The Ashkenazi Jewish (AJ) community has been identified as a group with elevated risk for numerous genetic diseases including hematological, biochemical diseases, and various types of cancers, most likely because of a genetic bottleneck that preceded a period of rapid population growth (Behar et al., 2004). This historical trajectory fostered a high prevalence of genetic variants related with numerous dominant and recessive conditions (Gusev et al., 2012; Palamara et al., 2012). The Jewish community represents the third religious group in the Mexican population (INEGI, 2020) and constitutes the third largest Jewish community in Latin America (Avni et al., 2011).

In Mexico, breast cancer is the leading cause of cancer-related deaths among women aged 20 to 59, and 5%–10% of cases can be explained by hereditary genetic factors. Pathogenic and Likely Pathogenic (P/LP) genetic variants in the BRCA1/2 (Breast Cancer 1/2) genes are the main cause of hereditary breast cancer. Among individuals of AJ ancestry, most breast cancers are due to three BRCA1/2 founder mutations (BRCA1: 185delAG [c.68_69del], 5382insC [c.5266dup]; BRCA2: 6174delT [c.5946del]); while in the Mexican population the founder mutation BRCA1 ex9-12del has a high frequency. The prevalence of pathogenic variants in non-BRCA genes has not been widely investigated in the Latin American Region generally, or Mexico specifically (Cock-Rada et al., 2018; Quezada Urban et al., 2018; Adaniel et al., 2019; Oliver et al., 2019; Sandoval et al., 2021; Solano et al., 2021).

While various studies have identified germline pathogenic variants associated with hereditary cancer syndromes in the Mexican population, there is currently no information on genetic alterations specifically focused on Mexicans who self-identify as AJ (Torres-Mejía et al., 2015; Villarreal-Garza et al., 2015; Moreno-Ortiz et al., 2016; Quezada Urban et al., 2018; Gallardo-Rincón et al., 2020). The lack of this information remains an important limitation to further evaluate the implications of identifying high risk populations in genomic testing and public health policies in Mexico. To address this gap, we conducted a genetic analysis of 143 genes associated with a variety of cancers to ascertain the prevalence and composition of pathogenic genetic variants among individuals of AJ ancestry who were born and live in Mexico.

Individuals of Ashkenazi Jewish ancestry have been identified as a population with a distinctive genetic background, characterized by a higher prevalence of certain pathogenic variants associated with susceptibility to both chronic and rare diseases, as evidenced by a relatively high frequency of alleles associated with breast and ovarian cancer (Ostrer, 2001; Xiao and Lauschke, 2021). We aimed to evaluate the germline cancer susceptibility mutation landscape in the AJ diaspora in Mexico. The landscape of germline pathogenic variants present in extensive panels of cancer associated genes have not been evaluated in recent generations of women of Ashkenazi Jewish origin, in particular in those populations after migration to Latin America. Moreover, most of the genetic studies on the AJ population are conducted in patients with a confirmed diagnosis of cancer and therefore, the reported frequency of founder pathogenic germline variants could be mainly influenced by the high proportion of inherited disease cases and may be underestimated in the unaffected AJ population. Population-based screening studies in AJ women without cancer diagnosis have reported BRCA1/2 mutation frequencies of 1.1%–2.9% (Metcalfe et al., 2010; Manchanda et al., 2015; 2020). Furthermore, the allelic composition of cancer susceptibility variants in genes distinct from BRCA1/2 is generally not evaluated in healthy populations at higher risk. As a result, it is possible that an important proportion of AJ germline carriers is not detected, especially in low- and middle-income countries where access to genetic counseling and germline testing is still restricted.

We showed that self-identification as AJ and the ancestry genetic composition agreed sufficiently to characterize AJ population in Mexico (Mathieson and Scally, 2020). As expected, admixture of genetic ancestries was present. However, a high proportion of participants (92%) shared ≥70% of the evaluated alleles with populations located in Europe. These combined results provide evidence that endogamy in the AJ population in Mexico is still persistent as confirmed by social studies showing that bicultural marriages were scarce among Jewish immigrants, as well as among the first generations born in Mexican territory (Goldsmit Brindis, 2010).

