Tumor protein p53 (TP53) is mutated in approximately 30% of breast cancers, but this frequency fluctuates widely between subclasses. We investigated the p53 mutation status in 572 breast tumors, classified into luminal, basal and molecular apocrine subgroups. As expected, the lowest mutation frequency was observed in luminal (26%), and the highest in basal (88%) tumors. Luminal tumors showed significantly higher frequency of substitutions (82 vs. 65%), notably A/T to G/C transitions (31 vs. 15%), whereas molecular apocrine and basal tumors presented much higher frequencies of complex mutations (deletions/insertions) (36 and 33%, respectively, vs. 18%). Accordingly, missense mutations were significantly more frequent in luminal tumors (75 vs. 54%), whereas basal tumors displayed significantly increased rates of TP53 truncations (43 vs. 25%), resulting in loss of function and/or expression. Interestingly, as basal tumors, molecular apocrine tumors presented with a high rate of complex mutations, but paradoxically, these were not associated with increased frequency of p53 truncation. As in luminal tumors, this could reflect a selective pressure for p53 gain of function, possibly through P63/P73 inactivation. Collectively, these observations point not only to different mechanisms of TP53 alterations, but also to different functional consequences in the different breast cancer subtypes.With more than one in ten women estimated to develop breast cancer in her life, breast cancer is the most frequent cancer of women. Breast cancer is a heterogeneous disease, usually classified into Luminal-A, Luminal-B, Basal-like, Normal-like and human epidermal growth factor receptor 2 (HER2)-enriched subclasses.1 However, at the moment, there is not a strict parallelism between subclasses and therapy, and in clinical practice, patient diagnosis is routinely based on estrogen receptor alpha (ERa) progesterone receptor and HER2 statuses. A simplified molecular classification based on ERa, androgen receptor (AR) and forkhead box protein A1 (FOXA1) expression has been recently proposed.2,3 The first class, ERaþ, corresponds to luminal tumors which present active estrogen signaling. The second class (ERa-, AR-and FOXA1-tumors), called basal, shows much higher proliferative and aggressive behaviors. Tumors of the third class (ERa-, ARþ and/or FOXA1þ), called molecular apocrine, present androgen and estrogen signaling despite ERa-status, and frequently overexpress HER2. 2Tumor protein p53 (TP53) encodes a multifunction transcription factor whose loss promotes tumor formation. 4 It is the most commonly mutated gene in human cancers. Approximately, 30% of breast cancers display TP53 mutation, but this frequency fluctuates from more than 80% in basallike to less than 15% in luminal-A subgroups.5 Mutations result from misrepair of DNA damages. The main mutation types are substitutions and complex mutations. Substitutions correspond to the replacement of a nucleotide pair by a different pair. They result essentially from replication of mismatch...
Mantle cell lymphomas (MCL) are characterized by their aggressive behavior and poor response to chemotherapy regimens. We report here evidence of increased in vitro radiation sensitivity in two cell lines that we have generated from two MCL patients (UPN1 and UPN2). However, despite their increased radiation sensitivity, UPN2 cells were totally resistant to apoptotic cell death, whereas UPN1 cells underwent massive apoptosis 6 h after irradiation. The frequency of induced chromosomal abnormalities was higher in UPN1 as compared to UPN2. Distinct mechanisms have been found to contribute to this phenotype: a major telomere shortening (UPN1 and UPN2), deletion of one ATM allele and a point mutation in the remaining allele in UPN2, mutation of p53 gene (UPN1 and UPN2) with absence of functional p53 as revealed by functional yeast assays. After irradiation, Ku70 levels in UPN1 increased and decreased in UPN2, whereas in the same conditions, DNA-PKcs protein levels decreased in UPN1 and remained unchanged in UPN2. Thus, irradiation-induced apoptotic cell death can occur despite the nonfunctional status of p53 (UPN1), suggesting activation of a unique pathway in MCL cells for the induction of this event. Overall, our study demonstrates that MCL cells show increased radiation sensitivity, which can be the result of distinct molecular events. These findings could clinically be exploited to increase the dismal response rates of MCL patients to the current chemotherapy regimens.
