| 1. |
- Antoniou, A, et al.
(författare)
-
Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies
- 2003
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 72:5, s. 1117-1130
-
Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers ( P trend .0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
|
|
| 2. |
- Gentile, Massimiliano, et al.
(författare)
-
Deletion mapping of chromosome segment 11q24-q25, exhibiting extensive allelic loss in early onset breast cancer
- 2001
-
Ingår i: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 92:2, s. 208-213
-
Tidskriftsartikel (refereegranskat)abstract
- Frequent allelic deletions at chromosome 11q24-q25 have been described in both early and late onset breast cancers, suggesting the existence of a gene locus implicated in the initiation and/or progression of the disease. In the present study we fine mapped this region further by loss of heterozygosity (LOH) analysis in a population of early onset breast cancer cases (n = 102, 22 to 36 years old). Loss of chromosomal material was assessed for possible association with patient survival as well as Nottingham histologic grade (NHG). Additionally, we investigated the involvement of the 11q24-q25 locus in a group of familial breast cancer cases with no detectable BRCA1 or BRCA2 gene alterations (n = 32, ages 28 to 40 years). Among the consecutive patients, extensive LOH was observed for all markers at 11q24-q25, with frequencies ranging from 42% to 54%. Deletion at the D11S4125 marker was found to be associated with reduced survival (p = 0.026), whereas the adjacent D11S387 marker correlated with higher histologic grade (p = 0.042). In the familial cases, the most telomeric markers showed substantially lower proportions of LOH, ranging from 10% to 21%. Comparison of the two patient groups demonstrated that this difference in LOH frequency was statistically significant for the D11S4098, D11S968, D11S387 and D11S4125 markers (p = 0.020, p = 0.029, p = 0.0070 and p = 0.0030, respectively). We conclude that 11q25 may harbor a gene implicated in early onset breast cancer. Our data suggest that the most probable position for this locus is defined by the markers D11S387 and D11S4125 and furthermore that it may play a less significant role in familial breast cancer cases not linked to either of the BRCA genes.
|
|
| 3. |
- Hedenfalk, Ingrid, et al.
(författare)
-
Molecular classification of familial non-BRCA1/BRCA2 breast cancer
- 2003
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 100:5, s. 2532-2537
-
Tidskriftsartikel (refereegranskat)abstract
- In the decade since their discovery, the two major breast cancer susceptibility genes BRCA1 and BRCA2, have been shown conclusively to be involved in a significant fraction of families segregating breast and ovarian cancer. However, it has become equally clear that a large proportion of families segregating breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately, despite intensive effort, the identification of additional breast cancer predisposition genes has so far been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/2 breast cancer families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Accordingly, the identification of a method to successfully subdivide BRCAx families into recognizable groups could be of considerable value to further genetic analysis. We have previously shown that global gene expression analysis can identify unique and distinct expression profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrate that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.
|
|
| 4. |
- Koul, Anjila, et al.
(författare)
-
Two BRCA1-positive epithelial ovarian tumors with metastases to the central nervous system: a case report
- 2001
-
Ingår i: Gynecologic Oncology. - : Elsevier BV. - 1095-6859 .- 0090-8258. ; 80:3, s. 399-402
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cerebral metastasis secondary to ovarian cancer is a rare phenomenon. While no clear relationship to known prognostic factors is found, others suggest this as a biologically diverse behavior of ovarian cancer. CASES: In a pilot study, 37 invasive epithelial ovarian cancer samples were analyzed to detect the frequency of BRCA1/BRCA2 mutations in the south of Sweden (results published). A retrospective follow-up revealed that 2 of these (2/37; 5.4%) patients developed central nervous system metastases during the course of their disease. Both patients had advanced surgical stage disease at the time of diagnosis, with histopathological serous type tumors that were negative for estrogen and progesterone receptors. One of these patients carried a germline BRCA1 mutation, whereas a somatic BRCA1 mutation was identified in the other patient. CONCLUSIONS: To the best of our knowledge the molecular genetic profile of these tumors is not found in the literature and it is suggested that such analyses could provide some insight for a better understanding of this rare phenomenon.
|
|
| 5. |
|
|
| 6. |
- Loman, Niklas, et al.
