Germline Pathogenic Variant Prevalence Among Latin American and US Hispanic Individuals Undergoing Testing for Hereditary Breast and Ovarian Cancer: A Cross-Sectional Study

Abstract

PURPOSE To report on pathogenic germline variants detected among individuals undergoing genetic testing for hereditary breast and/or ovarian cancer (HBOC) from Latin America and compare them with self-reported Hispanic individuals from the United States. METHODS In this cross-sectional study, unrelated individuals with a personal/family history suggestive of HBOC who received clinician-ordered germline multigene sequencing were grouped according to the location of the ordering physician: group A, Mexico, Central America, and the Caribbean; group B, South America; and group C, United States with individuals who self-reported Hispanic ethnicity. Relatives who underwent cascade testing were analyzed separately. RESULTS Among 24,075 unrelated probands across all regions, most were female (94.9%) and reported a personal history suggestive of HBOC (range, 65.0%-80.6%); the mean age at testing was 49.1 ± 13.1 years. The average number of genes analyzed per patient was highest in group A (A 63 ± 28, B 56 ± 29, and C 40 ± 28). Between 9.1% and 18.7% of patients had pathogenic germline variants in HBOC genes (highest yield in group A), with the majority associated with high HBOC risk. Compared with US Hispanics individuals the overall yield was significantly higher in both Latin American regions (A v C P = 1.64×10–9, B v C P < 2.2×10–16). Rates of variants of uncertain significance were similar across all three regions (33.7%-42.6%). Cascade testing uptake was low in all regions (A 6.6%, B 4.5%, and C 1.9%). CONCLUSION This study highlights the importance of multigene panel testing in Latin American individuals with newly diagnosed or history of HBOC, who can benefit from medical management changes including targeted therapies, eligibility to clinical trials, risk-reducing surgeries, surveillance and prevention of secondary malignancy, and genetic counseling and subsequent cascade testing of at-risk relatives.

Genomic disparity impacts variant classification of cancer susceptibility genes in Turkish breast cancer patients

“…The reclassifications are feasible due to the accumulation of larger genome databases and additional supporting evidence. Similarly, variant reclassification has been reported in ancestry‐based studies in underrepresented and diverse ethnic backgrounds 39,49–53 . Therefore, large prospective genetic studies are needed to assess the larger reclassification of variants in Turkish and other populations.…”

“…Similarly, variant reclassification has been reported in ancestry-based studies in underrepresented and diverse ethnic backgrounds. 39,[49][50][51][52][53] Therefore, large prospective genetic studies are needed to assess the larger reclassification of variants in Turkish and other populations. Furthermore, the development of large gnomAD-like databases representing the Turkish population and making such knowledge bases publicly available is a crucial next step in addressing the current limitations.…”

Ethnic‐specificity, evolution origin and deleteriousness of Asian BRCA variation revealed by over 7500 BRCA variants derived from Asian population

“…Table 1 lists the most common pathogenic BRCA variants in the Asian population. We tested the ethnic specificity of the 1762 Asian pathogenic BRCA variants by comparing them with the reported ones with clear ethnic origin information, including the 431 pathogenic BRCA variants collected from the Latino/Hispanic American population, 16 and the 466 pathogenic BRCA variants identified from Middle Eastern, North African and South European countries. 49 The results showed that only 192 of the 431 variants were shared accounting for 10.9% of the 1762 Asian pathogenic BRCA variants or 44.5% of the 431 Latin/Hispanic pathogenic BRCA variants (Figure 3A and Tables S8A‐S8C ); and only 264 of the 466 variants were shared accounting for 15% of the 1762 Asian pathogenic BRCA variants and 56.7% of the 466 pathogenic BRCA variants from Middle Eastern, North African and South European countries (Figure 3B and Tables S8D‐S8F ).…”

“…It is well determined that human BRCA variation is highly ethnic‐specific in human populations 9‐21 . Like in many human genetic studies, 22 however, the majority of current BRCA variation data were derived from the European descendant populations 23‐25 .…”

“…It is well determined that human BRCA variation is highly ethnic‐specific in human populations. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 Like in many human genetic studies, 22 however, the majority of current BRCA variation data were derived from the European descendant populations. 23 , 24 , 25 With highly heterogeneous genetic background, Asia has a population size of 4.7 billion or 60% of the world population ( https://www.worldometers.info/world-population/asia-population/ ), living in over 50 countries and regions across the geographically highly diversified Asia continent.…”