The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Abstract

Purpose To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients

“…In particular, there is substantial evidence that the CHEK2 c.1100delC variant increases the risk of developing CBC [19,20]. In addition, polygenic risk scores (PRS) of common variants, developed for association with first breast cancer, have been shown to predict CBC in the general BC population and in BRCA1/2 mutation carriers [21][22][23][24], particularly the extensively validated 313 SNP PRS [25]. With regard to the lifestyle and reproductive factors, there is evidence that body mass index (BMI) and parity at or around the time of the first primary invasive BC diagnosis are associated with CBC risk [26].…”

Polygenic risk scores of endo-phenotypes identify the effect of genetic background in congenital heart disease

“…However, continuing studies are exploring clinical scenarios where these scores might provide added benefit to existing algorithms that rely on serum and clinical diagnostic markers 78 , 79 or where they can be used to understand the phenotypic variability for individuals with a high-risk monogenic predisposition. 80 , 81 , 82 Despite the many challenges in the field of rare disease genetics and PRSs in general, we believe that PRSs can contribute significantly to our understanding of the genetic architecture of rare, understudied disorders like CHD, and we hope that, as PRS methods continue to improve, additional insight into and knowledge of the causes of CHD can be used to improve long-term outcomes in affected individuals.…”

Lynch syndrome: influence of additional susceptibility variants on cancer risk

“…the combination of many common, low-risk variants, in uence cancer risk, even though conclusive papers are yet to be published 12 . Studies in hereditary breast and ovarian cancer are encouraging 13 . Llach et al recently envisaged the possibility of personalized cancer screening in LS patients depending on modifying factors 14 .…”