Predictive models as a clinical decision support tool for genetic cancer risk assessment among Mexican patients at risk of hereditary colorectal cancer.
Authors: Rodriguez Olivares Jose Luis , Aguilar y Méndez Dione , Rivero Garcia Pamela , Aranda-Gutierrez Alejandro , Ortiz-Lopez Rocío , Santuario Facio Sandra , Rojas-Martinez Augusto , Barraza Leticia , Arteaga Vazquez Jazmin , De La Mora Hector , Kimball Tamara N. , Jeter Joanne M. , Weitzel Jeffrey N. , Chavarri Guerra Yanin 
Published: June 2024

10617 Background: Hereditary cancer syndromes, including Lynch syndrome (LS) with an increased risk of colorectal cancer (CRC), have prompted the development of clinical criteria and predictive models (PM) to identify at-risk individuals. However, these criteria have been validated with limited representation from the Latino population. Several factors may influence CRC penetrance, potentially leading to variations in PM performance across populations. Given that CRC ranks as the third most prevalent cancer worldwide, the increasing incidence of early-onset disease highlights the need for expanding Genetic Cancer Risk Assessment (GCRA) services. Methods: This prospective study included Mexican patients who were diagnosed with CRC and met NCCN criteria for GCRA. Participants were enrolled at two referral centers in Mexico, the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City and at the Hospital Zambrano Hellion TecSalud, Nuevo Leon. Participants' carrier risk was estimated using the PREMM5 model. Amsterdam II and revised Bethesda criteria, immunohistochemistry (IHC) for DNA mismatch repair (MMR) proteins in tumor tissue and multigene panel testing results were reviewed. For this analysis, only pathogenic and likely pathogenic (P/LP) variants in probands were reported. Results: From April 2016 to October 2023, 194 patients were included, with a median age at diagnosis of 45.0 (range 17-82) years, and 49.5% were women. P/LP variants were identified in 37.6% (n=73). 27.5% (n=50) were carriers of P/LP variants associated with LS (29 MLH1, 13 MSH2, 6 MSH6, and 2 PMS2). 11.8% (n=23) were carriers of P/LP variants in other genes (7 APC, 4 ATM, 3 CHEK2, 2 BRCA1, 2 TP53, 2 STK11, 1 PALB2, 1 BRIP1, and 1 MUTYH). Overall, carriers of PVs were diagnosed with CRC at a younger age than non-carriers (42 vs 46 years, p=0.034). The Amsterdam II criteria proved to be accurate (Sen 55%, Spe 91%, PPV 0.69, NPV 0.85), while the Bethesda criteria (Sen 98%, Spe 18%, PPV 0.29, NPV 0.96) and IHC for MMR proteins (Sen 94%, Spe 67%, PPV 0.61, NPV 0.95) were found to be highly sensitive. The area under the ROC curve for PREMM5 was 0.82 with a mean score 28.5 (2.1 – 50) in patients with LS and 6.0 (0.9 – 50) in non-carriers. Carriers of PVs had a higher rate of multiple primary malignancies than non-carriers (41.0% vs 19.0%, p=0.0014), and self-reported family history of CRC (65.7% vs 24.8%, p<0.001). Conclusions: Our results showed the PREMM5 model and IHC for MMR proteins effectively prioritized patients eligible for germline genetic testing in resource-limited settings. The performance of PREMM5 in this Mexican cohort was similar to that reported in the validation study of this model in other populations. Considering the spectrum of identified P/LP variants, the multigene panel test should be used in the comprehensive evaluation of Mexican patients with CRC.