Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries.
BACKGROUND
Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome.


METHODS
Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed.


RESULTS
Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene, 15 in the MLH1 gene and no pathogenic mutations were identified in the MSH6 gene. It was observed that the AUC for the PREMM (0.846), Barnetson (0.850), MMRpro (0.821) and Wijnen (0.807) models did not present significant statistical difference. The Myriad model presented lower AUC (0.704) than the four other models evaluated. Considering thresholds of ≥ 5%, the models sensitivity varied between 1 (Myriad) and 0.87 (Wijnen) and specificity ranged from 0 (Myriad) to 0.38 (Barnetson).


CONCLUSIONS
The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models.
Graduation Program, AC Camargo Hospital, Sao Paulo, Brazil. erikammsantos@gmail.com
Erika Maria
EM
Monteiro Santos
Mev Dominguez
MD
Valentin
Felipe
F
Carneiro
Ligia Petrolini
LP
de Oliveira
Fabio
F
de Oliveira Ferreira
Samuel Aguiar
SA
Junior
Wilson Toshihiko
WT
Nakagawa
Israel
I
Gomy
Victor Evangelista
VE
de Faria Ferraz
Wilson Araujo
WA
da Silva Junior
Dirce Maria
DM
Carraro
Benedito Mauro
BM
Rossi
D000328:Adult; D000368:Aged; D001938:Brazil; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D003906:Developing Countries; D005260:Female; D005817:Genetic Counseling; D018095:Germ-Line Mutation; D006801:Humans; D016013:Likelihood Functions; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity