Page 93 - Genomic Medicine in Emerging Economies

82 CHAPTER 5: Screening for Hereditary Cancer in Latin America

syndrome requires the presence of a genetically confirmed pathogenic mis-
match repair (MMR) variant (Sjursen et al., 2010; Dominguez-Valentin et al.,
2015; Da Silva et al., 2016; Tiwari et al., 2016). To select families for genetic
analysis, the Amsterdam criteria were developed to permit the identification of
MMR defects and their association within tumor spectrum (Vasen et al., 1999;
Umar et al., 2004). The Amsterdam criteria requires at least three affected
family members in two or more generations, with one being a first-degree
relative of the other two and at least one individual diagnosed before 50 years
of age (Vasen and Muller, 1991; Vasen et al., 1999). Amsterdam I applies to
families with three or more cases of colorectal cancer whereas Amsterdam-II
also includes extracolonic tumors, that is, endometrial cancer, cancer of the
upper urinary tract and cancer of the small bowel (Vasen and Muller, 1991;
Vasen et al., 1999). The Bethesda guidelines, originally designed to identify
tumors likely to have microsatellite instability (MSI), include aspects of the
tumor phenotype, but are less strict with regard to family history (Rodriguez-
Bigas et al., 1997; Umar et al., 2004). For this reason, families defined by the
Amsterdam criteria have shown a higher incidence of MMR gene mutations
than those defined by Bethesda. On the other hand, MSI or immunohisto-
chemical testing of tumors are used to select patients with a new colorectal
cancer diagnosis derived from germline diagnostic testing (Berg et al., 2009),
Lynch syndrome patients have an increased risk for the following cancers:
colorectal (lifetime risk = 70%–80%), endometrial (50%–60%), stomach
cancer (13%–19%), ovarian cancer (9%–14%), small intestine, biliary tract,
and brain as well as carcinoma of the ureters and renal pelvis (Kobayashi
et al., 2013).
Lynch syndrome is caused by germline pathogenic variants in one of the MMR
genes: MLH1, MSH2, MSH6 and PMS2 or deletion in the EPCAM gene, which
leads to methylation of the adjacent MSH2 promoter. Such variants are here
referred to as path_MMR (pathogenic variants in mismatch repair genes) and,
when specifying one of the genes, as path_MLH1, path_MSH2, path_MSH6,
path_PMS2 or path_EPCAM (Møller et al., 2015). The cumulative incidence of
any cancer at 70 years of age is 72% for path_MLH1 and path_MSH2 carriers
but lower in path_MSH6 (52%) and path_PMS2 (18%) carriers. Path_MSH6
and path_PMS2 carriers do not have increased risk for cancer before 40 years
of age (Møller et al., 2015; Møller et al., 2016). To date over 3100 unique DNA
variants across the MMR genes have been described in the International Society
for Gastrointestinal Hereditary Tumors (InSIGHT) (http://insight-group.org/
variants/database/), and a recent clinical InSiGHT consensus classification has
identified 57% of the MMR variants as pathogenic or likely pathogenic (Class
5 and 4), 32% as uncertain variants (Class 3), 4% as likely not pathogenic
(Class 2) and 7% as not pathogenic (Class 1) (Thompson et al., 2014; Da Silva
et al., 2016).