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Alan Stolier, MD/

Beyond BRCA Testing in Hispanic Population Founder Mutations in PALB2 and CHEK2 Predominate

Hispanic Beyond BRCA

Hispanic Americans are a rapidly growing segment of the United States population. Approximately 1 in 12 will develop breast cancer. The prognosis for these women is poor when compared to Americans of European ancestry. In 2013, Jeffrey Weitzel et al. examined BRCA test results in 746 Hispanics with a personal or family history of breast cancer. Mutations were detected in 25% of the cohort. Of interest, 11% of the 189, were large rearrangements. Furthermore, of the large rearrangements, 62% were BRCA1 ex9=12del, which appears to be a Mexican founder mutation.  This specific mutation represents 10-12% of all BRCA1 mutations in US population studies.

Now, multi-gene panels have begun to predominate the ordering habits of physicians and genetic counselors. Both high and intermediate-risk breast cancer susceptibility genes have consequently been noted to play an essential role in patients testing negative for the BRCA genes. In studies of these non-BRCA pathogenic variants, racial and ethnic minorities have generally been underrepresented.

In a recent study published in Cancer, Jeffrey Weitzel et al. studied 1054 high-risk Hispanic women diagnosed with breast or ovarian cancer and who tested negative for BRCA gene mutations. They found pathogenic variants in 49 BRCA negative Hispanic patients (4.6%).  Pathogenic variants were identified in 7 of the known or suspected breast cancer susceptibility genes. These included CHEK2 (n=20), PALB2 (n=18), ATM (n=5), BRIP1 (n=2), TP53 (n=3), CDH1 (n=1) and NF1 (n=1).

The PALB2 variant c.2167_2168del: pM723fs was detected in 9 patients. These variants were much more likely to have been diagnosed with ovarian cancer compared to those not carrying this variant. In CHEK2 carriers, the pathologic variant c.707T>C;pL236P was observed 14 times. This variant represented 70% of CHEK2 carriers in the study. The authors noted that this variant seemed comparable in prevalence and size of the effect to the 11delC CHEK2 mutation noted in the European population.

In summary, the authors pointed out that in Mexican-American patients, they found 3 recurrent pathogenic variants that account for 52% of the total. One PALB2 mutation accounted for 50% of all PALB2 pathologic variants. Interestingly they share this same PALB2 variant with Italian breast cancer families. Similarly, a single CHEK2 mutation represented 70% of pathologic variants in this cohort.


Comment: The identification of PALB2 and CHEK2 as the most common non- BRCA pathologic variants in the Hispanic population is quite impressive. Even more interesting is the high incidence of founder mutations in these two genes. Moreover, the authors point out that information may “enable enhanced screening” for this affected population. Yet as we enter the era of inexpensive gene panel testing (and possible universal testing) it is unlikely that we will revert to testing isolated genes even in populations that tend to harbor founder mutations.  

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