Clinicopathological and molecular characterization of Brazilian families at risk for Lynch syndrome

• Published in: Cancer genetics 2021-06, Vol.254-255, p.82-91
• Main Authors: de Paula, André Escremim, Galvão, Henrique de Campos Reis, Bonatelli, Murilo, Sabato, Cristina, Fernandes, Gabriela Carvalho, Berardinelli, Gustavo Noriz, Andrade, Carlos Eduardo Mattos, Neto, Maximiliano Cadamuro, Romagnolo, Luis Gustavo Capochim, Campacci, Natalia, Scapulatempo-Neto, Cristovam, Reis, Rui Manuel, Palmero, Edenir Inêz
• Format: Article
• Language: English
• Subjects: Colorectal cancer; DNA methylation; DNA mismatch repair; Inherited cancer; Lynch syndrome
• ISSN: 2210-7762; 2210-7770
• DOI: 10.1016/j.cancergen.2021.02.003

•Largest study of germline mutations in Lynch Syndrome-related genes in the Brazil•New pathogenic variants were identified.•Co-occurrence of germline variant and somatic MLH1 hypermethylation•Recurrent and founder variants could lead to a cost-effective genetic testing•MLH1 somatic methylation can be a second hit in some Lynch Syndrome tumors.•Predictive genetic testing enables more appropriate surveillance and prevention. Lynch syndrome (LS), is the most common hereditary colorectal cancer syndrome. However, it is poorly characterized in Brazil. Therefore, we aimed to determine the spectrum of pathogenic variants in Mismatch Repair (MMR) genes and investigate the MLH1 promotor methylation role as a second hit in LS tumors. Tumor screening through microsatellite instability and immunohistochemistry for MMR proteins was performed in 323 cases who met clinical criteria. BRAF-V600E and MLH1 promoter methylation were analyzed for all MLH1-deficient tumors. Patients with MMR deficient tumor proceeded to germline genetic testing. MMR deficient tumors were detected in 41% of patients recruited. About half of patients carried a pathogenic germline variant. Two recurrent variants in MLH1 and three novel pathogenic variants were identified. Furthermore, pathogenic germline variants with concomitant somatic MLH1 hypermethylation were found in 6% of cases. Predictive genetic testing was offered to 387 relatives. Overall, 127 tumors were diagnosed in 100 LS patients, from 62 unrelated families. Our molecular data provide new information about the spectrum of MMR mutations, which contributes to a better characterization of LS in Brazil. Furthermore, we call attention to the possibility of failure in the diagnosis of germline MLH1 mutation carriers when somatic MLH1 hypermethylation is used to rule out LS.