Abstract 4162: Prevalence of germline mutations and variants of uncertain significance (VUS) among Hispanics with suspected hereditary colorectal cancer syndromes
Authors: Perez-Mayoral Julyann , Cruz-Reyes Nicole , Rosa-Vazquez Andrea , Gonzalez-Pons Maria , Cruz-Correa Marcia 
Published: August 2019

Background: Colorectal cancer (CRC) is one of the leading causes of cancer death in Puerto Rico (PR) and U.S. Approximately 5-10% of all CRC cases are due to hereditary CRC syndromes. Some of the most common hereditary colorectal cancer syndromes include: Familial Adenomatous Polyposis (APC), Lynch Syndrome (MLH1, MSH2, MSH6, PMS2) and MUTYCH (MYH). Germline genetic testing is the gold standard for diagnosing these syndromes. The implications of obtaining a Variant of Uncertain Significance (VUS) in germline genetic testing results remains a clinical challenge especially among minority Hispanic populations. The aim of this project was to determine the prevalence of germline pathogenic mutations and VUS in CRC-risk genes; as well as the phenotype of Hispanic patients with suspected Hereditary CRC syndromes.

Methods: Germline genetic testing from patients with suspected hereditary CRC syndromes seen at the UPR Cancer Genetic Clinic during the period of 2015-2018 were evaluated. Sociodemographics, clinical, tumor and genetic testing data were accessed through the subject’s medical record. Descriptive statistics and frequency distribution tables were generated with the subject’s sociodemographic and clinical information, as well as germline genetic testing results.

Results: A total of 91 patients (61.5% female; mean age 51 years) with suspected hereditary CRC syndromes were tested for germline mutations in relevant CRC-risk genes. The most common malignancies reported were CRC (80%) and endometrial cancer (12%). The majority of patients (n=60) did not have germline mutations in hereditary CRC-risk genes. Mutations in CRC-risk genes were detected in 22% of patients (50% MYH, 45% MMR, 5% APC), while VUSs were detected in 12% (18% MYH, 45% MMR, 36% APC). There were no statistically significant differences with regards to gender, age, personal history of cancer or 1st degree family history of cancer across study groups. All patients with VUSs in MMR-genes had microsatellite stable tumors; while those with mutations in MMR-genes had microsatellite unstable tumors.

Conclusions: VUSs were present in a high-percentage of the patients evaluated for hereditary CRC syndromes. Furthermore, there were no phenotypical differences between patients with pathogenic mutations and those with VUSs. This presents a clinical challenge as non-European populations including Hispanics have genetic variances, which may in fact carry an increase risk for cancer. Future research is warranted to examine the significance and/or reclassify VUSs to improve assessment of genetic test results in admixed populations.

Citation Format: Julyann Perez-Mayoral, Nicole Cruz-Reyes, Andrea Rosa-Vazquez, Maria Gonzalez-Pons, Marcia Cruz-Correa. Prevalence of germline mutations and variants of uncertain significance (VUS) among Hispanics with suspected hereditary colorectal cancer syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4162.