Sex-Stratified Polygenic Risk Score Identifies Individuals at Increased Risk of Basal Cell Carcinoma

Abstract

The incidence of basal cell carcinoma (BCC) is higher among men than women. Susceptibility loci for BCC have been identified through genome-wide association studies, and two previous studies have found polygenic risk scores (PRS) to be significantly associated with the risk of BCC. However, to our knowledge, sex-stratified PRS analyses examining the genetic contribution to BCC risk among men and women have not been previously reported. To quantify the contribution of genetic variability on the BCC risk by sex, we derived a polygenic risk score and estimated the genetic relative risk distribution for men and women. Using 29 published single nucleotide polymorphisms, we found that the estimated relative risk of BCC increases with higher percentiles of the polygenic risk score. For men, the estimated risk of BCC is twice the average population risk at the 88th percentile, while for women, this occurs at the 99th percentile. Our findings indicate that there is a significant impact of genetic variation on the risk of developing BCC and that this impact may be greater for men than for women. Polygenic risk scores may be clinically useful tools for risk stratification, particularly in combination with other known risk factors for BCC development.

Polygenic Risk Scores Allow Risk Stratification for Keratinocyte Cancer in Organ-Transplant Recipients

“…In our study, we used additional methods to construct a more powerful PRS than the one in a previous study among patients who had undergone renal transplantation (Stapleton et al, 2019). First, we used a larger training dataset (i.e., N ¼ 594,881 for BCC) to build a more accurate PRS than that of the previous studies (Fritsche et al, Roberts et al, 2020;Stapleton et al, 2019). Second, after developing our PRS models on the basis of P-value thresholds, we applied them to an independent validation cohort recruited from the general population.…”

“…Our study offers a more comprehensive evaluation of the strength of the PRS by incorporating traditional pigmentation, sun exposure, and immunosuppression measures in the BCC and SCC prediction models. To our knowledge, no study has utilized them before (Fritsche et al, 2019;Roberts et al, 2020;Stapleton et al, 2019). Yet, these traditional risk factors are key in skin cancer prediction.…”

“…Our results are robust because we used independent datasets for the different stages of analyses: discovery, external validation, and testing across Europe, USA, and Australia. As of now, our study has used the largest training dataset to derive the PRS for BCC and SCC (Fritsche et al, 2019;Roberts et al, 2020;Stapleton et al, 2019). Furthermore, we used a large validation dataset (N ¼ 7,304) to optimize PRS model selection on the basis of the P-value thresholds, which enabled us to avoid overfitting.…”

Polygenic Risk Scores Stratify Keratinocyte Cancer Risk among Solid Organ Transplant Recipients with Chronic Immunosuppression in a High Ultraviolet Radiation Environment

“…Our study differs from other previous studies in a number of ways. First, we used LDpred (Vilhjálmsson et al 2015), a method which considers a large number of genetic markers at the PRS generation stage in contrast to the LD clump method used in the previous studies (Roberts et al 2020;Seviiri et al 2021;Stapleton et al 2020;Stapleton et al 2019). BCC and SCC have strong signals in high LD regions like HLA which might lead to inefficient harnessing of the available information.…”

Placenta DNA methylation at ZNF300 is associated with fetal sex and placental morphology

“…Genetic variation may help this understanding. Sex-specific differences in the effects of genetic risk factors on health outcomes have been reported [32] including for mortality rates after injury [33], susceptiblity to immune diseases [34], response to vaccination [35], chronic obstructive pulmonary disease risk [36], basal cell carcinoma [37], cardiometabolic disorders [38,39], and depression [40,41]. Genetic variation in placental tissue has also been shown to impact birth outcomes including large for gestational age [42], birthweight [43,44], and preterm birth [45], but studies to investigate differences in genetic risks by sex or to identify genetic variant associations with placenta size and morphology are lacking.…”