1. |
- Aaltonen, Kirsimari, et al.
(author)
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Familial breast cancers without mutations in BRCA1 or BRCA2 have low cyclin E and high cyclin D1 in contrast to cancers in BRCA mutation carriers
- 2008
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 14:7, s. 1976-83
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Journal article (peer-reviewed)abstract
- PURPOSE: We analyzed the expression of critical cell cycle regulators cyclin E and cyclin D1 in familial breast cancer, focusing on BRCA mutation-negative tumors. Cyclin E expression in tumors of BRCA1 or BRCA2 carriers is higher, and cyclin D1 expression lower, than in sporadic tumors. In familial non-BRCA1/2 tumors, cyclin E and cyclin D1 expression has not been studied. EXPERIMENTAL DESIGN: Cyclin E and cyclin D1 immunohistochemical expression was studied in tissue microarrays consisting of 53 BRCA1, 58 BRCA2, 798 familial non-BRCA1/2, and 439 sporadic breast tumors. RESULTS: In univariate analysis, BRCA1 tumors had significantly more frequently high cyclin E (88%) and low cyclin D1 (84%) expression than sporadic (54% and 49%, respectively) or familial non-BRCA1/2 (38% and 45%, respectively) tumors. BRCA2 tumors had significantly more frequently low cyclin D1 expression (68%) than sporadic or familial non-BRCA1/2 tumors and significantly more frequently high cyclin E expression than familial non-BRCA1/2 tumors. In a logistic regression model, cyclin expression, early age of onset, and estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) status were the independent factors most clearly distinguishing tumors of BRCA1 mutation carriers from other familial breast cancers. High cyclin E and low cyclin D1 expression were also independent predictors of BRCA2 mutation when compared with familial non-BRCA1/2 tumors. Most interestingly, lower frequency of high cyclin E expression independently distinguished familial non-BRCA1/2 tumors also from sporadic ones. CONCLUSIONS: Cyclin E and cyclin D1 expression distinguishes non-BRCA1/2 tumors from both sporadic and BRCA1- and BRCA2-associated tumors and may reflect different predisposition and pathogenesis in these groups.
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2. |
- Aaltonen, Kirsimari, et al.
(author)
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High cyclin B1 expression is associated with poor survival in breast cancer
- 2009
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 100:7, s. 1055-60
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Journal article (peer-reviewed)abstract
- Cyclin B1 regulates the G(2)-M transition of the cell cycle. Cyclin B1 expression is higher in premalignant and malignant than normal breast lesions. Correlation of cyclin B1 expression with other histopathological variables and prognostic role in breast cancer are not fully understood. Traditionally used prognostic criteria identify large subset of patients to receive adjuvant chemotherapy and to be exposed to adverse effects. A reliable and simple method helping prognostic evaluation in breast cancer is needed. We analysed cyclin B1 expression on 1348 invasive breast cancers and studied correlations with other histopathological variables and survival. High cyclin B1 correlated with high tumour grade, large tumour size and positive nodal status, oestrogen and progesterone receptor negativity, positive HER2 and p53 status, young age at diagnosis, and high cyclin E, cyclin A and Ki67 expression. Among patients not given adjuvant chemotherapy high cyclin B1 was a strong predictor of shorter overall and metastasis-free survival (RR 3.74, P<0.0005 and RR 3.51, P<0.0005, respectively), and remained as an independent prognostic factor also in multivariate analysis (RR 1.80, P=0.04 and RR 2.31, P=0.02, respectively). This study suggests high cyclin B1 associates with aggressive phenotype and is an independent prognostic factor in breast cancer.
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3. |
- Arason, Adalgeir, et al.
(author)
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Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families
- 2010
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 12:4, s. R50-
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Journal article (peer-reviewed)abstract
- Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.
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4. |
- Bartkova, Jirina, et al.