(författare)
-
Cancer incidence in relatives of a population-based set of cases of early-onset breast cancer with a known BRCA1 and BRCA2 mutation status
- 2003
-
Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 5:6, s. 175-186
-
Forskningsöversikt (refereegranskat)abstract
- Background Relatives of breast cancer cases have an increased risk of the disease. The risk increases with increasing numbers and decreasing age of onset of affected relatives. In families with a BRCA1 or a BRCA2 mutation, individual carrier status predicts the risk of breast cancer. In relatives of cases where both BRCA1 and BRCA2 mutations are excluded, the risk remains undetermined. Methods Standardized incidence ratios (SIRs) and cumulative cancer incidences were calculated for relatives of a population-based set of early-onset breast cancer index cases (younger than age 41 years) with a defined BRCA mutation status (n = 203). Results In first-degree relatives (FDRs) of mutation-negative cases, breast cancer incidences (SIR=2.3), prostate cancer incidences (SIR=1.7), cervix cancer incidences (SIR=3.3) and nonmelanoma skin cancer incidences (SIR=2.8) were increased. The risks of breast cancer, prostate cancer and nonmelanoma skin cancer were further increased in FDRs of breast cancer cases younger than 36 years of age. In high-risk individuals with at least one relative with breast cancer apart from the index case, but no BRCA mutation in the family, breast cancer incidence was increased (SIR=5.3); again the prostate cancer incidence was elevated (SIR=2.5). The cumulative incidence of breast cancer at ages 50 and 70 years for FDRs of index cases without a BRCA mutation was 3.6% and 12.8%, respectively. Similarly, the cumulative incidence of breast cancer for high-risk women was 6.3% and 21.1% at ages 50 and 70 years, and that for FDRs of BRCA mutation carriers was 17.2% and 27.7% at the same ages. Conclusion The incidence of breast cancer is increased for FDRs of women with early-onset breast cancer irrespective of the BRCA status in the family. Risk increases with decreasing age and with increasing number of affected relatives. The incidences of prostate cancer, cervix cancer and nonmelanoma skin cancer are elevated for FDRs of early-onset breast cancer cases without a BRCA mutation, indicating a possible association between these cancers and early-onset breast cancer.
|
|
| 7. |
- Loman, Niklas
(författare)
-
Clinical Aspects of Hereditary Breast Cancer
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A positive family history of breast cancer (BC) is one of the strongest predictors of the disease. Two major BC susceptibility genes, BRCA1 and BRCA2 were identified about a decade ago. In this thesis, studies of different biological. clinical and epidemiological aspects of hereditary BC are presented. In the first paper data on the expression of steroid hormone receptors in hereditary BC are presented. We confirm previously published data regarding the paucity of estrogen and progesterone receptors in BRCA1-associated BC, and report new findings in BRCA2-associated tumours and cases with an unidentified hereditary factor. Hormone receptor levels in these two groups do not differ significantly from each other or from an age-matched control population unselected for family history. The second paper is a cohort study of cancer incidence in relatives of BRCA1 and BRCA2 germline mutation carriers. Other cancers than BC and ovarian cancer do not appear to be greatly increased and require specific follow-up in carriers. The third study is a retrospective case-control study on the prognosis and clinical presentation of BRCA2-associated BC. BC in families with an identified BRCA2 mutation seemed to present at a more advanced stage at diagnosis compared with age and year of diagnoses matched controls. This translated into an increased risk to die from BC in this group, but overall survival was not significantly decreased. The fourth study is a population-based study of family history and BRCA1 and BRCA2 mutations in BC cases below the age of 41. A positive family history was very frequent in this group of young BC patients. About one-third of them had a family history including at least one first- or second-degree relative with BC. A positive BRCA1-mutation status was observed in 6.8% of the cases, and BRCA2-mutations were seen in 2.1% of the in women. BRCA1 and BRCA2 mutations were more prevalent in younger women, in women with a positive family history including at least one first-degree relative with breast or ovarian cancer, and in women that had already or did develop a bilateral BC during a median follow-up of 5.5 years. In the fifth study relative and cumulative cancer incidence in the first-degree relatives of the woman of the previous study were calculated and compared with the population. The BC risk was still increased in first-degree relatives of women with early-onset BC (below the age of 41) when BRCA-mutation carriers were excluded, in addition an association with prostate cancer was suggested. The risk of prostate cancer did only appear to be increased in relatives of women with BC below the age of 36. Furthermore, cumulative BC incidences were calculated for women with different hereditary backgrounds.
|
|
| 8. |
- Loman, Niklas, et al.
