CASES REPORT: CLINICAL, MOLECULAR AND GENETIC CHARACTERIZATION OF ARGENTINEAN CASES DIAGNOSED WITH COLORECTAL CANCER PREDISPOSING SYNDROMES

SOAREZ, J.N.; MAYORDOMO, A.C.; PIÑERO T.A.; GARCÍA-RIVELLO, HERNÁN; KALFAYAN, P.G.; VACCARO C.A.; PELTOMÄKI, PÄIVI; PAVICIC, W.

MAR DEL PLATA

Otro; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA

Lynch syndrome (LS) is characterized by DNA mismatch repair(MMR) deficiency caused by germline pathogenic (GL-path) variants.Some patients with suspected LS (displays a similar cancerpattern) have DNA MMR deficiencies but no detectable path alterationin those genes: called LS-like (LLS), and others are MMRproficient and does not exhibit microsatellite instability (MSI): calledFamilial colorectal cancer (CRC) type X (FCCX). Three such cases,classified as LLS (C1) and FCCX (C2-3) based on clinicopathologicaldata, cancer family history and MMR status by immunohistochemistry(IHC), were identified in our local referral register(ProCanHe-REM, HIBA, ARG). However, genetic aetiology has notbeen elucidated. The aim of our work was to carry out a detailedmolecular and genetic characterization to achieve its correct classification.IHC results: while C1 tumor showed no MSH2/6 proteins expression,C2/C3 conserved all four MMRs. MSI analysis (BAT25/26-D2S123-D5S346-D17S250 markers): C1 MSI-high status (3/5) andC2/C3 MSS (stable). MMR-MLPA analysis: no large rearrangementwas identified. We performed Target Cancer Panel (578 genes) GLand T seq for C1. No candidate GL variant was identified. At thesomatic level, MSH6 showed Loss of Heterozygosity (LOH, strictvalue 2.59, position 2:48010654-48030838, Hg19), supporting IHCresult. The mutational signature analysis identified five SBS signatures,linked to Homologous Recombination or MMR defects. ByGL exome sequencing no candidate variant was identified for C2;but C3 showed a variant of unknown significance: BMPR1A gene(c.749T/C, 10:88676964, Hg19; f=0.0000358), in silico predictedpath score 16/23. Segregation analysis (affected/non-affected relatives):variant co-segregate with CRC and high-dysplasia polyps. Insum, for C1 an extended panel, WES or RNA sequencing is requiredto complete classification; while for C3, combined clinical and moleculardata provided evidence to suspect the variant is causative ofFCCX syndrome.