Addressing the need for genetic cancer risk assessment in Mexico: From establishment of a formal program to delivery innovation and expansion.

Purpose: The purpose of this manuscript is to show the process of the establishment and adaptation of an oncogenetics program in Mexico.

Methods: The oncogentics program at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán was established as a traditional in-person service and adapted to include telemedicine counseling to expand services to other hospitals and persists as a mixed counseling model with research/commercial genetic testing.

Results: A total of 2222 participants were included with a median age of 47 years and 77.

Pathogenic variants in cancer susceptibility genes predispose to Ductal Carcinoma In situ of the breast.

Purpose: To determine the relationship between germline pathogenic variants (PVs) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS).

Methods: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls, and between DCIS and infiltrating ductal carcinoma (IDC) cases from a clinical-testing cohort (n=9,887), a population-based cohort (n=3,876) and the UK Biobank (n=2421). The risk of contralateral breast cancer for DCIS cases with PVs was estimated in the population-based cohort.

Uptake of Risk-Reducing Surgeries in an International Real-World Cohort of Hispanic Women.

Purpose: Women with pathogenic variants (PVs) in breast cancer (BC) and ovarian cancer (OC) associated genes are candidates for cancer risk-reducing strategies. Limited information is available regarding risk-reducing surgeries (RRS) among Hispanics. The aim of this study was to describe the uptake of RRS in an international real-world experience of Hispanic women referred for genetic cancer risk assessment (GCRA) and to identify factors affecting uptake.

Poor compliance with germline testing recommendations in colorectal cancer patients undergoing molecular residual disease testing.

Background: Approximately 15% of colorectal cancers (CRCs) are associated with germline mutations. There is increasing adoption of DNA-based assays for molecular residual disease (MRD) and growing evidence supporting its clinical utility, particularly for CRC by oncologists in the U.S.

Prevalence and spectrum of germline pathogenic variants in cancer susceptibility genes among mexican patients with exocrine pancreatic cancer.

Background: Although universal germline genetic testing is recommended for patients with exocrine pancreatic cancer (PC), access to genetic testing remains limited in low- and middle-income countries. This study aims to narrow the gap in our understanding of the spectrum of germline pathogenic and likely pathogenic variants (PVs) in cancer susceptibility genes in the Mexican population.

Methods: The landscape of PVs in cancer susceptibility genes was identified by next-generation sequencing multigene panel assays among patients with PC who were enrolled in the Clinical Cancer Genomics Community Research Network prospective registry in Mexico City.

Lynch syndrome in Mexican-Mestizo families: Genotype, phenotypes, and challenges in cascade testing among relatives at risk.

Lynch syndrome (LS) is the most frequent cancer predisposition syndrome affecting the colon and rectum. A pathogenic variant (PV) disrupting one of the mismatch repair (MMR) genes is responsible for the disease. The spectrum of tumors in LS is heterogeneous and includes cancer of the colon and rectum (CRC), endometrium, ovaries, stomach, small bowel, urinary tract, bladder, pancreas, and skin.

Addressing the Historic Challenges of and Variant Curation and the Need for More Diverse Representation.

Advancements in variant curation challenges: minority representation and incomplete data reporting.

Uptake of Risk-Reducing Measures, Cascade Testing, and Related Challenges Among Carriers of Breast Cancer-Associated Germline Pathogenic Variants in Mexico.

Purpose: Genetic cancer risk assessment (GCRA) provides pathogenic variant (PV) carriers with the invaluable opportunity to undertake timely cancer risk-reducing (RR) measures and initiate cascade testing (CT). This study describes the uptake of these strategies and the related barriers among breast cancer-associated germline PV carriers in Mexico.

Methods: Carriers who were at least 6 months after disclosure of genetic test results at two GCRA referral centers were invited to answer a survey assessing sociodemographic characteristics, awareness of their carrier status and its implications, uptake of RR measures according to international guidelines by PV, CT initiation, and associated challenges.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).

Methods: We analyzed >22 million variants for 398,238 women.

Hereditary cancer testing in a diverse sample across three breast imaging centers.

