Hereditary cancer syndromes in Latino populations: genetic characterization and surveillance guidelines

In Hispanics, deleterious BRCA mutations have been found in approximately 25% of women with BC [9]. The majority of the studies reporting the prevalence of BRCA mutations in Hispanics have been performed on heterogeneous groups of Hispanic women from different countries, including: Mexico [9‐11], Brazil [12‐14], Costa Rica [15], Chile [16, 17], Argentina [18], Peru [19], Colombia [20, 21], Venezuela [22], Bahamas [23], Cuba [24], and Puerto Rico [25] (Table 1). Recently, BRCA mutations in Latin American countries was published, which detailed the mutations found and how the prevalence changed from country to country [26]. All of these studies have shown that the BRCA mutation spectrum varies according to the country of origin. For example, women from Argentina, Mexico, and Brazil have a higher prevalence of BRCA1 mutations [13, 18, 27], whereas in women from the Caribbean (Cuba and Puerto Rico), BRCA2 is more frequently mutated [24, 25]. Studies of women with BC from Spain showed a larger number of rearrangements in both BRCA genes when compared to Hispanic women [28‐30]. Additionally, several mutations for both BRCA genes were found in Hispanic subpopulations, especially in Argentina where there is a higher proportion European admixture. Furthermore, a mutation (BRCA2 c.156_157insAlu) from Portugal was identified in the Northern/Central region and accounted for one-fourth of the BRCA1/2 mutations [31]. This same mutation was identified in several families of Brazil [31, 32].

Several populations have shown the presence of founder mutations, which include some Ashkenazi Jew mutations (BRCA1 185delGA; BRCA1 5382insC) observed in Mexico [33], Peru [19], and Brazil [13]. These founder mutations have also been reported in Spain [28‐30]. Therefore, these Ashkenazi Jew mutations are thought to come from areas of Spain where Jews communities settled during the early Common Era. The BRCA1 ex9-12 deletion found in Mexican women is also a founder mutation. This mutation has not observed in Spain or South American populations, and was found to pre-date Spanish colonization since it is estimated to have arisen approximately 1,480 years ago [10, 34, 35] (Table 1). Furthermore, two additional founder mutations of Galician and Spanish origin were found in Spain [28]. Of these, the BRCA1 c.211A > G Galician founder mutation was found in the groups of a US Hispanic and the Argentinian cohort [11, 18]. Three additional founder mutations: 2 in BRCA1 (BRCA1 c.3331_3334delCAAG and BRCA1 c.5123C > A) and 1 in BRCA2 (BRCA2 c.2806_2809delACAA) where described in Hispanics from Colombia [21]. These Colombian founder mutations were found in individuals that share the same haplotype, and therefore share a common ancestor [21]. The BRCA2 c.3922G > T mutation has only been identified in the Puerto Rican cohort, and in US Hispanic studies that include Puerto Ricans and not in other Latin American countries [26]. In Portugal, the BRCA2 c.156_157insAlu mutation seen in families of Portuguese descent was also identified as a founder mutation that occurred around 558 years ago [31, 32, 36]. Moreover, the BRCA1 c.5266dup mutation was identified as a founder Brazilian mutation of Eastern European origin [37]. The presence of these founder mutations in Latin America is tightly linked to migration patterns that shaped the genetic background of each Hispanic subpopulation up to present-day.

Several studies suggest that the prevalence of BRCA mutations in Hispanic women is higher than the prevalence of BRCA mutations among Ashkenazi Jews and non-Hispanic Whites [9, 11]. However, these observations are based on the predictability of BRCA genetic risk models that use non-Hispanic White women as reference to determine risk, thus the prevalence of BRCA mutations might differ from what has been reported [9]. Differences observed in the BRCA mutation spectrum of Hispanic populations could be due to variations in the contribution of each ancestral population to the genetic background of the Hispanic subgroups. In addition, there is very limited information on the mutation spectrum in some countries, such as Costa Rica, Bahama, and Cuba, among others. Therefore, the mutation spectrum of BRCA among Hispanic women is still understudied, which may our knowledge on the true percentage of BC in Hispanic populations that may be attributable to hereditary changes.

The clinical presentation of HBOC among Hispanic subpopulations is very similar to non-Hispanic cohorts [12, 17, 19, 21, 25, 36‐40]. Most studies reported that the majority of women that met inclusion criteria had BC diagnosed before age 50 (67.5%; range: 50.4–81.4%). Additionally, family history of BC was found on an average of 16.1% (range: 5.2–27%) of Hispanic women recruited in the studies described in this review. Comparisons of the age at BC diagnosis among the Hispanic subpopulations described above showed that Caribbean Hispanics (Bahamas, Puerto Rico and Cuba) were diagnosed at later ages (mean: 45.9 years; range: 40–51.8 years) than their South American (mean: 44 years), Central American (mean: 41.6 years) and US Hispanic (mean: 38.5 years) counterparts [17, 19, 21, 25, 28‐30, 32, 36‐41].

The National Comprehensive Cancer Network (NCCN) established guidelines for physicians to evaluate potential candidates for genetic counseling and testing [42]. The evaluation criteria for HBOC genetic testing include: personal history of BC before 50 years of age, one or more 1^st degree relatives with BC, family history of a BRCA1/2 mutation, and personal history of OC, among others. The information obtained from the genetic tests is used by physicians to guide the patient’s medical/surgical management. This management may include chemoprevention therapy, prophylactic surgery (double mastectomy, oophorectomy, and/or hysterectomy), and increased surveillance by mammography and breast MRI. Even though these guidelines have been established, underutilization of these guidelines for Hispanic patients that meet the criteria has been reported [43]. The reason for the low adherence to these guidelines is yet to be addressed, but it is believed that a combination of factors such as, socioeconomic, belief systems, and access to care contribute to this health disparity. Furthermore, the benefits of utilizing these guidelines in other countries, where prevalence of BRCA mutations is high, is still to be determined. For example, the high prevalence of BRCA mutations in the Bahamas supports the implementation of universal testing. However, countries such as Puerto Rico, that have a small number of mutations, could benefit even more from implementing these guidelines. Additionally, it is important to note that these guidelines where developed using studies mainly performed in non-Hispanic White women. Further studies are needed to elucidate whether NCCN guidelines are useful in Hispanic women or if the differences observed in the prevalence of BRCA mutations and clinical presentation, warrants changes to accommodate these differences.

FAP is characterized by the presence of hundreds to thousands of adenomatous polyps in the colon and rectum. These polyps appear during adolescence and, if left untreated, can develop into CRC by age 40. Affected individuals without a colectomy have close to 100% lifetime risk of developing CRC [44]. By age 20, most patients have at least 1 adenomatous polyp; by age 50, most have developed adenocarcinoma [44]. Thus, the recommended treatment for FAP is prophylactic colectomy in young adulthood [45].

Classic FAP has an incidence ranging from 1 in 8300 people to 1 in 22,000 people, depending on the country of origin [46]. FAP is caused by mutations in the APC gene [47]. Most cases have a family history of FAP, but close to 25% of cases are diagnosed as de novo mutations [48]. Identifying the specific APC mutation in a family can be used for targeted sequencing testing for pre-symptomatic, at-risk family members.

LS accounts for 2–4% of all CRC cases [44]. This syndrome is characterized by CRC at an early age and a high risk for a number of additional primary cancers, including endometrial and gastric cancer [57]. Approximately 1 in 35 individuals diagnosed with CRC has LS [58]. During their lifetime, individuals with LS will have up to a 70% risk of developing CRC [58]; women will have up to a 45% risk of developing endometrial cancer [59].