Prognostic evaluation of polygenic risk score underlying pan-cancer analysis: evidence from two large-scale cohorts

Xin, Junyi; Jiang, Xia; Li, Huiqin; Chen, Silu; Zhang, Zhengdong; Wang, Meilin; Gu, Dongying; Du, Mulong; Christiani, David C.

doi:10.1016/j.ebiom.2023.104454

Cited by 9 publications

(6 citation statements)

References 31 publications

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“…Here, leveraging the meta-analysis of EAS and EUR populations, we uncovered two variants, rs10967103 (9p21.2) and rs79067806 (12q12), linked to overall survival in colorectal cancer with substantial effect sizes (both HRs >1.5). Interestingly, these two prognostic variants were not associated with colorectal cancer susceptibility, indicating the diverse genetic background between the initiation and progression of colorectal cancer, which was consistent with previous findings 13 , 19 . Therefore, it will be necessary to identify variants carried with stronger effect sizes and increased statistical power among larger longitudinal populations, and to systematically decode the inconsistent features of the genetic architecture underlying the susceptibility and progression of colorectal cancer.…”

Section: Discussionsupporting

confidence: 91%

“…For example, we ever developed a EAS-EUR PRS framework derived from genome-wide SNPs that can effectively predict colorectal cancer risk in EAS and EUR populations, indicating the potential application of PRS in colorectal cancer risk stratification 9 . However, there was no significant association between PRS and the increased risk of cancer mortality among cancer patients, as evidenced by several prospective studies 19 , 24 and our previous findings 13 . Therefore, considering the limited clinical utility of PRS in disease survival evaluation, we proposed a robust PPS 287 framework, independent of clinical factors, that could be used for colorectal cancer survival stratification in EAS and EUR populations, as evidenced by three independent cohorts.…”

Section: Discussionmentioning

confidence: 51%

“…Noteworthily, survival probability is another critical indicator, that can reflect the tumor burden and prognosis of disease patients 12 . In particular, our previous study demonstrated the limited clinical utility of risk-based PRS in predicting cancer survival, emphasizing that a polygenic prognostic score (PPS) is needed instead for determining the genetic risk of death among colorectal cancer patients 13 .…”

Section: Introductionmentioning

confidence: 99%

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Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment

Xin,

Gu,

et al. 2024

Nat Commun

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The development of an effective survival prediction tool is key for reducing colorectal cancer mortality. Here, we apply a three-stage study to devise a polygenic prognostic score (PPS) for stratifying colorectal cancer overall survival. Leveraging two cohorts of 3703 patients, we first perform a genome-wide survival association analysis to develop eight candidate PPSs. Further using an independent cohort with 470 patients, we identify the 287 variants-derived PPS (i.e., PPS287) achieving an optimal prediction performance [hazard ratio (HR) per SD = 1.99, P = 1.76 × 10−8], accompanied by additional tests in two external cohorts, with HRs per SD of 1.90 (P = 3.21 × 10−14; 543 patients) and 1.80 (P = 1.11 × 10−9; 713 patients). Notably, the detrimental impact of pathologic characteristics and genetic risk could be attenuated by a healthy lifestyle, yielding a 7.62% improvement in the 5-year overall survival rate. Therefore, our findings demonstrate the integrated contribution of pathologic characteristics, germline variants, and lifestyle exposure to the prognosis of colorectal cancer patients.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

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Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment

Xin,

Gu,

et al. 2024

Nat Commun

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“…The validation population was consisted of European ancestry participants from the PLCO cohort and TCGA program (permissions from dbGaP: Project #32547). The genotyping and imputation process have been described in our previous studies [ 13 , 14 ]. Outlier individuals were removed using smartpca function from EIGENSOFT (version 5.0.2).…”

