| 1. |
|
|
| 2. |
- Dalgaard, Marlene D., et al.
(författare)
-
A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation
- 2012
-
Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 49:1, s. 58-65
-
Tidskriftsartikel (refereegranskat)abstract
- Background Testicular dysgenesis syndrome (TDS) is a common disease that links testicular germ cell cancer, cryptorchidism and some cases of hypospadias and male infertility with impaired development of the testis. The incidence of these disorders has increased over the last few decades, and testicular cancer now affects 1% of the Danish and Norwegian male population. Methods To identify genetic variants that span the four TDS phenotypes, the authors performed a genome-wide association study (GWAS) using Affymetrix Human SNP Array 6.0 to screen 488 patients with symptoms of TDS and 439 selected controls with excellent reproductive health. Furthermore, they developed a novel integrative method that combines GWAS data with other TDS-relevant data types and identified additional TDS markers. The most significant findings were replicated in an independent cohort of 671 Nordic men. Results Markers located in the region of TGFBR3 and BMP7 showed association with all TDS phenotypes in both the discovery and replication cohorts. An immunohistochemistry investigation confirmed the presence of transforming growth factor beta receptor type III (TGFBR3) in peritubular and Leydig cells, in both fetal and adult testis. Single-nucleotide polymorphisms in the KITLG gene showed significant associations, but only with testicular cancer. Conclusions The association of single-nucleotide polymorphisms in the TGFBR3 and BMP7 genes, which belong to the transforming growth factor b signalling pathway, suggests a role for this pathway in the pathogenesis of TDS. Integrating data from multiple layers can highlight findings in GWAS that are biologically relevant despite having border significance at currently accepted statistical levels.
|
|
| 3. |
- Fallah, Mahdi, et al.
(författare)
-
Risk of thyroid cancer in first-degree relatives of patients with non-medullary thyroid cancer by histology type and age at diagnosis: a joint study from five Nordic countries
- 2013
-
Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 50:6, s. 373-382
-
Tidskriftsartikel (refereegranskat)abstract
- Background We aimed to estimate lifetime cumulative risk of thyroid cancer (CRTC) in first-degree relatives of patients with non-medullary thyroid cancers (NMTC), including papillary (PTC)/follicular/oxyphilic/anaplastic thyroid carcinoma, by histology and age at diagnosis in patients and their relatives. Design A population-based cohort of 63 495 first-degree relatives of 11 206 NMTC patients diagnosed in 1955-2009 in Nordic countries was followed for cancer incidence. Standardised incidence ratios (SIRs) were calculated using histology-specific, age-specific, sex-specific, period-specific and country-specific incidence rates as reference. Results The 0-84-year CRTC in female relatives of a patient with PTC was 2%, representing a threefold increase over the general population risk (SIR=2.9, 95% CI 2.4 to 3.4; Men: CRTC=1%, SIR=2.5, 95% CI 1.9 to 3.3). When there were >= 2 PTC patients diagnosed at age <60 years in a family, CRTC for female relatives was 10% (male 24%). Twins had a 23-fold increased risk of concordant PTC. Family history of follicular/oxyphilic/anaplastic carcinoma increased CRTC in relatives to about 1-2%. Although no familial case of concordant oxyphilic/anaplastic carcinoma was found, familial risks of discordant histology types of NMTC were interchangeably high for most of the types, for example, higher risk of PTC when a first-degree relative had follicular (SIR=3.0, 95% CI 1.7 to 4.9) or anaplastic (SIR=3.6, 95% CI 1.2 to 8.4) carcinoma. The earlier a patient was diagnosed with PTC in a family, the higher was the SIR in his/her younger relatives. There was a tendency towards concordant age at diagnosis of thyroid cancer among relatives of PTC patients. Conclusions This study provides clinically relevant risk estimates for family members of NMTC patients.
|
|
| 4. |
- Helgadottir, Hildur, et al.
(författare)
-
High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families.
