Zdenek Kleibl

A comprehensive study evaluating germline FANCG variants in predisposition to breast and ovarian cancer

AbstractBackgroundMonoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear.MethodsHere, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk.ResultsThe frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss‐of‐heterozygosity of the wild‐type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations.ConclusionOur study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.

Population‐specific validation and comparison of the performance of 77‐ and 313‐variant polygenic risk scores for breast cancer risk prediction

AbstractBackgroundThe polygenic risk score (PRS) allows the quantification of the polygenic effect of many low‐penetrance alleles on the risk of breast cancer (BC). This study aimed to evaluate the performance of two sets comprising 77 or 313 low‐penetrance loci (PRS77 and PRS313) in patients with BC in the Czech population.MethodsIn a retrospective case‐control study, variants were genotyped from both the PRS77 and PRS313 sets in 1329 patients with BC and 1324 noncancer controls, all women without germline pathogenic variants in BC predisposition genes. Odds ratios (ORs) were calculated according to the categorical PRS in individual deciles. Weighted Cox regression analysis was used to estimate the hazard ratio (HR) per standard deviation (SD) increase in PRS.ResultsThe distributions of standardized PRSs in patients and controls were significantly different (p < 2.2 × 10−16) with both sets. PRS313 outperformed PRS77 in categorical and continuous PRS analyses. For patients in the highest 2.5% of PRS313, the risk reached an OR of 3.05 (95% CI, 1.66–5.89; p = 1.76 × 10−4). The continuous risk was estimated as an HRper SD of 1.64 (95% CI, 1.49–1.81; p < 2.0 × 10−16), which resulted in an absolute risk of 21.03% at age 80 years for individuals in the 95th percentile of PRS313. Discordant categorization into PRS deciles was observed in 248 individuals (9.3%).ConclusionsBoth PRS77 and PRS313 are able to stratify individuals according to their BC risk in the Czech population. PRS313 shows better discriminatory ability. The results support the potential clinical utility of using PRS313 in individualized BC risk prediction.

Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?

Ovarian cancer (OC) is one of the leading causes of cancer-related deaths in women. Most patients are diagnosed with advanced epithelial OC in their late 60s, and early-onset adult OC diagnosed ≤30 years is rare, accounting for less than 5% of all OC cases. The most significant risk factor for OC development are germline pathogenic/likely pathogenic variants (GPVs) in OC predisposition genes (including BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, Lynch syndrome genes, or BRIP1), which contribute to the development of over 20% of all OC cases. GPVs in BRCA1/BRCA2 are the most prevalent. The presence of a GPV directs tailored cancer risk-reducing strategies for OC patients and their relatives. Identification of OC patients with GPVs can also have therapeutic consequences. Despite the general assumption that early cancer onset indicates higher involvement of hereditary cancer predisposition, the presence of GPVs in early-onset OC is rare (<10% of patients), and their heritability is uncertain. This review summarizes the current knowledge on the genetic predisposition to early-onset OC, with a special focus on epithelial OC, and suggests other alternative genetic factors (digenic, oligogenic, polygenic heritability, genetic mosaicism, imprinting, etc.) that may influence the development of early-onset OC in adult women lacking GPVs in known OC predisposition genes.