Page 95 - Genomic Medicine in Emerging Economies

84 CHAPTER 5: Screening for Hereditary Cancer in Latin America

de Freitas et al., 2015; Garcia et al., 2015; Cajal et al., 2016; Castro-Mujica et
al., 2016; Dominguez-Valentin et al., 2016; Germini et al., 2016; Moreno-Ortiz
et al., 2016; Ortiz et al., 2016; Rossi et al., 2016; Vaccaro et al., 2016; Rossi et
al., 2017). We identified 6 out of 15 countries, that is, Argentina, Brazil, Chile,
Colombia, Uruguay and Puerto Rico, where germline genetic testing for Lynch
syndrome is available and 3 countries, that is, Bolivia, Peru, and Mexico, where
tumor testing is used in the diagnosis of Lynch syndrome (Rossi et al., 2017).
The spectrum of pathogenic MMR variants included path_MLH1 up to 54%,
path_MSH2 up to 43%, path_MSH6 up to 10%, path_PMS2 up to 3% and path_
EPCAM up to 0.8%. Frequent regions included exon 11 of MLH1 (15%), exons
3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11
and 13 of PMS2 (31% and 23%, respectively) (Rossi et al., 2017).

Fifteen published data from Latin America MMR Lynch syndrome spec-
trum contained information for 982 suspected Lynch syndrome families
(Table 5.4). Overall, considering all studies, 37.9% of patients have a muta-
tion but the higher mutation rate is obtained in patients meeting Amsterdam
criteria (204/355, 57.4%), compared with Bethesda patients (70/383, 18.2%).
From the 373 path_MMR carriers, MLH1 was affected in 52.5% (196/373),
MSH2 in42.4% (158/373), MSH6 in 3.8% (14/373), PMS2 in 0.8% (3/373)
and EPCAM in 0.5% (2/373) (Table 5.4) (Rossi et al., 2017). Seven founder
mutations have also been identified among the Latin American Lynch syn-
drome families. Four of them have been suggested to constitute potential
founder mutations in other populations, for example, the Italian-Quebec
MLH1 c.545+3A>G, the Newfoundland MSH2 c.942+A>T, the Portuguese
MSH2 c.388_389delCA and the Spanish MSH2 exon 7 deletion (Hampel
et al., 2005; Kobayashi et al., 2013; Møller et al., 2015; Rubenstein et al., 2015).
In Colombia, the MSH2 c.1039-8T_1558+896dup was suggested to represent
a founder mutation and in Chile, the MLH1 c.1731+3A>T and the MSH2
c.2185_2192delATGTTGGAinsCCCT were associated with a strong Amerindian
genetic ancestry (Alvarez et al., 2010; Alonso-Espinaco et al., 2011; Domin-
guez-Valentin et al., 2013; Vaccaro et al., 2016). The Latin American popula-
tion consists mainly of an admixture of Amerindians and Europeans, with a
lower component of African ancestry. The proportion of these ancestries is vari-
able among countries, being Argentina, Brazil, and Uruguay having a stronger
European component. In Chile the European and Amerindian components are
45% and 55% respectively; in Colombia, Peru and Bolivia, a large part of the
populations has Spanish colonist and American Indian ancestry, and in Brazil
a significant part of the population has African and American Indian roots
(Dominguez-Valentin et al., 2013; Vaccaro et al., 2016).

Interestingly, the clinic pathological features of pathogenic MMR carriers
described in Latin American families are in accordance with other studies,