Comprehensive germline analysis in young adults of Latin American descent with early-onset cancer.

Abstract

e22600 Background: Approximately 8% of adult cancer patients carry a pathogenic germline variant (PGV), and 35% have variants of uncertain significance (VUS). However, the genetic profiles of Latinos, the fastest-growing demographic group in the U.S., are less well-characterized compared to those of African or European descent. Young adults (diagnosed at age ≤45) are more likely to carry germline mutations. Here, we report the results of comprehensive germline testing in this group. Methods: A retrospective institutional chart review was conducted on 2,160 patients over 3 years. Among these, 277 patients were diagnosed with malignancies at age ≤45 and self-reported as being of Latin American descent. Of these, 78 underwent comprehensive genetic testing (48- or 70-gene panels) as part of their clinical care. Statistical analyses included a binomial test to evaluate prevalence, ANOVA to assess equality of mean mutation counts across primary sites, and Fisher’s exact test to examine associations. Statistical significance was set at p < 0.05. Results: Among the 78 patients, cancer diagnoses were as follows: 59% breast, 26% GI, and the remainder hematologic, germ cell, and sarcoma. Sixteen (21%) had a PGV, 29 (37%) had a VUS, and 49% were reportedly normal. The median age at diagnosis was 38 years (range: 20–45). PGV and VUS prevalence (21% and 37%, respectively) were significantly greater than zero among all patients (p < 0.0001). There was no evidence to support an association between primary site and PGV (p = 0.21) or VUS status (p = 0.56), nor between family history and PGV status (p = 0.14). However, there was a significant association between family history and VUS status. Among the 16 patients with a family history and a VUS, 69% had breast and 31% GI cancers. The median number of PGVs was 0 (range: 0–2), and the median number of VUS was 0 (range: 0–3). While mean PGV and VUS counts differed significantly from zero across all patients, mean PGV and VUS counts did not differ significantly across primary sites (p = 0.14 and p = 0.59, respectively). Of the 29 patients with a VUS, 9 (31%) had multiple variants, most commonly in the ATM, AXIN, MSH, and POLE genes. Of the 24 patients with a VUS and no PGV, 12 (50%) had a family history. Conclusions: Individuals of Latino ancestry have a diverse genetic background, influenced by contributions from Indigenous, African, and European origins, leading to distinct genomic characteristics. Our findings suggest a notable prevalence of pathogenic variants among Latino young adults, as well as high rates of VUS that may warrant further evaluation, particularly in the context of early-onset cancer and a family history of cancer. These insights underscore the importance of considering comprehensive germline testing for cancer patients under 45. Further research and data collection focused on Latino populations are needed to better understand and address potential disparities in cancer risk and outcomes.