(författare)
-
Prognosis and clinical presentation of BRCA2-associated breast cancer
- 2000
-
Ingår i: European Journal of Cancer. - 1879-0852. ; 36:11, s. 1365-1373
-
Tidskriftsartikel (refereegranskat)abstract
- 54 female breast cancer patients from 22 families with BRCA2 germ line mutations from Sweden and Denmark were compared with 214 age- and date of diagnosis-matched controls identified among breast cancer patients from South Sweden. At diagnosis, BRCA2-associated cases were more often node-positive (N+). OR=1.9 (95% confidence interval (CI)=1.0-3.6; P=0.036), and were more often clinical stage IV: OR=4.6 (95% CI=1.3-17; P=0.021) than the controls. Bilateral disease was also more common among the BRCA2-associated cases: OR=2. 4 (95% CI=1.1-5.3; P=0.027). Breast cancer-specific survival (BCSS) was significantly worse among the BRCA2-associated cases: RR=2.0 (95% CI=1.2-3.4; P=0.010). When stage was corrected for in a multivariate analysis, BCSS was no longer significantly worse for the BRCA2-associated cases: RR=1.6 (95% CI=0.85-3.1). The corresponding effect after correction for bilateral disease was: RR=1.8 (95% CI=1.0-3.1; P=0.034). The unfavourable prognosis in BRCA2-associated breast cancer seems, to a great extent, to be a consequence of the higher clinical stage at diagnosis. The increased presence of bilateral cancers appears to have less impact on survival in this group of hereditary breast cancer. Data presented here needs to be taken into account when counselling healthy carriers of BRCA2 germ line mutations.
|
|
| 9. |
- Salahshor, Sima, et al.
(författare)
-
Low frequency of E-cadherin alterations in familial breast cancer
- 2001
-
Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 3:3, s. 199-207
-
Tidskriftsartikel (refereegranskat)abstract
- In order to explore the possible role of E-cadherin in familial cancer, 19 familial breast cancer patients, whose tumours demonstrated loss of heterozygosity (LOH) at the E-cadherin locus, were screened for germline mutations. No pathogenic germline alterations were detected in these individuals. However, a somatic mutation was found (49-2A-->C) in one of the tumours. This tumour showed a pattern of both ductal and lobular histology. Another 10 families with cases of breast, gastric and colon cancer were also screened for germline mutations, and no mutations were found. A missense mutation in exon 12 of E-cadherin (1774G-->A; Ala592Thr) was previously found in one family with diffuse gastric cancer, and colon and breast cancer. An allelic association study was performed to determine whether the Ala592Thr alteration predisposes to breast cancer. In total, we studied 484 familial breast cancer patients, 614 sporadic breast cancer patients and 497 control individuals. The frequencies of this alteration were similar in these groups. However, a correlation between the Ala592Thr alteration and ductal comedo-type tumour was seen. These results, together with previously reported studies, indicate that germline mutations and, more commonly, somatic mutations in E-cadherin may have an influence on the behaviour of the tumours, rather than predispose to breast cancer.
|
|
| 10. |
- Thompson, D, et al.
(författare)
-
Cancer Incidence in BRCA1 mutation carriers
- 2002
-
Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 94:18, s. 1358-1365
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Germline BRCA1 mutations confer a substantial lifetime risk of breast and ovarian cancer, but whether cancer at other sites is increased is less clear. To evaluate the risks of other cancers in BRCA1 mutation carriers, we conducted a cohort study of 11 847 individuals from 699 families segregating a BRCA1 mutation that were ascertained in 30 centers across Europe and North America. Methods: The observed cancer incidence was compared with the expected cancer incidence based on population cancer rates. Relative risks (RRs) of each cancer type in BRCA1 carriers relative to risks for the general population were estimated by weighting individuals according to their estimated probability of being a mutation carrier. All statistical tests were two-sided. Results: BRCA1 mutation carriers were at a statistically significantly increased risk for several cancers, including pancreatic cancer (RR = 2.26, 95% confidence interval [CI] = 1.26 to 4.06, P = .004) and cancer of the uterine body and cervix (uterine body RR = 2.65, 95% CI = 1.69 to 4.16, P<.001; cervix RR = 3.72, 95% CI = 2.26 to 6.10, P<.001). There was some evidence of an elevated risk of prostate cancer in mutation carriers younger than 65 years old (RR = 1.82, 95% CI = 1.01 to 3.29, P = .05) but not in those 65 years old or older (RR = 0.84, 95% CI = 0.53 to 1.33, P = .45). Overall, increases in the risk for cancer at sites other than the breast or ovary were small and evident in women (RR = 2.30, 95% CI = 1.93 to 2.75, P = .001) but not in men (RR = 0.95, 95% CI = 0.81 to 1.12, P = .58). Conclusions: In carriers of BRCA1 mutations, the overall increased risk of cancer at sites other than breast and ovary is small and is observed in women but generally not in men. BRCA1 mutations may confer increased risks of other abdominal cancers in women and increased risks of pancreatic cancer in men and women.
|
|