Section: Methodsmentioning

confidence: 99%

An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study

Cheng,

Wu,

Xin

et al. 2024

J Transl Med

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Background Early-onset prostate cancer (EOPC, ≤ 55 years) has a unique clinical entity harboring high genetic risk, but the majority of EOPC patients still substantial opportunity to be early-detected thus suffering an unfavorable prognosis. A refined understanding of age-based polygenic risk score (PRS) for prostate cancer (PCa) would be essential for personalized risk stratification. Methods We included 167,517 male participants [4882 cases including 205 EOPC and 4677 late-onset PCa (LOPC)] from UK Biobank. A General-, an EOPC- and an LOPC-PRS were derived from age-specific genome-wide association studies. Weighted Cox proportional hazard models were applied to estimate the risk of PCa associated with PRSs. The discriminatory capability of PRSs were validated using time-dependent receiver operating characteristic (ROC) curves with additional 4238 males from PLCO and TCGA. Phenome-wide association studies underlying Mendelian Randomization were conducted to discover EOPC linking phenotypes. Results The 269-PRS calculated via well-established risk variants was more strongly associated with risk of EOPC [hazard ratio (HR) = 2.35, 95% confidence interval (CI) 1.99–2.78] than LOPC (HR = 1.95, 95% CI 1.89–2.01; I2 = 79%). EOPC-PRS was dramatically related to EOPC risk (HR = 4.70, 95% CI 3.98–5.54) but not to LOPC (HR = 0.98, 95% CI 0.96–1.01), while LOPC-PRS had similar risk estimates for EOPC and LOPC (I2 = 0%). Particularly, EOPC-PRS performed optimal discriminatory capability for EOPC (area under the ROC = 0.613). Among the phenomic factors to PCa deposited in the platform of ProAP (Prostate cancerAge-basedPheWAS; https://mulongdu.shinyapps.io/proap), EOPC was preferentially associated with PCa family history while LOPC was prone to environmental and lifestyles exposures. Conclusions This study comprehensively profiled the distinct genetic and phenotypic architecture of EOPC. The EOPC-PRS may optimize risk estimate of PCa in young males, particularly those without family history, thus providing guidance for precision population stratification.

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“…This allows researchers to evaluate the cumulative contribution of these genetic variants to disease prevalence and incidence in a population [ 20 ]. PRS has been widely used in the field of genetics to predict the risk of various diseases, such as cancer, cardiovascular disease, and diabetes [ 21 – 23 ]. PRS has also been utilized to evaluate the genetic risk of developing BPH and identify individuals who may be at a higher risk of developing severe symptoms.…”

Section: Introductionmentioning

confidence: 99%

Polygenic risk score predicting susceptibility and outcome of benign prostatic hyperplasia in the Han Chinese

Hung,

Chang,

Hsiao

et al. 2024

Hum Genomics

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Background Given the high prevalence of BPH among elderly men, pinpointing those at elevated risk can aid in early intervention and effective management. This study aimed to explore that polygenic risk score (PRS) is effective in predicting benign prostatic hyperplasia (BPH) incidence, prognosis and risk of operation in Han Chinese. Methods A retrospective cohort study included 12,474 male participants (6,237 with BPH and 6,237 non-BPH controls) from the Taiwan Precision Medicine Initiative (TPMI). Genotyping was performed using the Affymetrix Genome-Wide TWB 2.0 SNP Array. PRS was calculated using PGS001865, comprising 1,712 single nucleotide polymorphisms. Logistic regression models assessed the association between PRS and BPH incidence, adjusting for age and prostate-specific antigen (PSA) levels. The study also examined the relationship between PSA, prostate volume, and response to 5-α-reductase inhibitor (5ARI) treatment, as well as the association between PRS and the risk of TURP. Results Individuals in the highest PRS quartile (Q4) had a significantly higher risk of BPH compared to the lowest quartile (Q1) (OR = 1.51, 95% CI = 1.274–1.783, p < 0.0001), after adjusting for PSA level. The Q4 group exhibited larger prostate volumes and a smaller volume reduction after 5ARI treatment. The Q1 group had a lower cumulative TURP probability at 3, 5, and 10 years compared to the Q4 group. PRS Q4 was an independent risk factor for TURP. Conclusions In this Han Chinese cohort, higher PRS was associated with an increased susceptibility to BPH, larger prostate volumes, poorer response to 5ARI treatment, and a higher risk of TURP. Larger prospective studies with longer follow-up are warranted to further validate these findings.

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Prognostic evaluation of polygenic risk score underlying pan-cancer analysis: evidence from two large-scale cohorts

Cited by 9 publications

References 31 publications

Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment

Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment

An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study

Polygenic risk score predicting susceptibility and outcome of benign prostatic hyperplasia in the Han Chinese

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