- 2014
-
Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 51:8, s. 545-552
-
Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in the tumour suppressor gene CDKN2A occur in 5-20% of familial melanoma cases. A single founder mutation, p.Arg112dup, accounts for the majority of CDKN2A mutations in Swedish carriers. In a national program, carriers of p.Arg112dup mutation have been identified. The aim of this study was to assess cancer risks in p.Arg112dup carriers and their first degree relatives (FDRs) and second degree relatives (SDRs).
|
|
| 5. |
- Roudgari, Hassan, et al.
(författare)
-
Prostate cancer risk assessment model: a scoring model based on the Swedish Family-Cancer Database
- 2012
-
Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 49:5, s. 345-352
-
Tidskriftsartikel (refereegranskat)abstract
- Background Many prostate cancer (PC) risk assessment models have been developed, however almost none include familial history. Aim To produce a risk assessment model for PC based on familial background of related cancers. Method 976 859 independent index men aged >= 30 in year 1998 and their family members in the Swedish Family-Cancer Database (FCD2010) were randomly divided into development (60%) and validation (40%) datasets (follow-up 10 years). The HR from Cox model was used to extrapolate risk scores. Results Specified scores were: for PC in situ at age <60 years in index man, 5; for PC at age <60 years in each first-degree relative (FDR), 15; for PC at age >= 60 years in each FDR, 10; for PC at age <60 years in each second-degree relative, 5; for breast cancer in each FDR, 2; for oesophageal carcinoma in situ in index man, 2; and for oesophagus cancer in each FDR, 2. Based on the findings, if the milestone age for a PC screening programme was 60 years or more, the recommended starting age for the men with the score-group 6-10 would be 54 years; score-group 11-15, 52 years; score-group 16-20, 50 years; score-group 21-25, 44 years; and for the score-group 26+ it should start before age 40. The concordance index in development and validation sets was 0.885 (95% CI 0.883 to 0.888). No significant difference was found between curves from development and validation datasets (internally validated using twofold validation and bootstrapping). Conclusion Familial history of relevant malignancies can be used as risk factors to estimate a man's prior risk of developing PC. The prostate cancer risk assessment model could satisfactorily assess risk of developing prostate cancer.
|
|
| 6. |
- Thorwarth, Anne, et al.
(författare)
-
Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum
- 2014
-
Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 51:6, s. 375-387
-
Tidskriftsartikel (refereegranskat)abstract
- Background NKX2-1 encodes a transcription factor with large impact on the development of brain, lung and thyroid. Germline mutations of NKX2-1 can lead to dysfunction and malformations of these organs. Starting from the largest coherent collection of patients with a suspected phenotype to date, we systematically evaluated frequency, quality and spectrum of phenotypic consequences of NKX2-1 mutations. Methods After identifying mutations by Sanger sequencing and array CGH, we comprehensively reanalysed the phenotype of affected patients and their relatives. We employed electrophoretic mobility shift assay (EMSA) to detect alterations of NKX2-1 DNA binding. Gene expression was monitored by means of in situ hybridisation and compared with the expression level of MBIP, a candidate gene presumably involved in the disorders and closely located in close genomic proximity to NKX2-1. Results Within 101 index patients, we detected 17 point mutations and 10 deletions. Neurological symptoms were the most consistent finding (100%), followed by lung affection (78%) and thyroidal dysfunction (75%). Novel symptoms associated with NKX2-1 mutations comprise abnormal height, bouts of fever and cardiac septum defects. In contrast to previous reports, our data suggest that missense mutations in the homeodomain of NKX2-1 not necessarily modify its DNA binding capacity and that this specific type of mutations may be associated with mild pulmonary phenotypes such as asthma. Two deletions did not include NKX2-1, but MBIP, whose expression spatially and temporarily coincides with NKX2-1 in early murine development. Conclusions The high incidence of NKX2-1 mutations strongly recommends the routine screen for mutations in patients with corresponding symptoms. However, this analysis should not be confined to the exonic sequence alone, but should take advantage of affordable NGS technology to expand the target to adjacent regulatory sequences and the NKX2-1 interactome in order to maximise the yield of this diagnostic effort.
|
|
