Mutations and polymorphisms of the p21B transcript in breast cancer

Abstract

p21 WAF1/CIP1 , transcribed from the CDKN1A locus, plays a key role executing p53-induced growth arrest. The recent discovery that an alternative transcript, p21B, induces apoptosis, suggests an additional important function of this gene. Here, we report p21 and p21B mutation status in large cohorts of breast cancers and compare distributions of p21B polymorphisms in cancer patients to healthy controls. In 521 breast tumor samples analyzed, only one point mutation affecting the p21B protein was observed. No mutations were found when screening a panel of 20 established cell lines. A novel polymorphism, p21B G128T was identified. Haplotype analysis revealed no association between this variant and the previously identified p21B polymorphism p21B T35C or any of the known p21 WAF1/CIP1 polymorphisms. As previously reported for p21B T35C , distribution of p21B G128T was similar among breast cancer patients and healthy controls (n 5 691 and 1,015; incidence 6.1 vs. 4.8%; p 5 0.273, respectively). No association between p21B G128T or p21B T35C and response to chemotherapy with an anthracycline-containing regimen or paclitaxel was recorded. Our findings do not suggest mutations or polymorphisms of p21B to play a major role with respect to either breast cancer risk or sensitivity towards chemotherapy. ' 2007 Wiley-Liss, Inc.Key words: p21; p21B; polymorphism; breast cancer p21B is a recently discovered protein translated from an alternative transcript of the CDKN1A gene, commonly known as the locus encoding p21 WAF1/CIP1 . Expression of p21B is driven by an independent promoter, and the processed transcript consists of a short first exon spliced to a longer exon harboring the p21B coding region. The promoter as well as the complete coding region of p21B is located within intron 1 of p21 WAF1/CIP1 , thus, the two proteins do not share any amino acid sequence. 1 Transcription of p21B, similar to transcription of p21 WAF1/CIP1 , is induced by p53. 1 However, while p21 WAF1/CIP1 is a mediator of cell cycle arrest through inhibition of the cyclin E-CDK2 complex, p21B has been linked to induction of apoptosis. 1 As a few studies have examined somatic mutations affecting p21 WAF1/CIP1 in human cancers, 2-7 no study has examined mutations affecting the p21B transcript. Several polymorphisms within the CDKN1A locus have been reported, the most prevalent being p21 C93A . Case control studies on this variant has provided conflicting evidence, suggesting an association to risk of different cancer forms. [8][9][10][11][12][13][14][15][16] In contrast, the only p21B polymorphism previously identified is p21B T35C , 17 previously reported by us not to be associated with breast cancer risk. 18 We here present the results from screening of 521 breast tumor samples for somatic alterations in the p21 WAF1/CIP1 and p21B transcripts. Further, we screened blood samples from an additional 170 breast cancer patients (132 patients with operable stage I and II breast cancers and 38 patients with stage III disease) together with samples from 1,015 ...

Elevated levels of the steroidogenic factor 1 are associated with over-expression of CYP19 in an oestrogen-producing testicular Leydig cell tumour

“…(29). The RNA concentration was measured on a Nanodrop ND1000 spectrophotometer and adjusted to 1 μg/μl.…”

Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers

“…Sequencing was performed as described previously [39] using primers specific for the different RB1 fragments (Table 2). The sequences generated were compared with wild-type RB1 (GenBank accession number: L11910) for sequence alterations.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…In addition, some of p53's downstream targets, such as CDKN1A (coding for p21), have a very low mutation frequency in cancers, making assessment of their impact on therapy response challenging. 75,76 However, Zenz et al 77 found expression of miR-34a, a p53-inducible micro-RNA, to predict resistance to fludarabine in chronic lymphatic leukemias independent of TP53 and 17p deletion status.…”