| 1. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 2. |
- Carpten, JD, et al.
(författare)
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HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome
- 2002
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 32:4, s. 676-680
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Tidskriftsartikel (refereegranskat)abstract
- We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.
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| 3. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 4. |
- McBrien, Owen R., et al.
(författare)
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SN2018kzr : A Rapidly Declining Transient from the Destruction of a White Dwarf
- 2019
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 885:1
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Tidskriftsartikel (refereegranskat)abstract
- We present SN2018kzr, the fastest declining supernova-like transient, second only to the kilonova, AT2017gfo. SN2018kzr is characterized by a peak magnitude of M-r & xfffd;=& xfffd;?17.98, a peak bolometric luminosity of ?1.4 & xfffd;& x5e0;10(43) erg s(?1), and a rapid decline rate of 0.48 & xfffd;& xfffd;0.03 mag day(?1) in the r band. The bolometric luminosity evolves too quickly to be explained by pure Ni-56 heating, necessitating the inclusion of an alternative powering source. Incorporating the spin-down of a magnetized neutron star adequately describes the lightcurve and we estimate a small ejecta mass of M-ej & xfffd;=& xfffd;0.10 & xfffd;& xfffd;0.05 M. Our spectral modeling suggests the ejecta is composed of intermediate mass elements including O, Si, and Mg and trace amounts of Fe-peak elements, which disfavors a binary neutron star merger. We discuss three explosion scenarios for SN2018kzr, given the low ejecta mass, intermediate mass element composition, and high likelihood of additional powering?the core collapse of an ultra-stripped progenitor, the accretion induced collapse (AIC) of a white dwarf, and the merger of a white dwarf and neutron star. The requirement for an alternative input energy source favors either the AIC with magnetar powering or a white dwarf?neutron star merger with energy from disk wind shocks.
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| 5. |
- Srinivasaragavan, Gokul P., et al.
(författare)
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A Sensitive Search for Supernova Emission Associated with the Extremely Energetic and Nearby GRB 221009A
- 2023
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Ingår i: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 949:2
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Tidskriftsartikel (refereegranskat)abstract
- We report observations of the optical counterpart of the long gamma-ray burst GRB 221009A. Due to the extreme rarity of being both nearby (z = 0.151) and highly energetic (E ( gamma,iso) >= 10(54) erg), GRB 221009A offers a unique opportunity to probe the connection between massive star core collapse and relativistic jet formation across a very broad range of gamma-ray properties. Adopting a phenomenological power-law model for the afterglow and host galaxy estimates from high-resolution Hubble Space Telescope imaging, we use Bayesian model comparison techniques to determine the likelihood of an associated supernova (SN) contributing excess flux to the optical light curve. Though not conclusive, we find moderate evidence (K (Bayes) = 10(1.2)) for the presence of an additional component arising from an associated SN, SN 2022xiw, and find that it must be substantially fainter (<67% as bright at the 99% confidence interval) than SN 1998bw. Given the large and uncertain line-of-sight extinction, we attempt to constrain the SN parameters (M (Ni), M (ej), and E (KE)) under several different assumptions with respect to the host galaxy's extinction. We find properties that are broadly consistent with previous GRB-associated SNe: M (Ni) = 0.05-0.25 M (circle dot), M (ej) = 3.5-11.1 M (circle dot), and E (KE) = (1.6-5.2) x 10(52) erg. We note that these properties are weakly constrained due to the faintness of the SN with respect to the afterglow and host emission, but we do find a robust upper limit on M (Ni) of M (Ni) < 0.36 M (circle dot). Given the tremendous range in isotropic gamma-ray energy release exhibited by GRBs (seven orders of magnitude), the SN emission appears to be decoupled from the central engine in these systems.
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