BACKGROUND: Monoallelic 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. METHODS: Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk. RESULTS: The 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. CONCLUSION: Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.
- MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu * genetika MeSH
- nádory vaječníků * genetika MeSH
- oprava DNA genetika MeSH
- protein FANCG * genetika MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- zárodečné mutace * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The subset of ovarian cancer (OC) diagnosed ≤ 30yo represents a distinct subgroup exhibiting disparities from late-onset OC in many aspects, including indefinite germline cancer predisposition. We performed DNA/RNA-WES with HLA-typing, PRS assessment and survival analysis in 123 early-onset OC-patients compared to histology/stage-matched late-onset and unselected OC-patients, and population-matched controls. Only 6/123(4.9%) early-onset OC-patients carried a germline pathogenic variant (GPV) in high-penetrance OC-predisposition genes. Nevertheless, our comprehensive germline analysis of early-onset OC-patients revealed two divergent trajectories of potential germline susceptibility. Firstly, overrepresentation analysis highlighted a connection to breast cancer (BC) that was supported by the CHEK2 GPV enrichment in early-onset OC(p = 1.2 × 10-4), and the presumably BC-specific PRS313, which successfully stratified early-onset OC-patients from controls(p = 0.03). The second avenue pointed towards the impaired immune response, indicated by LY75-CD302 GPV(p = 8.3 × 10-4) and diminished HLA diversity compared with controls(p = 3 × 10-7). Furthermore, we found a significantly higher overall GPV burden in early-onset OC-patients compared to controls(p = 3.8 × 10-4). The genetic predisposition to early-onset OC appears to be a heterogeneous and complex process that goes beyond the traditional Mendelian monogenic understanding of hereditary cancer predisposition, with a significant role of the immune system. We speculate that rather a cumulative overall GPV burden than specific GPV may potentially increase OC risk, concomitantly with reduced HLA diversity.
- MeSH
- checkpoint kinasa 2 genetika MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- nádory vaječníků * genetika MeSH
- studie případů a kontrol MeSH
- věk při počátku nemoci * MeSH
- zárodečné mutace * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The 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. METHODS: In 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. RESULTS: The 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%). CONCLUSIONS: Both 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.
- MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- genetické rizikové skóre MeSH
- hodnocení rizik metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- multifaktoriální dědičnost genetika MeSH
- nádory prsu * genetika MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37). The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors. Based on these observations, we classified this variant as likely pathogenic.
- MeSH
- checkpoint kinasa 2 * genetika MeSH
- dospělí MeSH
- genetická predispozice k nemoci * genetika MeSH
- introny * genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu * genetika MeSH
- nádory vaječníků genetika MeSH
- prekurzory RNA genetika MeSH
- sestřih RNA * genetika MeSH
- zárodečné mutace * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Německo MeSH
Východiska: Karcinom prsu je komplexní, multifaktoriální onemocnění, na jehož vzniku se podílejí i genetické faktory. Kromě relativně vzácných patogenních variant ve vysoce či středně penetrantních nádorových predispozičních genech ovlivňují riziko vzniku karcinomu prsu i početné nízce penetrantní alely, které vnímáme jako faktory polygenní dědičnosti. Nízce penetrantní alely mají samostatně zanedbatelný význam, avšak jejich kumulativní účinek může dosáhnout klinicky významných hodnot a lze jej vyjádřit pomocí skóre polygenního rizika (polygenic risk score – PRS), které se v současnosti zvažuje jako možný nástroj pro přesnější odhad absolutního a kumulativního rizika onkologického onemocnění u konkrétní osoby. Cíl: V zahraničí již bylo vyvinuto několik setů pro jednonukleotidový polymorfizmus (single nucleotide polymorphism – SNP) pro stanovení PRS za účelem využití metody v individualizaci rizika v klinické praxi. Následující text si klade za cíl osvětlit základy stanovení PRS a jeho interpretaci jako možného predikčního nástroje. Využití PRS by však mělo být vždy podmíněno genetickým vyšetřením patogenních variant v nádorových predispozičních genech.
