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

M. Hovhannisyan, P. Zemankova, P. Nehasil, K. Matejkova, M. Borecka, M. Cerna, T. Dolezalova, L. Dvorakova, L. Foretova, K. Horackova, S. Jelinkova, P. Just, M. Kalousova, J. Kral, E. Machackova, B. Nemcova, M. Safarikova, D. Springer, B....

. 2024 ; 130 (17) : 2978-2987. [pub] 20240508

Language English Country United States

Document type Journal Article, Comparative Study

Persistent link   https://www.medvik.cz/link/bmc24019184

Grant support
LX22NPO5102 Ministry of Education, Youth and Sports of the Czech Republic
DRO-VFN-64165 Ministry of Health of the Czech Republic
NU20-09-00355 Ministry of Health of the Czech Republic
COOPERATIO Grant Agency, Charles University
SVV260631 Grant Agency, Charles University
UNCE/24/MED/022 Grant Agency, Charles University

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.

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$a Hovhannisyan, Milena $u Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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$a Population-specific validation and comparison of the performance of 77- and 313-variant polygenic risk scores for breast cancer risk prediction / $c M. Hovhannisyan, P. Zemankova, P. Nehasil, K. Matejkova, M. Borecka, M. Cerna, T. Dolezalova, L. Dvorakova, L. Foretova, K. Horackova, S. Jelinkova, P. Just, M. Kalousova, J. Kral, E. Machackova, B. Nemcova, M. Safarikova, D. Springer, B. Stastna, S. Tavandzis, M. Vocka, T. Zima, J. Soukupova, P. Kleiblova, C. Ernst, Z. Kleibl, M. Janatova
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$a 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.
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