, especially colorectal cancer (CRC), due to germline alterations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Inactivation increases risk of mutations in DNA synthesis and the presence of structural anomalies, such as microsatellite instabilities (MSI). Sporadic causes can have the same effect because of somatic methylation of the MLH1 promoter, simultaneous with the BRAF mutation in CRC. Tumors outside this pattern and wich presente the loss, constitute a group called Lynch-like syndrome (LLS).

Objetivo

The diagnosis of Lynch-like Syndrome depends on more extensive genetic testing for possible causes, with tests that rule out the sporadic route of tumor formation and assess the origin of the loss of expression in immunohistochemistry (IHC), in order to personalize the form of treatment.

Métodos

In the case study of patient J.S.F., with no comorbidities, adopted and with a first-degree relative who died of CRC at the age of 35, colonoscopy with biopsy and endoscopic tattooing is initially performed to extract tissue and genetic material for molecular testing and IHQ.
A panel of 26 genes, with analysis of CNVs (copy-number variants), is carried out to provide information on hereditary CRC. Variants of uncertain significance (VUS) in regions very close to the genes studied require specific gene PCR for exact localization in the genome.
The negative germ panel, in the workflow, moves on to the stage of evaluating somatic causes of loss of expression, with analysis of the sporadic pathway through the MLH1 promoter methylation test and BRAF mutation (CRC only).
Once sporadicity has been ruled out, the last stage is the somatic panel with a more varied investigation of genes and detection of microsatellite instability.

Resultados

The germline panel of 26 genes showed normality in the MLH1 and VUS in PMS2 (relative to the variant p.Thr728Alafs*7) in a region of high similarity with the PMS2CL pseudogene, as well as VUS in APC (p.Asp1939Val). Gene-specific PCR found a variant in the PMS2CL pseudogene, rectifying the report for non-somatic loss of MLH1 expression. In addition to the germline panel, the MLH1 promoter methylation analysis and the search for a V600E variant in the BRAF gene were both negative.
The somatic panel of 500 genes found high microsatellite instability and other variants with predictive potential: MLH1: NM_000249.4 c.991 G>T, p.Glu331Ter; ERBB2: NM_004448.4 c.2524G>A, p.Val842Ile; KRAS: NM_004985.5 c.35G>A, p.Gly12Asp; PIK3CA: NM_006218.4 c.3140A>G, p.His1047Arg.
With new gastrointestinal complaints, another colonoscopy showed follicular lymphoid hyperplasia and tubular adenoma with low-grade dysplasia in the transverse colon, whose pairing of the adenomas with normal tissue also showed no alteration in the MLH1 gene.

Conclusões

Although the patient had tumors with clinical features of heredity, his condition is a deficiency in DNA mismatch repair caused by a somatic mutation in the MLH1 gene. The negative BRAF mutation and MLH1 methylation tests ruled out the sporadic hypothesis and the broad somatic panel confirmed the diagnosis of Lynch-like syndrome. As a result, he is being followed up genetically without the need for family research.

Palavras Chave

Lynch-like syndrome; dMMR