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- Fernebro, Josefin, et al.
(författare)
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Gene expression profiles relate to SS18/SSX fusion type in synovial sarcoma
- 2006
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 118:5, s. 1165-1172
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Tidskriftsartikel (refereegranskat)abstract
- We applied 27k spotted cDNA microarray slides to assess gene expression profiles in 26 samples from 24 patients with synovial sarcomas (SS). The data were analyzed in relation to histopathologic type, cytogenetic aberrations, gene fusion type and development of distant metastases. Supervised analysis based on gene fusion type in 12 SS with SS18/SSXI and 9 with SS18/SSX2 revealed significant differences in gene expression profiles. Among the discriminators were several genes that have previously been found to be upregulated in SS, including AXL, ZIC2, SPAG7, AGRN, FOXC1, NCAM1 and multiple metallothioneins. Histopathology and degree of cytogenetic complexity did not significantly influence expression, whereas a genetic signature that related to development of metastases could be discerned, albeit with a high false-positive rate. In conclusion, our findings demonstrate differentially expressed genes for the 2 major gene fusion variants in SS, SS18/SSX1 and SS18/SSX2, and thereby suggest that these result in different downstream effects. (c) 2005 Wiley-Liss, Inc.
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- Goldstein, Alisa M., et al.
(författare)
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High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL
- 2006
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Ingår i: Cancer Research. - 1538-7445 .- 0008-5472. ; 66:20, s. 9818-9828
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Tidskriftsartikel (refereegranskat)abstract
- GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, cdVS2-105A > G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.
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- Heikkinen, Katri, et al.
(författare)
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RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability
- 2006
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 27:8, s. 1593-1599
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Tidskriftsartikel (refereegranskat)abstract
- The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P = 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G > A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxyterminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.
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- Isinger Ekstrand, Anna, et al.
(författare)
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CHEK2 1100delC in patients with metachronous cancers of the breast and the colorectum
- 2006
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Development of multiple primary tumors is a hallmark of hereditary cancer. At least 1/10 of breast cancers and colorectal cancers occur because of heredity and recently the cell cycle kinase 2, CHEK2 1100delC allele has been identified at a particularly high frequency in families with hereditary breast and colorectal cancer. Methods: We utilized the Southern Sweden population-based cancer registry to identify women with double primary breast and colorectal cancer and sequenced tumor material in order to assess the contribution of the CHEK2 1100delC to the development of such metachronous tumors. Results: Among the 75 patients successfully analyzed, 2 (2.5%) carried the CHEK2 1100delC allele. which was not significantly different (p = 0.26) from the 1% (3/300) carriers identified in the control group. Conclusion: In summary, our data suggest that the CHEK2 1100delC is not a major cause of double primary breast and colorectal cancer in Sweden, which suggests that this patient group should not routinely be screened for the CHEK2 1100delC variant.
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