A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.

Rossi BM1, Palmero EI2, López-Kostner F3, Sarroca C4, Vaccaro CA5, Spirandelli F6, Ashton-Prolla P7, Rodriguez Y8, de Campos Reis Galvão H9, Reis RM10,11, Escremim de Paula A2, Capochin Romagnolo LG9, Alvarez K3, Della Valle A4, Neffa F4, Kalfayan PG5, Spirandelli E6, Chialina S6, Gutiérrez Angulo M12, Castro-Mujica MDC13, Sanchez de Monte J14, Quispe R15, da Silva SD16,17, Rossi NT18, Barletta-Carrillo C13, Revollo S15, Taborga X15, Morillas LL19, Tubeuf H20,21, Monteiro-Santos EM1, Piñero TA22, Dominguez-Barrera C23, Wernhoff P24, Martins A20, Hovig E25,26, Møller P25,27,28, Dominguez-Valentin M29.

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Abstract

BACKGROUND:

Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America.

METHODS:

Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome.

RESULTS:

We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet.

CONCLUSION:

The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.