MUTYH-associated polyposis or MUTYH-associated neoplasia? First two case reports in Argentina

ANTELO, MARINA; MILITO, DANIELA; COLLIA, KARINA; CORAGLIO, MARIANA; GUTIERREZ, ALEJANDRO; RHEES JENNIFER; SHIA, J.; ROCA, ENRIQUE; CUATRECASAS, MIRIAM; SOLANO, ANGELA; CARDOSO, FLORENCIA; ARNOLD, M.; MOREIRA, L.; LEOZ, MARIA LIZ; CARBALLAL, SABELA; CASTELLS, ANTONI; BOLAND, RICHARD C.; GOEL, AJAY; BALAGUER, FRANCESC

New Orleans

Congreso; 18th. Annual Meeting of the collaborative Group of the Americas on Inherited Colorectal Cancer; 2014

collaborative Group of the Americas on Inherited Colorectal Cancer

Background: Biallelic MUTYHmutations cause an infrequent autosomal recessively inherited disorder with acumulative risk of colorectal cancer (CRC) of 80%. It has been defined as MUTYH-associated polyposis (MAP) because it clinicallyresults in both classical and attenuated polyposis, but it can alsomanifest as an isolated early-onset CRC in almost 30% of the cases. Besides,family history (FH) of CRC can also be widely variable, so a less specific but more realistic name for this disease disease, such as MUTYH-associated neoplasia(MAN), has been proposed by John R.T. Monson in 2012. To date, more than80 mutations have been described, with the Y165C and G382D variants accounting for 80% of the documented mutations inCaucasian populations. Here,we report the first two Argentine patients with MAN, focusing on theirheterogeneous personal and familial history of CRC and polyps, and themolecular algorithm to reach their diagnosis. Patients: Two patients were referred for evaluationto the High-Risk Colorectal Cancer Clinic. Case 1: a 56 year-old womanhad a recent diagnosis of classical adenomatous polyposis and 2 synchronousCRC´s, and she was operated receiving a total coloproctectomy + ileal pouch.Her upper GI endoscopy was normal. She had no FH of CRC. We ordered an APCmutational analysis, and it was done with NGS (next generation sequencing)together with the complete analysis of MUTYH. The APC testing was negative. Case2: a 29 year-old woman had been diagnosed with a stageIII rectal cancer and 2 small synchronous adenomas, and had recievedneoadyuvant therapy and a Dixon surgery. Sucesive colonoscopies during the last5 years were normal.Her upper GI endoscopy was normal. The only FH of tumors was her mother with aCRC at 45 years-old.  Immunohistochemical staining of the 4 mismatch-repairproteins and microsatellite instability testing wereperformed to evaluate Lynch syndrome, showing normal expression of proteins andmicrosatellite stability.None of the two cases had known consanguinity. Results: Case 1: The complete MUTYH genetic testing showed abiallelic G382D mutation. Her only sister presented an attenuated colonicpolyposis (15 adenomas), and her two children had no polyps. Case 2: Thegenetic testing of the two most prevalent MUTYH mutations showed an heterzygousY176C mutation; the posterior whole genetic test of this gene evidenced a secondinfrequent mutation named W472S. Two of her 6siblings were diagnosed with attenuated polyposis (12-30 adenomas) and recieved total colectomies.Conclusions: Patients with MAN can mimic all hereditary colorectal cancer syndromes,with the exception of hamartomatous polyposis. Therefore, MUTYH biallelicmutations should be considered not only in APC negative polyposis patients, butalso in microsatellite stable early-onset CRC, regardless of FH. Furthergenetic investigation of this gene is needed to evaluate the possibility ofother prevalent variants of this rare and heterogeneous syndrome in LatinAmerican population.