Background: Breast cancer is a complex, multifactorial disease influenced by many genetic factors. Besides the relatively rare pathogenic variants in high or moderate penetrant cancer predisposition genes, breast cancer risk is modified by numerous low risk alleles considered to be polygenic genetic factors. While the risks associated with individual polygenic loci are negligible, its cumulative effect can reach clinically significant values and it can be expressed as a polygenic risk score (PRS). PRS is recently considered to be a possible tool improving assessment of absolute and cumulative risks at the individual level. Purpose: Several single nucleotide polymorphism sets for PRS assessment have recently been developed and prepared for their implementation into clinical practice. The following text aims to explain the fundamental principles of the PRS assessment and its interpretation as a candidate prediction tool. The use of the PRS should always depend on genetic analysis of pathogenic variants in cancer predisposition genes including its current limitations.
- Klíčová slova
- polygenní dědičnost karcinomu prsu, sporadický karcinom prsu,
- MeSH
- genetická predispozice k nemoci MeSH
- lidé MeSH
- multifaktoriální dědičnost MeSH
- nádory prsu * etiologie genetika MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10-17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
Hepatocellular carcinoma (HCC) mainly stems from liver cirrhosis and its genetic predisposition is believed to be rare. However, two recent studies describe pathogenic/likely pathogenic germline variants (PV) in cancer-predisposition genes (CPG). As the risk of de novo tumors might be increased in PV carriers, especially in immunosuppressed patients after a liver transplantation, we analyzed the prevalence of germline CPG variants in HCC patients considered for liver transplantation. Using the panel NGS targeting 226 CPGs, we analyzed germline DNA from 334 Czech HCC patients and 1662 population-matched controls. We identified 48 PVs in 35 genes in 47/334 patients (14.1%). However, only 7/334 (2.1%) patients carried a PV in an established CPG (PMS2, 4×NBN, FH or RET). Only the PV carriers in two MRN complex genes (NBN and RAD50) were significantly more frequent among patients over controls. We found no differences in clinicopathological characteristics between carriers and non-carriers. Our study indicated that the genetic component of HCC is rare. The HCC diagnosis itself does not meet criteria for routine germline CPG genetic testing. However, a low proportion of PV carriers may benefit from a tailored follow-up or targeted therapy and germline testing could be considered in liver transplant recipients.
- Publikační typ
- časopisecké články MeSH
Polyunsaturated fatty acids (PUFA) influence many physiological functions. Associations have been found between single nucleotide polymorphisms (SNP) in the FADS1 (Fatty acid desaturase 1) gene and the relative abundance of PUFA in serum lipids. This study examines the relationship between two SNPs in the FADS1 gene (rs174546, rs174537) and the fatty acid (FA) composition of serum lipids in adolescents (13-18 years). We used DNA samples (670 children; 336 girls and 334 boys) from the Childhood Obesity Prevalence and Treatment (COPAT) project. Genomic DNA was extracted from peripheral blood leukocytes in whole blood samples. For genotype analysis, TaqMan SNP Genotyping assays (Applied Biosystems) were used. Fatty acid composition of serum lipids was assessed using gas chromatography. The T-statistic and regression were used for statistical evaluations. Minor allele T carriers in both SNPs had significant lower level of palmitic acid (16:0, phospholipids) and arachidonic acid (20:4[n-6], phospholipids) in both sexes. In girls, we found a significant positive association between minor allele T carriers and eicosadienoic acid (20:2[n-6], cholesteryl esters) in both SNPs. Being a minor allele T carrier was significantly positively associated with dihomo-γ-linolenic acid (20:3[n-6], phospholipids) in boys in both SNPs. SNPs (including rs174546, rs174537) in the FADS gene cluster should have impacted desaturase activity, which may contribute to different efficiency of PUFA synthesis.
- MeSH
- alely MeSH
- delta-5 desaturasa mastných kyselin MeSH
- desaturasy mastných kyselin genetika MeSH
- dítě MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- mastné kyseliny * MeSH
- mladiství MeSH
- obezita dětí a dospívajících * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
