Five-year absolute risk estimates of colorectal cancer based on CCRAT model and polygenic risk scores: A validation study using the Quebec population-based cohort CARTaGENE.

The objective was to evaluate the predictive performance of the Colorectal Cancer Risk Assessment Tool (CCRAT) and three polygenic risk scores (Hsu et al., 2015; Law et al., 2019, Archambault et al., 2020) to predict the occurrence of colorectal cancer at five years in a Quebec population-based cohort. By using the CARTaGENE cohort, we computed the absolute risk of colorectal cancer with the CCRAT model, the polygenic risk scores (PRS) and combined clinico-genetic models (CCRAT + PRS). We also tailored the CCRAT model by using the marginal age-specific colorectal incidence rates in Canada and the risk score distribution. We reported the calibration and the discrimination. Performances of the PRSs, combined and tailored CCRAT models were compared to the original CCRAT model. The expected-to-observed ratio of the original CCRAT model was 0.54 [0.43-0.68]. The c-index was 74.79 [68.3-80.5]. The tailored CCRAT model improved the expected-to-observed ratio (0.74 [0.59-0.94]) and c-index (76.39 [69.7-82.1]). All PRS improved the expected-to-observed ratios (around 0.83, confidence intervals including one). PRSs' c-indexes were not significantly different from CCRAT models. Results from the combined models were close to those from the PRS models, Archambault combined model's c-index being significantly higher than the original and tailored CCRAT models (78.67 [70.8-86.5]; p < 0.001 and p = 0.028, respectively). In this Quebec cohort, CCRAT model has a good discrimination with a poor calibration. While the tailored CCRAT provides some gain in calibration, clinico-genetic models improved both calibration and discrimination. However, better calibrations must be obtained before a practical use among the inhabitants of Quebec province.

Validation of breast cancer risk assessment tools on a French-Canadian population-based cohort.

OBJECTIVES: Evaluate the accuracy of the Breast Cancer Risk Assessment Tool (BCRAT), International Breast Cancer Intervention Study risk evaluation tool (IBIS), Polygenic Risk Scores (PRS) and combined scores (BCRAT+PRS and IBIS +PRS) to predict the occurrence of invasive breast cancers at 5 years in a French-Canadian population. DESIGN: Population-based cohort study. SETTING: We used the population-based cohort CARTaGENE, composed of 43 037 Quebec residents aged between 40 and 69 years and broadly representative of the population recorded on the Quebec administrative health insurance registries. PARTICIPANTS: 10 200 women recruited in 2009-2010 were included for validating BCRAT and IBIS and 4555 with genetic information for validating the PRS and combined scores. OUTCOME MEASURES: We computed the absolute risks of breast cancer at 5 years using BCRAT, IBIS, four published PRS and combined models. We reported the overall calibration performance, goodness-of-fit test and discriminatory accuracy. RESULTS: 131 (1.28%) women developed a breast cancer at 5 years for validating BCRAT and IBIS and 58 (1.27%) for validating PRS and combined scores. Median follow-up was 5 years. BCRAT and IBIS had an overall expected-to-observed ratio of 1.01 (0.85-1.19) and 1.02 (0.86-1.21) but with significant differences when partitioning by risk groups (p<0.05). IBIS' c-index was significantly higher than BCRAT (63.42 (59.35-67.49) vs 58.63 (54.05-63.21), p=0.013). PRS scores had a global calibration around 0.82, with a CI including one, and non-significant goodness-of-fit tests. PRS' c-indexes were non-significantly higher than BCRAT and IBIS, the highest being 64.43 (58.23-70.63). Combined models did not improve the results. CONCLUSIONS: In this French-Canadian population-based cohort, BCRAT and IBIS have good mean calibration that could be improved for risk subgroups, and modest discriminatory accuracy. Despite this modest discriminatory power, these tools can be of interest for primary care physicians for delivering a personalised message to their high-risk patients, regarding screening and lifestyle counselling.

Quantifying the Predictive Accuracy of a Polygenic Risk Score for Predicting Incident Cancer Cases : Application to the CARTaGENE Cohort.

