| 1. |
- Lawrenson, Kate, et al.
(author)
-
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Journal article (peer-reviewed)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
- Cremers, Ruben G., et al.
(author)
-
The role of the prostate cancer gene 3 urine test in addition to serum prostate-specific antigen level in prostate cancer screening among breast cancer, early-onset gene mutation carriers
- 2015
-
In: Urologic Oncology: Seminars and Original Investigations. - : Elsevier BV. - 1078-1439. ; 33:5, s. 19-202
-
Journal article (peer-reviewed)abstract
- Objective: To evaluate the additive value of the prostate cancer gene 3 (PCA3) urine test to serum prostate-specific antigen (PSA) in prostate cancer (PC) screening among breast cancer, early-onset gene (BRCA) mutation carriers. This study was performed among the Dutch participants of IMPACT, a large international study on the effectiveness of PSA screening among BRCA mutation carriers. Materials and methods: Urinary PCA3 was measured in 191 BRCA1 mutation carriers, 75 BRCA2 mutation carriers, and 308 noncarriers. The physicians and participants were blinded for the results. Serum PSA level≥3.0. ng/ml was used to indicate prostate biopsies. PCA3 was evaluated (1) as an independent indicator for prostate biopsies and (2) as an indicator for prostate biopsies among men with an elevated PSA level. PC detected up to the 2-year screening was used as gold standard as end-of-study biopsies were not performed. Results: Overall, 23 PCs were diagnosed, 20 of which were in men who had an elevated PSA level in the initial screening round. (1) PCA3, successfully determined in 552 participants, was elevated in 188 (cutoff≥25; 34%) or 134 (cutoff≥35; 24%) participants, including 2 of the 3 PCs missed by PSA. PCA3 would have added 157 (≥25; 28%) or 109 (≥35; 20%) biopsy sessions to screening with PSA only. (2) Elevated PCA3 as a requirement for biopsies in addition to PSA would have saved 37 (cutoff≥25) or 43 (cutoff≥35) of the 68 biopsy sessions, and 7 or 11 PCs would have been missed, respectively, including multiple high-risk PCs. So far, PCA3 performed best among BRCA2 mutation carriers, but the numbers are still small. Because PCA3 was not used to indicate prostate biopsies, its true diagnostic value cannot be calculated. Conclusions: The results do not provide evidence for PCA3 as a useful additional indicator of prostate biopsies in BRCA mutation carriers, as many participants had an elevated PCA3 in the absence of PC. This must be interpreted with caution because PCA3 was not used to indicate biopsies. Many participants diagnosed with PC had low PCA3, making it invalid as a restrictive marker for prostate biopsies in men with elevated PSA levels.
|
|
| 18. |
- Dominguez-Valentin, M, et al.
(author)
-
No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study
- 2021
-
In: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 10:13
-
Journal article (peer-reviewed)abstract
- Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
- Moller, P, et al.
(author)
-
Survival in prospectively ascertained familial breast cancer: Analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy
- 2002
-
In: International Journal of Cancer. - : Wiley. - 0020-7136. ; 101:6, s. 555-559
-
Journal article (peer-reviewed)abstract
- Dedicated clinics have been established for the early diagnosis and treatment of women at risk for inherited breast cancer, but the effects of such interventions are currently unproven. This second report on prospectively diagnosed inherited breast cancer from the European collaborating centres supports the previous conclusions and adds information on genetic heterogeneity and the effect of oophorectomy. Of 249 patients, 20% had carcinoma in situ (CIS), 54% had infiltrating cancer without spread (CaNO) and 26% had cancer with spread (CaN+). Five-year survival was 100% for CIS, 94% for CaNO and 72% for CaN+ (p = 0.007). Thirty-six patients had BRCA1 mutations, and 8 had BRCA2 mutations. Presence of BRCA1 mutation was associated with infiltrating cancer, high grade and lack of oestrogen receptor (p < 0.05 for all 3 characteristics). For BRCA1 mutation carriers, 5-year survival was 63% vs. 91% for noncarriers (p = 0.04). For CaNO patients, mutation carriers had 75% S-year disease-free survival vs. 96% for noncarriers (p = 0.01). Twenty-one of the mutation carriers had undergone prophylactic oophorectomy, prior to or within 6 months of diagnosis in 13 cases. All but I relapse occurred in the I S who had kept their ovaries, (p < 0.01); no relapse occurred in those who had removed the ovaries within 6 months (p = 0.04) Contralateral cancer was more frequently observed in mutation noncarriers, but this finding did not reach statistical significance. Our findings support the concept that BRCA1 cancer is biologically different from other inherited breast cancers. While current screening protocols appear satisfactory for the majority of women at risk of familial breast cancer, this may not be the case for BRCA1 mutation carriers. The observed effect of oophorectomy was striking.
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
|
|
