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- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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- Dareng, EO, et al.
(author)
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Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- 2022
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In: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 30:3, s. 349-362
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Journal article (peer-reviewed)abstract
- Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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- Serrano, L. M., et al.
(author)
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The HD 93963 A transiting system: A 1.04d super-Earth and a 3.65 d sub-Neptune discovered by TESS and CHEOPS
- 2022
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 667
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Journal article (peer-reviewed)abstract
- We present the discovery of two small planets transiting HD 93963A (TOI-1797), a GOV star (M-* = 1.109 +/- 0.043M(circle dot), R-* = 1.043 +/- 0.009 R-circle dot) in a visual binary system. We combined TESS and CHEOPS space-borne photometry with MuSCAT 2 ground-based photometry, 'Alopeke and PHARO high-resolution imaging, TRES and FIES reconnaissance spectroscopy, and SOPHIE radial velocity measurements. We validated and spectroscopically confirmed the outer transiting planet HD 93963 A c, a sub-Neptune with an orbital period of P-c approximate to 3.65 d that was reported to be a TESS object of interest (TOI) shortly after the release of Sector 22 data. HD 93963 A c has amass of M-c = 19.2 +/- 4.1 M-circle plus and a radius of R-c = 3.228 +/- 0.059 R-circle plus, implying a mean density of rho(c) = 3.1 +/- 0.7 g cm(-3). The inner object, HD 93963 A b, is a validated 1.04 d ultra-short period (USP) transiting super-Earth that we discovered in the TESS light curve and that was not listed as a TOI, owing to the low significance of its signal (TESS signal-to-noise ratio approximate to 6.7, TESS + CHEOPS combined transit depth D-b = 141.5(-8.3)(+8.5) ppm). We intensively monitored the star with CHEOPS by performing nine transit observations to confirm the presence of the inner planet and validate the system. HD 93963 A b is the first small (R-b = 1.35 +/- 0.042 R-circle plus) USP planet discovered and validated by TESS and CHEOPS. Unlike planet c, HD 93963 Ab is not significantly detected in our radial velocities (M-b = 7.8 +/- 3.2 M-circle plus). The two planets are on either side of the radius valley, implying that they could have undergone completely different evolution processes. We also discovered a linear trend in our Doppler measurements, suggesting the possible presence of a long-period outer planet. With a V-band magnitude of 9.2, HD 93963 A is among the brightest stars known to host a USP planet, making it one of the most favourable targets for precise mass measurement via Doppler spectroscopy and an important laboratory to test formation, evolution, and migration models of planetary systems hosting ultra-short period planets.
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- Huyghe, Jeroen R, et al.
(author)
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Genetic architectures of proximal and distal colorectal cancer are partly distinct
- 2021
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In: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
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Journal article (peer-reviewed)abstract
- Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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| 8. |
- Murgas, F., et al.
(author)
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TOI-674b: An oasis in the desert of exo-Neptunes transiting a nearby M dwarf
- 2021
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 653
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Journal article (peer-reviewed)abstract
- Context. The NASA mission TESS is currently doing an all-sky survey from space to detect transiting planets around bright stars. As part of the validation process, the most promising planet candidates need to be confirmed and characterized using follow-up observations. Aims. In this article, our aim is to confirm the planetary nature of the transiting planet candidate TOI-674b using spectroscopic and photometric observations. Methods. We use TESS, Spitzer, ground-based light curves, and HARPS spectrograph radial velocity measurements to establish the physical properties of the transiting exoplanet candidate TOI-674b. We perform a joint fit of the light curves and radial velocity time series to measure the mass, radius, and orbital parameters of the candidate. Results. We confirm and characterize TOI-674b, a low-density super-Neptune transiting a nearby M dwarf. The host star (TIC 158588995, V = 14.2 mag, J = 10.3 mag) is characterized by its M2V spectral type with M = 0.420 ± 0.010 M , R = 0.420 ± 0.013 R , and Teff = 3514 ± 57 K; it is located at a distance d = 46.16 ± 0.03 pc. Combining the available transit light curves plus radial velocity measurements and jointly fitting a circular orbit model, we find an orbital period of 1.977143 ± 3 × 10-6 days, a planetary radius of 5.25 ± 0.17 R , and a mass of 23.6 ± 3.3 M implying a mean density of ρp =0.91 ± 0.15 g cm-3. A non-circular orbit model fit delivers similar planetary mass and radius values within the uncertainties. Given the measured planetary radius and mass, TOI-674b is one of the largest and most massive super-Neptune class planets discovered around an M-type star to date. It is found in the Neptunian desert, and is a promising candidate for atmospheric characterization using the James Webb Space Telescope.
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