Pomen poligenskega točkovnika za oceno ogroženosti z rakom dojk pri ženskah

Oblak, Tjaša (avtor), Žgajnar, Janez (mentor)

Uvod Rak dojk je najpogostejši rak žensk in njegova incidenca vztrajno narašča. Državni presejalni programi omogočajo zgodnje odkrivanje bolezni pri ženskah, starejših od 50. let, ko je incidenca raka dojk najvišja. Presejanje po 50. letu ne omogoča zgodnjega odkrivanja raka dojk pri mlajših ženskah, ki so bolj ogrožene za nastanek raka dojk, v Slovenji pa približno šestina žensk zboli za rakom dojk v starosti med 40 in 50 let. Starost je namreč le eden izmed številnih dejavnikov ogroženosti za nastanek raka dojk, med katere spadajo tudi genetski dejavnik ter dejavniki iz osebne in reproduktivne anamneze. Del nepojasnjene komponente dedovanja raka dojk se pripisuje polimorfizmom posameznih nukleotidov (SNP), njihov skupni prispevek pa izražamo s poligenskimi točkovniki ogroženosti (PRS). PRS lahko vključimo v matematične modele za izračun ogroženosti za nastanek raka dojk, katerih namen je prepoznavanje nadpovprečno ogroženih žensk že v mlajših letih. Metode V naši raziskavi smo analizirali 502 ženski, ki so med 40. in 49. letom zbolele za rakom dojk in so bile zdravljene med letoma 2014 in 2018 na Onkološkem inštitutu v Ljubljani. Preiskovanke so izpolnile vprašalnike o osebni in družinski anamnezi in odvzeli smo jim vzorce krvi za genotipizacijo 18 SNP. Na osnovi genotipizacije smo izračunali PRS18 in ga vključili v napovedni model S-IBIS, ki ocenjuje 10-letno ogroženost za nastanek raka dojk. Genotipizacijo 18 SNP smo izvedli tudi na vzorcih anonimizirane genomske DNA zdravih žensk, ki smo jih uporabili za kontrolno skupino pri izračunu PRS18. V skupini preiskovank smo statistično primerjali oceno 10-letne ogroženosti za nastanek raka dojk s podatkom o PRS18 ali brez njega. Rezultati Brez vključitve PRS18 je bilo 83,3 % preiskovank ocenjenih kot nadpovprečno ogroženih v primerjavi s splošno populacijo v starosti 40 let. Z vključitvijo PRS18 je ta delež upadel na 80,7 %. Povprečna ocena ogroženosti brez PRS18 je znašala 2,0 %, z vključitvijo PRS18 pa 2,3 %, pri čemer se je statistično značilno razširila porazdelitev preiskovank po vrednostih ogroženosti. PRS18 je bil značilno večji pri preiskovankah v primerjavi s kontrolno skupino (p < 0,001). Zaključek Program S-IBIS se je izkazal za učinkovitega pri prepoznavanju žensk z večjo ogroženostjo za raka dojk. Vključitev PRS18 je povečala natančnost ocene, vendar ni bistveno izboljšala prepoznavanja visoko ogroženih žensk. Naša raziskava je prva, ki je v Sloveniji validirala oceno ogroženosti z modelom S-IBIS pri bolnicah z rakom dojk in prva, ki je vključevala PRS18. Na podlagi naših rezultatov v Sloveniji ne bi bilo smiselno implementirati strategije personaliziranega presejanja žensk, mlajših od 50 let, ki bi upoštevala podatek o PRS18 pri izračunu ocene ogroženosti s programom S-IBIS.

• Jezik: Slovenski jezik
• Ključne besede: rak dojk, personalizirano presejanje, polimorfizmi posameznih nukleotidov, ogroženosti, Tyrer-Cuzickov algoritem
• Vrsta gradiva: Doktorsko delo/naloga
• Organizacija: MF - Medicinska fakulteta
• Leto izida: 2024
• PID: 20.500.12556/RUL-166132
• Datum objave v RUL: 21.12.2024

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Impact of polygenic risk score on breast cancer risk assessment for women

Izvleček

Introduction Breast cancer is the most common cancer in women and its incidence continues to rise. National screening programs allow early detection of the disease in women over 50, when the incidence of breast cancer is the highest. However, such screening does not allow early detection of breast cancer in younger women who are at higher risk. Around one sixth of women in Slovenia develop breast cancer between the ages of 40 and 50. Age is only one of many risk factors for breast cancer, which also include genetic factors and personal and reproductive histories. Part of the unexplained hereditary component of breast cancer is attributed to single nucleotide polymorphisms (SNPs), and their cumulative effect is expressed by polygenic risk scores (PRS). PRS can be integrated into mathematical models to calculate the risk of breast cancer in order to identify women with an above-average risk at a younger age. Methods In our study, we analyzed the data of 502 women diagnosed with breast cancer between the ages of 40 and 49 who were treated at the Institute of Oncology Ljubljana between 2014 and 2018. The participants completed a questionnaire about their personal and family medical histories and blood samples were taken for genotyping of 18 SNPs. Based on the genotyping, we calculated PRS18 and integrated it into the S-IBIS prediction model, which estimates the 10-year breast cancer risk. Genotyping of the 18 SNPs was also performed on anonymized genomic DNA samples from healthy women who were used as a control group for the calculation of the PRS18. In the group of participants, we statistically compared the 10-year breast cancer risk estimates with or without PRS18. Results Without the inclusion of PRS18, 83.3% of the participants were classified as being at above-average risk compared to women in the general population at age 40. With the inclusion of PRS18, this percentage dropped to 80.7%. The average risk score without PRS18 was 2.0%, whereas with the inclusion of PRS18 it increased to 2.3% and the distribution of risk scores among the participants widened significantly. PRS18 was significantly higher in the participants compared to the control group (p < 0.001). Conclusion The S-IBIS program proved to be effective in identifying women at higher risk of breast cancer. The inclusion of PRS18 increased the accuracy of the estimate, but did not significantly improve the identification of women at higher risk of breast cancer. Our study is the first in Slovenia to validate the S-IBIS risk model in breast cancer patients and the first to include PRS18. Based on our results, it would not be advisable to implement a personalized screening strategy for women under 50 years of age in Slovenia that includes PRS18 in the S-IBIS risk calculation.

• Ključne besede: breast cancer, personalized screening, single nucleotide polymorphisms, risk assessment, Tyrer-Cuzick algorithm