(author)
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Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer : MRE11 as a candidate familial cancer-predisposing gene
- 2008
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In: Molecular Oncology. - : Wiley. - 1574-7891. ; 2:4, s. 296-316
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Journal article (peer-reviewed)abstract
- The MRE11, RAD50, and NBS1 genes encode proteins of the MRE11-RAD50-NBS1 (MRN) complex critical for proper maintenance of genomic integrity and tumour suppression; however, the extent and impact of their cancer-predisposing defects, and potential clinical value remain to be determined. Here, we report that among a large series of approximately 1000 breast carcinomas, around 3%, 7% and 10% tumours showed aberrantly reduced protein expression for RAD50, MRE11 and NBS1, respectively. Such defects were more frequent among the ER/PR/ERBB2 triple-negative and higher-grade tumours, among familial (especially BRCA1/BRCA2-associated) rather than sporadic cases, and the NBS1 defects correlated with shorter patients' survival. The BRCA1-associated and ER/PR/ERBB2 triple-negative tumours also showed high incidence of constitutively active DNA damage signalling (gamma H2AX) and p53 aberrations. Sequencing the RAD50, MRE11 and NBS1 genes of 8 patients from non-BRCA1/2 breast cancer families whose tumours showed concomitant reduction/loss of all three MRN-complex proteins revealed two germline mutations in MRE11: a missense mutation R202G and a truncating mutation R633STOP (R633X). Gene transfer and protein analysis of cell culture models with mutant MRE11 implicated various destabilization patterns among the MRN complex proteins including NBS1, the abundance of which was restored by re-expression of wild-type MRE11. We propose that germline mutations qualify MRE11 as a novel candidate breast cancer susceptibility gene in a subset of non-BRCA1/2 families. Our data have implications for the concept of the DNA damage response as an intrinsic anti-cancer barrier, various components of which become inactivated during cancer progression and also represent the bulk of breast cancer susceptibility genes discovered to date.
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5. |
- Ding, Yuan C, et al.
(author)
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A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
- 2012
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In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 21:8, s. 1362-1370
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Journal article (peer-reviewed)abstract
- BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
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6. |
- Eerola, Hannaleena, et al.
(author)
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Basal cytokeratins in breast tumours among BRCA1, BRCA2 and mutation-negative breast cancer families
- 2008
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In: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-542X. ; 10:1, s. R17-
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Finding new immunohistochemical markers that are specific to hereditary breast cancer could help us to select candidates for BRCA1/BRCA2 mutation testing and to understand the biological pathways of tumour development. METHODS: Using breast cancer tumour microarrays, immunohistochemical expression of cytokeratin (CK)-5/6, CK-14 and CK-17 was evaluated in breast tumours from BRCA1 families (n = 46), BRCA2 families (n = 40), non-BRCA1/BRCA2 families (n = 358) and familial breast cancer patients with one first-degree relative affected by breast or ovarian cancer (n = 270), as well as from patients with sporadic breast cancer (n = 364). Staining for CK-5/6, CK-14 and CK-17 was compared between these groups and correlated with other clinical and histological factors. RESULTS: CK-5/6, CK-14 and CK-17 were detected mostly among oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative and high-grade tumours. We found the highest percentages of samples positive for these CKs among ER-negative/HER2-negative tumours. In univariate analysis, CK-14 was significantly associated with tumours from BRCA1 (39%; P < 0.0005), BRCA2 (27%; P = 0.011), and non-BRCA1/BRCA2 (21%; P < 0.005) families, as compared with sporadic tumours (10%). However, in multivariate analysis, CKs were not found to be independently associated with BRCA1 or BRCA2 mutation status, and the most effective predictors of BRCA1 mutations were age at onset, HER2 status, and either ER or PR status. CONCLUSION: Although our study confirms that basal CKs can help to identify BRCA1 mutation carriers, this effect was weaker than previously suggested and CKs did not independently predict BRCA1 mutation either from sporadic or familial breast cancer cases. The most effective, independent predictors of BRCA1 mutations were age at onset, HER2 status, and either ER or PR status, as compared with sporadic or non-BRCA1/BRCA2 cancers.
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7. |
- Fagerholm, Rainer, et al.
(author)
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NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer
- 2008
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 40:7, s. 844-53
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Journal article (peer-reviewed)abstract
- NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1(*)2, rs1800566(T), NM_000903.2:c.558C>T) that disables NQO1 strongly predicts poor survival among two independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 10(-5)). Survival after metastasis was reduced among NQO1(*)2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1(*)2-homozygous breast carcinoma cells in vitro, reflecting both p53-linked and p53-independent roles of NQO1. We propose a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggest that the NQO1 genotype is a prognostic and predictive marker for breast cancer.