With the increasing use of polygenic risk scores (PRS) there is a need for adapted methods to evaluate the predictivity of these tools. In this work, we propose a new pseudo-R 2 criterion to evaluate PRS predictive accuracy for time-to-event data. This new criterion is related to the score statistic derived under a two-component mixture model. It evaluates the effect of the PRS on both the propensity to experience the event and on the dynamic of the event among the susceptible subjects. Simulation results show that our index has good properties. We compared our index to other implemented pseudo-R 2 for survival data. Along with our index, two other indices have comparable good behavior when the PRS has a non-null propensity effect, and our index is the only one to detect when the PRS has only a dynamic effect. We evaluated the 5-year predictivity of an 18-single-nucleotide-polymorphism PRS for incident breast cancer cases on the CARTaGENE cohort using several pseudo-R 2 indices. We report that our index, which summarizes both a propensity and a dynamic effect, had the highest predictive accuracy. In conclusion, our proposed pseudo-R 2 is easy to implement and well suited to evaluate PRS for predicting incident events in cohort studies.

High-resolution genomic analysis of human mitochondrial RNA sequence variation.

Mutations in the mitochondrial genome are associated with multiple diseases and biological processes; however, little is known about the extent of sequence variation in the mitochondrial transcriptome. By ultra-deeply sequencing mitochondrial RNA (>6000×) from the whole blood of ~1000 individuals from the CARTaGENE project, we identified remarkable levels of sequence variation within and across individuals, as well as sites that show consistent patterns of posttranscriptional modification. Using a genome-wide association study, we find that posttranscriptional modification of functionally important sites in mitochondrial transfer RNAs (tRNAs) is under strong genetic control, largely driven by a missense mutation in MRPP3 that explains ~22% of the variance. These results reveal a major nuclear genetic determinant of posttranscriptional modification in mitochondria and suggest that tRNA posttranscriptional modification may affect cellular energy production.

Genomic architecture of sickle cell disease in West African children.

Sickle cell disease (SCD) is a congenital blood disease, affecting predominantly children from sub-Saharan Africa, but also populations world-wide. Although the causal mutation of SCD is known, the sources of clinical variability of SCD remain poorly understood, with only a few highly heritable traits associated with SCD having been identified. Phenotypic heterogeneity in the clinical expression of SCD is problematic for follow-up (FU), management, and treatment of patients. Here we used the joint analysis of gene expression and whole genome genotyping data to identify the genetic regulatory effects contributing to gene expression variation among groups of patients exhibiting clinical variability, as well as unaffected siblings, in Benin, West Africa. We characterized and replicated patterns of whole blood gene expression variation within and between SCD patients at entry to clinic, as well as in follow-up programs. We present a global map of genes involved in the disease through analysis of whole blood sampled from the cohort. Genome-wide association mapping of gene expression revealed 390 peak genome-wide significant expression SNPs (eSNPs) and 6 significant eSNP-by-clinical status interaction effects. The strong modulation of the transcriptome implicates pathways affecting core circulating cell functions and shows how genotypic regulatory variation likely contributes to the clinical variation observed in SCD.

Rare allelic forms of PRDM9 associated with childhood leukemogenesis.

One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless there remains a significant excess of rare alleles among patients relative to controls. We successfully replicated this latter observation in an independent cohort of 50 children with B-ALL, where we found an excess of rare PRDM9 alleles in aneuploid and infant B-ALL patients. PRDM9 variability in humans is thought to influence genomic instability, and these data support a potential role for PRDM9 variation in risk of acquiring aneuploidies or genomic rearrangements associated with childhood leukemogenesis.

Evidence for additive and interaction effects of host genotype and infection in malaria.

The host mechanisms responsible for protection against malaria remain poorly understood, with only a few protective genetic effects mapped in humans. Here, we characterize a host-specific genome-wide signature in whole-blood transcriptomes of Plasmodium falciparum-infected West African children and report a demonstration of genotype-by-infection interactions in vivo. Several associations involve transcripts sensitive to infection and implicate complement system, antigen processing and presentation, and T-cell activation (i.e., SLC39A8, C3AR1, FCGR3B, RAD21, RETN, LRRC25, SLC3A2, and TAPBP), including one association that validated a genome-wide association candidate gene (SCO1), implicating binding variation within a noncoding regulatory element. Gene expression profiles in mice infected with Plasmodium chabaudi revealed and validated similar responses and highlighted specific pathways and genes that are likely important responders in both hosts. These results suggest that host variation and its interplay with infection affect children's ability to cope with infection and suggest a polygenic model mounted at the transcriptional level for susceptibility.