The proportion of AJ individuals carrying p or LP germline variants identified (26.7%) confirms the persistent elevated risk for chronic diseases, including cancer among AJ communities in Mexico as reported in a prior publication on this population (Morgenstern-Kaplan et al., 2022). Sixteen percent of the participants carried a p variant in a high-risk cancer gene. All p variants found correspond to founder mutations previously described in the AJ population, which have not been reported in the Mexican non-Jewish population (Ellis et al., 1998; Shaag et al., 2005) and were detected in individuals without personal history of cancer. Pathogenic and LP variants were significantly associated with younger age confirming the elevated prevalence of germline genetic variants in the AJ population and the need for timely genetic testing and counseling before disease onset. Interestingly, several reports have shown that almost 50% of Jewish participants with cancer that harbor a high-risk pathogenic variant have no family history (Walsh et al., 2017; Tennen et al., 2020).

In this work, we did not detect P or LP variants in BRCA1 or BRCA2 genes. However, CHEK2 LP variants were detected at a frequency of 2.9%. This frequency is not higher than those found in other previous reports for AJ breast cancer patients but slightly higher for cancer-free AJ women (Shaag et al., 2005). For cancer-free AJ women the probability of having a pathogenic mutation in CHEK2 is 1.4%–1.7% and the chance for a mutation in BRCA1 or BRCA2 is less than 2.5% (Walsh et al., 2017). This result highlights the importance of comprehensive genetic testing with a multigene panel to identify CHEK2 alterations, as well as private mutations in susceptibility genes for AJ women with no founder or p variant in BRCA1 or BRCA2. In addition, further evidence involving treatment decisions strongly reinforces consideration for CHEK2 testing. A recent study has shown poorer clinical outcomes for breast cancer patients diagnosed with invasive, early-onset breast cancer who carry a CHEK2 pathogenic variant (Greville-Heygate et al., 2020). These results also echo the recommendations regarding prudent use of consumer directed genetic tests targeting high-risk populations including exclusively highly prevalent founder pathogenic variants. For example, the FDA-Authorized, Direct-To-Consumer BRCA Test commercialized by 23andMe^Ⓡ only identifies three BRCA1 p variants common in people of Ashkenazi Jewish ancestry. A negative result of this test must lead to complementary testing.

Among the recognized risk factors for breast cancer, the participants reported greater current alcohol consumption compared with the overall prevalence of alcohol consumption in Mexican women (64 percent versus 39 percent, respectively) (ENCODAT, 2017). In 2020, 1.3% (range 0.7%–2.1%) of all cancer cases diagnosed in women in Mexico were attributed to alcohol consumption (Rumgay et al., 2021). Considering the underlying elevated cancer risk AJ populations have, additional efforts promoting reduction of alcohol consumption should be envisioned in this community.

Interpretation of current results should consider some limitations in this study. Despite our stringent selection criteria to include a fair representation sample of the AJ community in Mexico, participants identified were born and lived in the central capital of the country and therefore do not fully represent AJ women from other regions of the country. Since in this study we investigated volunteers without medical indication, it is possible that there is a recruitment bias toward low-risk participants, as high-risk individuals may have already been analyzed by commercial laboratory testing. This may explain why common founder mutations in BRCA1/2 were not detected in this population. Despite the vast size of our gene panel, this strategy is not able to identify variants in promoters or remote regulatory regions, or those present in sites involved in mRNA processing such as 5′- and 3′-UTRs. Intronic variants that may affect splicing are also not covered. It is possible that these non-coding variants may contribute to the pathogenic allele pool of this population as has been shown in other reports (Hansmann et al., 2012; Burke et al., 2018; Evans et al., 2018; Montalban et al., 2019). Additional investigations involving whole genome sequencing and functional analysis are required to better understand the impact and composition of pathogenic genetic variation in this population.

This is the first study that estimates the prevalence of P and LP alleles in Mexican women who self-identify as AJ, showing an elevated frequency (26.7%) of participants with P or LP germline variants in cancer susceptibility genes, of which 14% were in high-risk genes. In the study sample of Ashkenazi Jewish individuals, we did not identify common pathogenic mutations in the BRCA1/2 genes but found high-penetrance mutations in other cancer associated genes such as MSH6, APC and MSH2. Pathogenic variants in HBOC moderate-risk genes such as CHEK2 were frequent in study participants without personal history of cancer. These findings need to be further explored as to better describe the cancer genetic risk of women who identify as AJ in Mexico and develop targeted cancer prevention programs focused both on genetic screening and modifiable risk factors such as reduction of alcohol consumption.