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. RESULTS: Of the eligible carriers, 246/384 (64%) answered the survey (median age: 44 years). Most were female (88%), married/in domestic partnership (66%), and had personal breast/ovarian cancer history (61%). PVs included BRCA1/2 (75%), CHEK2 (10%), PALB2 (5%), ATM (5%), NF1 (2%), RAD51C (2%), PTEN (1%), and TP53 (1%). Most (87%) participants were aware of their carrier status. When recommended, 37% underwent RR bilateral mastectomy, 48% RR oophorectomy, 70% annual mammogram, and 20% breast magnetic resonance imaging. Challenges hindering the uptake of RR measures included financial limitations (67%), lack of recommendation by their physician (35%), and fear (24%). Nearly all (98%) claimed sharing their results with their relatives. CT was initiated in 63% of families and was associated with carriers being married/in domestic partnership (P = .04) and believing GCRA was useful (P < .001). CONCLUSION: Despite the resource-constrained setting, relevant rates of RR measures and CT were observed. Targeted interventions to reduce out-of-pocket expenses and improve patient-physician communication and patients' understanding on carrier status are warranted to enhance the overall benefit of GCRA and ultimately improve the provision of patient-centered care to both carriers and their at-risk relatives.

Novel RB1 germline mutation in a healthy man.

BACKGROUND: Retinoblastoma (Rb) most frequently presents as a unilateral sporadic disease up to 40% of cases, however, arise from a monoallelic germline pathogenic variant. Only 10% of the germline mutations are inherited, and high penetrance is seen in up to 90% of these cases. As an effort to optimize counseling and screening, mutations are classified according to inheritance patterns. However, RB1 spectrum is highly heterogeneous, and information for unaffected carriers remains scarce. MATERIALS AND METHODS: The Mexican family of a 5-month-old patient diagnosed with Rb was studied. The family consisted of five individuals (father, mother, and three siblings). Genetic testing using a next-generation sequencing assay targeting RB1 with oligonucleotide baits designed to capture its exons and 20 bases flanking intronic sequences was performed in every family member. Clinical history and a complete ophthalmological examination (best-corrected visual acuity, slit-lamp biomicroscopy, macular optical coherence tomography, fundus autofluorescence, optical coherence tomography angiography, and electrophysiological studies) were performed in members testing positive to RB1 mutation. RESULTS: The father and her five-month-old daughter tested positive for a non-synonymous RB1 mutation c.459del (p.Lys154Serfs*21). The girl presented with bilateral retinoblastoma, successfully treated with cryotherapy and intravenous chemotherapy. The father had no relevant findings on imaging studies or ophthalmologic evaluation. CONCLUSIONS: This report describes a rare case of a novel low-penetrance RB1 germline mutation. Long-term follow-up of the father will include periodic evaluation of the eyes and orbits, and surveillance for systemic sarcoma and secondary malignancies. Implications for unaffected individuals need to be further studied.

A novel method to detect the Mexican founder mutation BRCA1 ex9­12del associated with breast and ovarian cancer using quantitative polymerase chain reaction and TaqMan® probes.

In 2015, according to the National Institute of Statistics and Geography (INEGI), malignant breast tumors were the first cause of cancer fatality in women (6,273 fatalities) in Mexico, whereas 2,793 fatalities in women were due to ovarian cancer. A total of 5­10% of breast cancer and 10­15% of ovarian cancer cases are caused by a hereditary breast­ovarian cancer syndrome, with mutations predominantly identified in the BRCA1 and BRCA2 genes. Recently, the Mexican founder mutation BRCA1 ex9­12del was identified (deletion of exons 9­12 with recombination between introns 8­12). This is the most frequently reported mutation in hereditary breast/ovarian cancer in Mexico. Current detection methods include end­point polymerase chain reaction (PCR) and Multiplex Ligation­dependent Probe Amplification (MLPA). In the present study a cheap, sensitive and fast detection method was developed based on quantitative PCR and two TaqMan® probes, one to detect the deletion (recombination region between introns 8 and 12), and the other one a region from exon 11. With this assay, 90 samples were able to be analyzed in 2 h using 2.5 ng of DNA/reaction at a cost of ~2­3 USD. This method is capable of detecting positive samples for DNA deletion and excluding negative ones. Therefore, the method proposed may be a useful high­throughput diagnostic option that could be useful in future association or prevalence studies that use large populations.