| 1. |
|
|
| 2. |
- Antoniou, A. C., et al.
(författare)
-
Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers : Implications for risk prediction
- 2010
-
Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 70:23, s. 9742-9754
-
Tidskriftsartikel (refereegranskat)abstract
- The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10-11 - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.
|
|
| 3. |
|
|
| 4. |
- Borg, Helena
(författare)
-
Bladder and bowel dysfunction in children with anorectal malformations : Blås och tarmdysfunktion hos barn med anorektala missbildningar
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Bowel dysfunction is seen in all children with anorectal malformations (ARMs) and is strongly related to associated anomalies commonly found in these patients. The presence of a megarectosigmoid (MRS) further contributes to chronic constipation and overflow incontinence. There is a great heterogeneity in reported functional results probably due to the fact that the criteria used to evaluate long-term outcome have been quite variable. In addition, results are often given for different ages together. By using more precise criteria as developed by the Krickenbeck conference 2005, and by following ARM patients longitudinally, the reporting of functional outcome should be more uniform and reliable. Aims: To study the impact of spinal cord malformation on bladder and bowel function and to describe changes in bowel function during long term follow up in children with ARM. To identify predictors influencing bowel functional outcome and evaluate outcome after surgical or conservative treatment of MRS. Finally, to longitudinally follow bladder function in these children and to identify the prevalence of neurogenic (NBD) and non-neurogenic bladder dysfunction. Material and methods: 41 patients with ARM, excluding perineal fistulas, were consecutively included in this prospective longitudinal study. Investigations of bowel function were performed at ages 5, 10, 15 yrs. using a structured questionnaire and three weeks registrations of bowel movements, soiling, use of pads and enemas. 52 healthy children of similar ages and gender were used as control. The bowel was also investigated with a colostogram in the neonatal period, followed by a contrast enema 6 months after stoma closure and after that on an individual basis if MRS was diagnosed. Investigations of bladder function were performed with urodynamics before and after the PSARP procedure and regularly during follow-up in patients with an obvious NBD. In addition, at the ages 5, 10 and 15 yrs. all children were aimed to be investigated with a structured urinary questionnaire, a three-day voiding/leakage diary and flow-residual measurements. Scoring systems were used for evaluation of bowel and bladder function. Spinal cord malformations were diagnosed with spinal ultrasound followed by MRI in the neonatal period. Sacral anomalies were detected by plain radiographs. Results: There was a successive improvement in bowel function during childhood and adolescence, but function did not achieve the level of healthy children. At the age of 10 years continence overall was achieved in 59%. Neurogenic bladder dysfunction was found in 22% of children with ARM and symptoms remained constant during follow up. Symptoms of non-neurogenic LUTD were present in 34%. However, the findings were transient and in most cases seen only at one of the follow up evaluations. Negative predictors for bowel function during follow up were spinal cord malformation in combination with NBD, complex type of fistula (high recto- urethral and bladder neck fistula) and sacral agenesis. Whether non-neurogenic LUTD was associated with constipation and poor bowel function could not be confirmed even if these children had lower bowel scores than those with normal bladder function. MRS was not established as a predictor of bowel function, although girls with MRS at age 5 years had lower bowel scores compared to patients with normal rectal configuration. It was also shown that surgical treatment of MRS did not have better outcome regarding bowel function compared to bowel management only. Conclusion: In this longitudinal study of ARM patients from childhood to adolescence, bowel function overall was shown to improve when estimated in relation to continence, soiling and constipation. Bladder function was also evaluated and NBD was diagnosed in 22%, and non-neurogenic bladder symptoms in 34% of the patients. Negative predictors for improvement in bowel function during growing up were spinal cord malformation, NBD and complex type of fistula malformation. MRS did not emerge as a predictor for functional outcome.
|
|
| 5. |
- Borg, Helena, et al.
(författare)
-
Four-hour voiding observations detect neurogenic lower urinary tract dysfunction in neonates with anorectal malformation
- 2021
-
Ingår i: Journal of Pediatric Urology. - : Elsevier BV. - 1477-5131. ; 17:1
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Neurogenic lower urinary tract dysfunction (LUTD) has been reported in 20–50% of children with anorectal malformations (ARM). As neurogenic LUTD represents an inherent risk of renal deterioration and urinary tract infections, an early diagnosis is important. The gold standard for evaluating neurogenic LUTD involves invasive urodynamic testing but a useful addition should be an easy-to-perform, non-invasive method of screening. Objective: In this study, we evaluate non-invasive 4 h voiding observations as a screening method for neurogenic LUTD in ARM children. Study design: Thirty-four patients with ARM, excluding those with perineal fistulas, were evaluated using both 4 h voiding observation and urodynamic testing before and after posterior sagittal anorectoplasty (PSARP) at median ages of 0.3 and 1.1 years. In the urodynamic assessment, the gold standard for neurogenic LUTD, nine children received the diagnosis, eight innate and one post-surgery. Results: Five boys with a high urethral fistula and anomalies of the spinal cord had urodynamically diagnosed neurogenic LUTD, a dysfunction also identified in the 4 h voiding observations. The pattern was characterised both by an increase in the number of voiding and the number of interrupted voiding, urinary leakage and elevated residual urine (Figure). In three girls with a vestibular fistula and tethered cord, an urodynamic investigation identified suspected mild neurogenic LUTD. In the voiding observations, an abnormal voiding pattern was not as obvious in the girls as in the five males. One girl with cloaca showed signs of postsurgical denervation damage, which was easily identified in the 4 h voiding observations (high capacity and elevated residual urine). Discussion: In the present study, gender differences in the severity of dysfunction reflected in the free voiding pattern in infants with ARM and neurogenic LUTD is probably the result of the different underlying causes of neurogenic LUTD in boys and girls. Boys with the condition have a congenital malformation of the caudal part of the spinal cord and girls a tethering of the cord. The most obvious limitation of the study was the low number of patients. Despite this, we consider the results worth reporting, since we found that results in the free voiding observations effectively confirmed what was established in the urodynamic investigations. Conclusion: In pre-PSARP patients, 4 h voiding observations can be used to screen for severe neurogenic LUTD requiring attention and treatment. When post-surgical denervation is suspected, the voiding observation is also a good method for indicating the diagnosis.[Formula presented] © 2020 Journal of Pediatric Urology Company
|
|
| 6. |
- Borg, Helena, et al.
