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

Abstract

BackgroundGenetic 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. MethodsEleven 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.ResultsWe 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.ConclusionThe 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.

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes

“…41 Although their population prevalence is not well understood, founder mutations in MSH2 (c.1906G>C, p.A636P) and MSH6 (c.3959_3962delCAAG and c.3984_3987dupGTCA) appear to account for the majority of Lynch syndrome cases in individuals of Ashkenazi Jewish ancestry. 42,43 Additional data are identifying other candidate founder mutations in various populations with undefined prevalence, including Americans of German ancestry, 44 African Americans, 45 Latinos, 46 Poles, 47 and many other groups. 48 Founder mutations may account for a sizeable fraction of individuals with BMMRD syndrome, which is caused by biallelic inheritance of pathogenic germline variants in the same MMR gene.…”

Genetics and genomics in Peru: Clinical and research perspective

“…These studies in Latin America have reported about 18% of patients diagnosed at a young age have pathogenic variants in genes not traditionally associated with CRC (e.g., ATM [OMIM #607585], CHEK2 [OMIM #604373], BRCA1 , BRCA2 , CDKN2A [OMIM #600160], PALB2 [OMIM #610355]). MHL1 (OMIM #120436) pathogenic variants were more frequent in patients from Peru, Mexico and Chile, whereas MSH2 (OMIM #609309) pathogenic variants occurred mostly in patients from Colombia and Argentina (Ñique Carbajal, Sánchez Renteria, Lettiero, Wernhoff, & Domínguez‐Valentin, ; Rossi et al, ).…”

“…). MHL1 (OMIM #120436) pathogenic variants were more frequent in patients from Peru, Mexico and Chile, whereas MSH2 (OMIM #609309) pathogenic variants occurred mostly in patients fromColombia and Argentina (Ñique Carbajal, Sánchez Renteria, Lettiero, Wernhoff, & Domínguez-Valentin, 2014;Rossi et al, 2017).…”

Evaluation of MLH1 variants of unclear significance

“…[12][13][14][15] Families that fulfilled the Amsterdam criteria and/or the Bethesda guidelines [16][17][18] Patients were informed about their inclusion into the registries and written informed consent was obtained from all participants during genetic counseling sessions. The data include results from germline DNA testing, tumor testing (based on microsatellite instability analysis and/or immunohistochemistry) and family history.…”

“…In these cases, it is possible to perform functional testing to assess the impact of a variant, which has frequently served to approach a classification for such variants. 12 In this work, we have tested nine small coding variants identified in 9 South American individuals. 11 Genetic counselling and testing has recently been introduced in Latin America and has led to the identification of several yet uncharacterized genetic variants in MLH1.…”