Purpose: Up to 10% of all breast cancers (BC) are attributed to inherited pathogenic variants (PV) in BC susceptibility genes; however, most carriers of PVs remain unidentified. Here, we sought to determine the yield of hereditary cancer gene PVs among diverse women attending breast imaging centers, who could benefit from enhanced surveillance and/or risk reduction interventions.

Methods: This cross-sectional retrospective cohort study included consecutive women, unselected for personal or family cancer history, who were offered genetic testing for hereditary cancer genes at the time of breast imaging at three centers (November 2020-March 2022).

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.

Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT).

Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.

Unlabelled: Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C-/- cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region.

Profiling the Somatic Mutational Landscape of Breast Tumors from Hispanic/Latina Women Reveals Conserved and Unique Characteristics.

Unlabelled: Somatic mutational profiling is increasingly being used to identify potential targets for breast cancer. However, limited tumor-sequencing data from Hispanic/Latinas (H/L) are available to guide treatment. To address this gap, we performed whole-exome sequencing (WES) and RNA sequencing on 146 tumors and WES of matched germline DNA from 140 H/L women in California.

Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2.

Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.

Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies.

Maternal Malignancy After Atypical Findings on Single-Nucleotide Polymorphism-Based Prenatal Cell-Free DNA Screening.

Objective: To evaluate the incidence and clinical outcomes of cell-free DNA results suspicious for maternal malignancy on prenatal cell-free DNA screening with single-nucleotide polymorphism (SNP)-based technology.

Methods: This retrospective cohort study included data from SNP-based, noninvasive prenatal screening samples from a commercial laboratory from January 2015 to October 2021. Maternal plasma was screened for trisomy 21, 18, and 13; monosomy X; and triploidy.

Integration of a Cross-Ancestry Polygenic Model With Clinical Risk Factors Improves Breast Cancer Risk Stratification.

Purpose: To develop and validate a cross-ancestry integrated risk score (caIRS) that combines a cross-ancestry polygenic risk score (caPRS) with a clinical estimator for breast cancer (BC) risk. We hypothesized that the caIRS is a better predictor of BC risk than clinical risk factors across diverse ancestry groups.

Methods: We used diverse retrospective cohort data with longitudinal follow-up to develop a caPRS and integrate it with the Tyrer-Cuzick (T-C) clinical model.

Whole exome sequencing and replication for breast cancer among Hispanic/Latino women identifies as a susceptibility gene for estrogen-receptor-negative breast cancer.

Introduction: Breast cancer (BC) is one of the most common cancers globally. Genetic testing can facilitate screening and risk-reducing recommendations, and inform use of targeted treatments. However, genes included in testing panels are from studies of European-ancestry participants.

Variable number tandem repeats (VNTRs) as modifiers of breast cancer risk in carriers of BRCA1 185delAG.

Despite substantial efforts in identifying both rare and common variants affecting disease risk, in the majority of diseases, a large proportion of unexplained genetic risk remains. We propose that variable number tandem repeats (VNTRs) may explain a proportion of the missing genetic risk. Herein, in a pilot study with a retrospective cohort design, we tested whether VNTRs are causal modifiers of breast cancer risk in 347 female carriers of the BRCA1 185delAG pathogenic variant, an important group given their high risk of developing breast cancer.

Development and Validation of a Breast Cancer Polygenic Risk Score on the Basis of Genetic Ancestry Composition.

Purpose: Polygenic risk scores (PRSs) for breast cancer (BC) risk stratification have been developed primarily in women of European ancestry. Their application to women of non-European ancestry has lagged because of the lack of a formal approach to incorporate genetic ancestry and ancestry-dependent variant frequencies and effect sizes. Here, we propose a multiple-ancestry PRS (MA-PRS) that addresses these issues and may be useful in the development of equitable PRSs across other cancers and common diseases.

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation.

Influence of germline genotype on the survival of patients with triple-negative breast cancer.

The presence of pathogenic variants (PVs) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with PVs can develop treatment resistance through the appearance of reversion mutations and restored expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of CNVs may have improved survival after treatment compared to carriers of other PVs or wild-type.