(författare)
-
Impact of spinal cord malformation on bladder function in children with anorectal malformations.
- 2009
-
Ingår i: Journal of pediatric surgery. - : Elsevier BV. - 1531-5037 .- 0022-3468. ; 44:9, s. 1778-85
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Risk factors for the presence of neurogenic bladder dysfunction (NBD) in children born with high anorectal malformations (ARMs), were investigated, to identify the need for urodynamics in these patients. MATERIAL AND METHODS: The study included 37 patients with high ARMs (21 boys and 16 girls). Bladder function was evaluated with urodynamics both before and after anorectoplasty (posterior sagittal anorectoplasty [PSARP]). All patients were investigated with spinal radiograph. Spinal ultrasound was performed in the neonatal period, and magnetic resonance imaging was added in case of abnormal ultrasound or urodynamics and in case of cloacal malformation. RESULTS: In ARM patients with rectourethral and vestibular fistulas and cloacas, NBD was identified in 9 children (25%). The bladder dysfunction was innate in all cases except in one girl with cloaca, indicating that the risk of iatrogenic denervation seems minimal using the PSARP technique. All children with innate NBD had a spinal cord malformation either as spinal cord regression or tethering with or without a lipoma. Concerning vertebral status, almost all children with NBD had partial sacral agenesis. Abnormal perineal appearance was highly correlated to NBD in boys, especially in those with a spinal cord regression malformation. Innate NBD was not found in any child with normal spinal cord. CONCLUSION: From these results, we suggest that spinal ultrasound and perineal inspection are used as screening procedures for NBD in children with ARM. Urodynamic investigation is recommended only when spinal cord anomalies or other signs indicative of NBD are present. In case of spinal cord malformation, repeated urodynamics during follow-up is mandatory because of the risk for developing tethered cord syndrome.
|
|
| 7. |
- Borg, Helena, et al.
(författare)
-
Longitudinal study of bowel function in children with anorectal malformations.
- 2013
-
Ingår i: Journal of pediatric surgery. - : Elsevier BV. - 1531-5037 .- 0022-3468. ; 48:3, s. 597-606
-
Tidskriftsartikel (refereegranskat)abstract
- Longitudinal follow-up of changes in bowel function in children with anorectal malformations (ARMs) with or without spinal cord pathology and neurogenic bladder dysfunction (NBD) as they grow. Another purpose was to identify predictors influencing bowel functional outcome.
|
|
| 8. |
- Borg, Helena, et al.
(författare)
-
Megarectosigmoid in children with anorectal malformations: Long term outcome after surgical or conservative treatment.
- 2014
-
Ingår i: Journal of pediatric surgery. - : Elsevier BV. - 1531-5037 .- 0022-3468. ; 49:4, s. 564-9
-
Tidskriftsartikel (refereegranskat)abstract
- Megarectosigmoid (MRS) is commonly seen in children with anorectal malformations (ARM) and contributes to the high incidence of constipation. Surgical resection has been advocated by some, whereas others propose intense bowel management as the treatment of choice. The aim of this study was to evaluate outcome of both bowel function and configuration after surgical or conservative treatment of MRS in ARM patients.
|
|
| 9. |
- Borg, Helena, et al.
(författare)
-
Reply to Letter to the Editor.
- 2015
-
Ingår i: Journal of pediatric surgery. - : Elsevier BV. - 1531-5037 .- 0022-3468. ; 50:6
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 10. |
- Calabrese, Claudia, et al.
(författare)
-
Genomic basis for RNA alterations in cancer
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 578:7793, s. 129-136
-
Tidskriftsartikel (refereegranskat)abstract
- Transcript alterations often result from somatic changes in cancer genomes1. Various forms of RNA alterations have been described in cancer, including overexpression2, altered splicing3 and gene fusions4; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)5. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed 'bridged' fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.
|
|
