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We identified in breast cancer cases two germline alterations, R62H and R71W, in presenilin-2 (PS-2), a gene involved in familial Alzheimer's disease (FAD). The role of these alleles in FAD is unclear, but neither allele affected Aβ(42)/Aβ(40) ratio. However, both R62H and R71W alterations compromised PS-2 function in Notch signaling in Caenorhabditis elegans and cell growth inhibition in mouse embryonic fibroblasts, and these effects were dependent on gene dosage. We found that both alterations enhanced the degradation of the PS-2 full-length protein, indicating that they may have a loss-of function effect. The effect of the R71W alteration was noticeably stronger, and we observed an almost threefold higher frequency of this allele in breast cancer cases versus controls, but this difference did not reach statistical significance. Nonetheless, these results collectively suggest that the novel PS-2 alleles described here, especially R71W, affect PS-2 function and may potentially confer a moderate risk of susceptibility to breast cancer.Oncogene (2006) 25, 3557–3564. doi:10.1038/sj.onc.1209397; published online 13 February 2006 [ABSTRACT FROM AUTHOR]

Many growth-suppressing signals converge to control the levels of the CDK inhibitor p21[SUPCIP1/WAF1]. Some human cancers exhibit low levels of expression of p21[SUPCIP1/WAF1]and mutations inp53 have been implicated in this down-regulation. To evaluate whether the presence of p53 mutations was related to the in vivo expression of p21[SUPCIP1/WAF1] mRNA in sarcomas we measured the p21[SUPCIP1/WAF1] mRNA levels for a group of 71 primary bone and soft tissue tumours with known p53 status. As expected, most tumours withp53 mutations expressed low levels of p21[SUPCIP1/WAF1] mRNA. However, we identified a group of tumours withp53 gene mutations that exhibited normal or higher levels ofp21[SUPCIP1/WAF1] mRNA. The p53 mutations in the latter group were not the common missense mutations in exons 4-9, but were predominantly nonsense mutations predicted to result in truncation of the p53 protein. The results of this study suggest that different types ofp53 mutations can have different effects on the expression of downstream genes such as p21[SUPCIP1/WAF1] in human sarcomas. [ABSTRACT FROM AUTHOR]