| 11. |
- Thompson, Patricia A., et al.
(författare)
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Loss of LRIG1 Locus Increases Risk of Early and Late Relapse of Stage I/II Breast Cancer
- 2014
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 74:11, s. 2928-2935
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Tidskriftsartikel (refereegranskat)abstract
- Gains and losses at chromosome 3p12-21 are common in breast tumors and associated with patient outcomes. We hypothesized that the LRIG1 gene at 3p14.1, whose product functions in ErbB-family member degradation, is a critical tumor modifier at this locus. We analyzed 971 stage I/II breast tumors using Affymetrix Oncoscan molecular inversion probe arrays that include 12 probes located within LRIG1. Copy number results were validated against gene expression data available in the public database. By partitioning the LRIG1 probes nearest exon 12/13, we confirm a breakpoint in the gene and show that gains and losses in the subregions differ by tumor and patient characteristics including race/ethnicity. In analyses adjusted for known prognostic factors, loss of LRIG1 was independently associated with risk of any relapse (HR, 1.90; 95% CI, 1.32-2.73), relapse >= 5 years (HR, 2.39; 95% CI, 1.31-4.36), and death (HR, 1.55; 95% CI, 1.11-2.16). Analyses of copy number across chromosome 3, as well as expression data from pooled, publicly available datasets, corroborated the hypothesis of an elevated and persistent risk among cases with loss of or low LRIG1. We concluded that loss/low expression of LRIG1 is an independent risk factor for breast cancer metastasis and death in stage I/II patients. Increased hazard in patients with loss/low LRIG1 persists years after diagnosis, suggesting that LRIG1 is acting as a critical suppressor of tumor metastasis and is an early clinical indicator of risk for late recurrences in otherwise low-risk patients.
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| 12. |
- 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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| 13. |
- Wibom, Carl, et al.
(författare)
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Glioma Gwas Hits - Markers for Risk or for Prognosis?
- 2014
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 16:Suppl. 2, s. ii109-ii110
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Tidskriftsartikel (refereegranskat)abstract
- One obstacle to developing new treatments for glioma is the generally poor understanding of glioma aetiology. The only generally accepted environmental risk factor or glioma is ionizing radiation. Glioma aetiology has also been shown to contain a genetic component, in part through observations that individuals in families with a history of glioma have an elevated risk of developing glioma themselves. The genetic component in glioma aetiology has been further substantiated through genome wide association studies (GWAS). These studies have identified associations between a number of common genetic variants and an increased glioma risk. However, the studies have all been of case-control design (i.e. including cases at diagnosis), and as such they presumably suffer from a degree of survival bias. Survival bias risks being introduced in a study when rapidly fatal cases are not included. This is an inherent risk of case-control designs, which is particularly pronounced when studying a disease with very poor prognosis, such as glioma. Ultimately, survival bias may result in erroneous conclusions, as it is impossible to separate associations with prognosis from associations with risk of disease. To accurately confirm previously identified glioma risk variants, and ascertain whether they are associated with risk or with prolonged survival, we investigated these variants in a set of pre-diagnostic serum samples (594 cases and 591 matched controls). Analyses of population based, pre-diagnostic samples eliminates the risk of survival bias, and enables distinction between genetic variants associated with glioma risk (i.e. aetiology) and genetic variants associated with prognosis. The serum samples were acquired through The Janus Serum Bank, a Norwegian population based biobank reserved for cancer research. Variant detection was achieved by means of cycling temperature capillary electrophoresis. Our investigation confirmed the association with glioma risk for the investigated variants within five genomic regions; 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). This is indicative of these variants being truly associated with glioma risk, and thus may impact gliomagenesis. However, previously identified risk variants within the 5p15.33 (TERT) and 7p11.2 (EGFR) could not be positively confirmed by this study. The lack of positive confirmation raises the question whether EGFR and TERT genetic variants are linked with prolonged survival, rather than with glioma aetiology.
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