BackgroundWe have previously shown that angiopoietin-like 4 (angptl4) mRNA, a hypoxia-inducible gene, is highly expressed in clear cell renal-cell carcinoma (ccRCC), the most common subtype of RCC for which no specific marker is available. We here investigated whether angptl4 mRNA 1) could be a useful diagnostic and/or prognostic marker of ccRCC in a large and comprehensive retrospective series, 2) induction is dependent on the VHL status of tumors.Methodology/Principal FindingsUsing in situ hybridization, we report that angptl4 mRNA is expressed in 100% of both sporadic (n = 102) and inherited (n = 6) primary ccRCCs, without any statistical association with nuclear grade (p = 0.39), tumor size (p = 0.09), stage grouping (p = 0.17), progression-free survival (p = 0.94), and overall survival (p = 0.80). Angptl4 mRNA was also expressed in 26 (87%) of 30 secondary ccRCCs but neither in any other secondary RCCs (n = 7). In contrast, angptl4 mRNA was neither expressed in 94% non-ccRCC renal tumors (papillary RCCs (n = 46), chromophobe RCCs (n = 28), and oncocytomas (n = 9)), nor in non-renal clear cell carcinomas (n = 39). Angptl4 expression was also examined in tumors associated (n = 23) or not associated (n = 66) with VHL disease. 40 (98%) hemangioblastomas expressed angptl4 whereas all pheochromocytomas (n = 23) and pancreatic tumors (n = 25) were angptl4-negative, whatever their VHL status.Conclusions/SignificanceAngptl4 mRNA expression was highly associated with ccRCC (p = 1.5 10−49, Chi square test) allowing to define its expression as a diagnosis marker for primary ccRCC. Moreover, angptl4 mRNA allows to discriminate the renal origin of metastases of clear-cell carcinomas arising from various organs. Finally, inactivation of VHL gene is neither necessary nor sufficient for angptl4 mRNA induction.
Tumor protein 53 (TP53) is the most commonly altered gene in human cancers. In breast cancers, TP53 is mutated in approximately 30% of all cases, but this frequency fluctuates widely within the different molecular subclasses. Different types of mutations may be observed, such as substitutions (replacement of a nucleotide pair by another one), or complex mutations (deletions or insertions of one or more nucleotides). Mutation types may reflect mechanism of DNA lesion or DNA repair deficiencies. Furthermore, mutations can give rise to different effects such as truncating mutations leading to loss of function, or missense mutations often leading to dominant negative activity. Those mutation effects can be advantageous in tumorigenesis and thus can be subject to selective pressure. Here we classified 572 breast tumors in three groups, according to microarray data: luminal, basal and molecular apocrine. TP53 status was assessed by a yeast-based functional assay (FASAY) and cDNA sequencing. We then assessed whether any feature of TP53 mutations would be preferentially associated to a specific subtype of breast cancer. - In term of TP53 mutation frequencies, as expected, lowest frequency was observed in luminal subgroup (26%) and highest in basal (90%) and molecular apocrine (70%). Notably, much higher rate of TP53 mutations occurred in luminal B subgroup (41%) than in luminal A one (17%), suggesting that TP53 may be an important feature in progression from luminal A to B. - In term of mutations types, luminal tumors showed high frequency of substitutions, while molecular apocrine and basal presented increased rate of deletions and insertions, reflecting probably increased rate of DNA breaks. This suggests that same mutational events may occur in basal and molecular apocrine tumors. - In term of mutation effects, we found high frequency of missense mutations in luminal tumors (notably AT to GC) and much higher rate of truncating mutations in basal tumors. These observations point to an existence of different selection pressure in each of them, such as a strong pressure for P53 mutations with potential dominant negative inhibition of P73/P63 (recently shown to favor invasion), in luminal tumors. Collectively, these results point not only to different mechanisms of P53 gene inactivation, but also different functional consequences among the different breast cancer subclasses. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-02-09.
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