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8. |
- Fletcher, Olivia, et al.
(author)
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Family history, genetic testing, and clinical risk prediction : pooled analysis of CHEK2 1100delC in 1,828 bilateral breast cancers and 7,030 controls
- 2009
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In: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 18:1, s. 230-4
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Journal article (peer-reviewed)abstract
- If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2 1100delC should be approximately 5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be approximately 9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2 1100delC carriers was 6.43 (95% confidence interval, 4.33-9.56; P < 0.0001), significantly greater than the published estimate for a first primary (P < 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (P(trend) = 0.0003) and Finland (P(trend) = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2 1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2 1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2 1100delC and other moderate penetrance alleles in women with a family history of breast cancer.
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9. |
- Garcia-Closas, Montserrat, et al.
(author)
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Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics
- 2008
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In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 4:4, s. e1000054-
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Journal article (peer-reviewed)abstract
- A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
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10. |
- Hagman, Anna, et al.
(author)
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Obstetric and neonatal outcome after oocyte donation in 106 women with Turner syndrome: a Nordic cohort study.
- 2013
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In: Human reproduction (Oxford, England). - : Oxford University Press (OUP). - 1460-2350 .- 0268-1161. ; 28:6, s. 1598-609
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Journal article (peer-reviewed)abstract
- What are the obstetric and neonatal outcomes of deliveries after oocyte donation (OD) in women with Turner syndrome (TS)? SUMMARY ANSWER: Pregnancies among women with TS carry a substantial risk, particularly for hypertensive disorders. Potentially life-threatening complications occurred in 3.3% of pregnancies. The neonatal outcomes were generally reassuring, with similar rates of preterm birth and low birthweight (LBW) as after conventional IVF and better than previously reported in deliveries after OD in women with TS. WHAT IS KNOWN ALREADY: OD pregnancies in women with TS are known to be high-risk pregnancies. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 106 women with TS who delivered after OD (n = 122 deliveries, n = 131 newborns) in three Nordic countries (Finland, Denmark, Sweden) between 1992 and 2011. PARTICIPANTS, SETTING AND METHODS: Women with TS who delivered after OD in three Nordic countries were identified (n = 110). Four women declined to participate or were lost to follow-up, thus 106 women were included in the study. The medical data from fertility clinics, antenatal clinics and the hospitals where the women had been treated and/or delivered were scrutinized. MAIN RESULTS AND THE ROLE OF CHANCE: In this cohort, the karyotype was 45,X in 44% of the women with TS. Ten women (9.4%) had a known cardiac defect before pregnancy. Single embryo transfer was performed in 70.3% of the cases and the multiple birth rate was 7.4%. In total, 35.0% of the pregnancies were associated with a hypertensive disorder including pre-eclampsia in 20.5%. Potentially life-threatening complications occurred in four pregnancies (3.3%), including one woman with aortic dissection, one with mild regurgitation of the tricuspid and mitral valve, one with a mechanical heart valve who developed HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) and one who underwent a post-partum hysterectomy due to severe haemorrhaging. Neonatal outcomes were reassuring, with a preterm birth rate of 8.0% and LBW rate of 8.8% in singletons. Major birth defects were found in 3.8% of the children. The perinatal mortality was 2.3% (3/131), including a set of extremely preterm twins. LIMITATIONS, REASONS FOR CAUTION: Although this study was performed over a period of almost 20 years in three different countries, with a low drop-out rate and little missing data, much larger series are needed to assess rare events. This study also lacks an appropriate control group. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that cardiovascular evaluation before and during pregnancy may contribute to favourable obstetric outcomes in many cases. Maternal outcomes were in agreement with the literature while neonatal outcomes were generally better than previously reported. The outcomes were consistent across the three countries, supporting generalizability to similar populations. STUDY FUNDING/COMPETING INTEREST(S): No conflict of interest was reported. The study was supported by grants from the Gothenburg Medical Society, the Medical Care Executive Board of the Region Västra Götaland, grants from the ALF agreement at the Sahlgrenska University Hospital, the Hjalmar Svensson foundation, NFOG Nordic Fund, the Finnish Society of Paediatric and Adolescent Gynecology and Liv och hälsa Foundation in Finland. The Nordic Expert group's research work was unconditionally supported by MSD Finland, Norway and Denmark.
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