Precise, Genotype-First Breast Cancer Prevention: Experience With Transferring Monogenic Findings From a Population Biobank to the Clinical Setting

Abstract

Although hereditary breast cancer screening and management are well accepted and established in clinical settings, these efforts result in the detection of only a fraction of genetic predisposition at the population level. Here, we describe our experience from a national pilot study (2018–2021) in which 180 female participants of Estonian biobank (of >150,000 participants in total) were re-contacted to discuss personalized clinical prevention measures based on their genetic predisposition defined by 11 breast cancer–related genes. Our results show that genetic risk variants are relatively common in the average-risk Estonian population. Seventy-five percent of breast cancer cases in at-risk subjects occurred before the age of 50 years. Only one-third of subjects would have been eligible for clinical screening according to the current criteria. The participants perceived the receipt of genetic risk information as valuable. Fluent cooperation of project teams supported by state-of-art data management, quality control, and secure transfer can enable the integration of research results to everyday medical practice in a highly efficient, timely, and well-accepted manner. The positive experience in this genotype-first breast cancer study confirms the value of using existing basic genomic data from population biobanks for precise prevention.

Polygenic Risk Score Predicts Modified Risk in BRCA1 Pathogenic Variant c.4035del and c.5266dup Carriers in Breast Cancer Patients

“…Additionally, the study cohort does not reflect the general population of BRCA1 PV carriers as the samples were obtained due to diagnostic germline variant testing in a clinical setting, which introduces potential selection biases. Although previous studies in our region have demonstrated that the tested BRCA1 PVs-c.4035del and c.5266dup-account for approximately 80% of identified BRCA1 PVs [4,[8][9][10][11], it is important to acknowledge that this study focused only on these variants and did not investigate individuals with additional BRCA1 PVs relevant to the development of BC and OC. This may result in an incomplete understanding of the genetic landscape and may not capture the full population of BRCA1 PV carriers.…”

“…Every year, approximately 1200 and 300 women are diagnosed with BC and ovarian cancer (OC) in Latvia, respectively [2]. Female carriers of pathogenic variants (PVs) in high and moderate penetrance susceptibility genes, such as BRCA1 DNA repair-associated gene (BRCA1), BRCA2 DNA repair-associated gene (BRCA2), tumor protein p53 gene (TP53), partner and localizer of BRCA2 gene (PALB2), checkpoint kinase 2 gene (CHEK2), and ATM serine/threonine kinase gene (ATM), are at a highly increased risk of developing BC and OC compared with women in the general population [3,4].…”

“…The corresponding OC risk has been estimated to be 34% to 44% for female BRCA1 PV carriers [6,7]. In the Baltic region, previous research by several groups has demonstrated that two germline PVs in the BRCA1 gene-c.4035del and c.5266dup-are founder variants in these populations and account for approximately 80% of all identified PVs in the BRCA1 gene in BC and OC patients [4,[8][9][10][11].…”

The Prevalence and Molecular Landscape of Lynch Syndrome in the Affected and General Population

“…For the EstBB cohort, the library preparation methods, quality control and array genotyping have been described elsewhere [21]. Genotype calling for sequencing, array data and quality control has been described previously [11].…”

“…Details of this cohort are shown in Supplementary file (Tables S1 and S2), where all disease-causing variants found in the EstBB cohort can also be seen. It has been shown in previous EstBB studies that approximately 60% of Biobank participants are interested in further investigations and will come to genetic counseling [11].…”