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PubMed2007

Germ-line genetic variation of TP53 in osteosarcoma.

BACKGROUND: Osteosarcoma (OS) has been well described in individuals with germ-line TP53 mutations (Li-Fraumeni Syndrome) but typically occurs sporadically in adolescents and young adults. Single nucleotide polymorphisms (SNPs), the most common germ-line genetic variation, have been associated with risk for other types of cancer. We hypothesized that genetic variation in TP53 could be associated with OS risk based on its critical role in cell growth and effect of somatic mutations in OS tumors. PROCEDURE: Twelve common SNPs in TP53 were genotyped in a case-control study of sporadic OS. These SNPs spanned the TP53 locus and captured common haplotypes. Genotype data were analyzed using contingency tables for additive, dominant, and recessive genetic models. PHASEv2.1 and HaploStats were used to evaluate haplotypes. RESULTS: The recessive model suggested an increased risk of OS when two copies of TP53-34 C>G variant (IVS2+38, rs1642785) were present, P = 0.041, odds ratio (OR) 6.70 (95% confidence interval [CI] 1.06-41.6). The TP53-01 variant C>G (Pro72Arg, rs1042522) may also be associated with increased risk for OS, P = 0.028, OR 7.5 (95% CI 1.20-46.3). Common TP53 haplotypes as well as the remaining 10 SNPs were not associated with risk for OS. CONCLUSIONS: These data do not indicate a strong link between variation in TP53 and OS risk, although they provide preliminary evidence of an increased risk of OS associated with variants at IVS2+38 and Pro72Arg. The findings warrant replication in further studies.

Adolescent↗

PubMed2005

Mutation and methylation analysis of TP53 in adrenal carcinogenesis.

AIM: To investigate the role of coding region mutation and promoter hypermethylation of TP53 in adrenocortical cancer formation. METHODS: Twenty sporadic adrenocortical cancers (ACCs) and five normal adrenal tissue samples were available for analysis. Coding region mutation of TP53 in 20 ACCs was examined by polymerase chain amplification using intronic primers for exons 2-11 and direct sequencing of the product. In 10 ACCs and five normal adrenal tissue specimens, methylation of the 16 CpG sites within the TP53 promoter was examined using bisulphite methylation sequencing. RESULTS: Coding region mutation in TP53 was demonstrated in 5 of 20 ACCs. There were four mis-sense mutations and one frameshift mutation. Four of 5 patients with a TP53 mutation had metastases at diagnosis or detected soon thereafter and 3 of 4 died of disease within 12 months of surgical resection. No methylation was seen in the TP53 promoter in 10 ACC and the five normal adrenal tissues examined. CONCLUSION: Coding region mutation in TP53 occurs in 25% of ACCs with a trend toward a poorer prognosis. Promoter methylation of TP53 is not present in ACC as a mechanism for tumour suppressor gene (TSG) inactivation and, therefore, other genes in the 17p13 region are implicated in adrenal carcinogenesis.

Adrenal Gland Neoplasms↗

PubMed2004

The European flounder (Platichthys flesus) TP53 functions as a temperature-sensitive transcription factor which inhibits cell growth in yeast.

Numerous studies focus on biological roles of the TP53 tumor suppressor gene in mammals but little is known about the actual function of TP53 in lower vertebrates. In this study, we used an in vivo functional assay in yeast to address the transactivation capacity of the flounder TP53 protein. We showed that the flounder TP53 acts as a sequence-specific transcription factor which is able to transactivate various human promoters containing a p53-responsive element (RE). This transcriptional activity was completely abrogated in the Val147Glu TP53 mutant previously identified in two flounder hepatic hyperplasia. In addition, we showed that the wild-type (wt) flounder TP53 but not the Val147Glu mutant inhibits cell growth when expressed in yeast. We finally reported that transcription regulation and growth inhibition by the wild-type flounder TP53 is temperature-dependent. The flounder TP53 optimal temperature appeared lower than those reported for the Xenopus and human homologues.

Animals↗

PubMed2005

The possible role of TP53 mutation status in the treatment of squamous cell carcinomas of the head and neck (HNSCC) with radiotherapy with different overall treatment times.

BACKGROUND AND PURPOSE: TP53-mutations have been shown to influence the radiosensitivity of HNSCC. Furthermore, HNSCC with mutated TP53, may have a higher proliferative potential caused by a lack of control in G1 checkpoint. Our aim of the study was to identify the role of TP53 mutations for the outcome of radiotherapy. PATIENTS AND METHODS: DNA extracted from 180 paraffin-embedded formalin-fixed pretreatment biopsies of HNSCC was screened for mutations in exon 4C-10 by denaturing high-pressure liquid chromatography (DHPLC) followed by sequencing. Treatment was 66-68Gy, 2Gy/fx with overall treatment times of 6.5 and 5.5 weeks according to the DAHANCA-guidelines. Endpoints were local control at T-site, disease-specific and crude survival. RESULTS: 125 of 180 carcinomas (69%) carried in total 176 mutations. 72 carcinomas were WT (40%) and 108 carcinomas (60%) carried mutations giving dysfunctional p53. Overall, mutations in TP53 were not associated with the endpoints. However, when dichotomising according to TP53 status and evaluating the effect of the overall treatment time then tumours with mutant TP53 did benefit from 6 instead of 5fx/wk regarding local control, P=0.005; RR: 0.33 (C.I 95%:0.15-0.75) whereas WT-tumours did not (P=0.9). These observations were also reflected in the disease-specific and crude survival. CONCLUSIONS: If all patients were considered regardless of treatment schedule, then TP53-mutations were not related to local control or survival. However, mutations in TP53 may be associated with HNSCC that benefit of a reduced overall treatment time of radiotherapy.

Adult↗

PubMed1999

Cumulation of TP53 mutations and p16INK4A/p15INK4B homozygous deletions in human papilloma virus type 16 positive scrotal cancer.

Scrotal cancer is the first described occupational cancer. The frequency of occupation-related scrotal cancer is very rare because of better hygiene and protective clothing. Human papilloma viruses (oncogenic types 16 and 18) were reported as the causative agents in the pathogenesis of scrotal cancers. E5, E6, and E7 proteins, expressed by human papilloma virus type 16, affect the cell cycle at the G1 checkpoint. TP53, p16INK4A, and p15INK4B were reported as the transcription factors that regulate the cell cycle on the same pathway. Here, the mutation pattern of TP53, p16INK4A, and p15INK4B genes and the homo/hemizygous deletion patterns of p16INK4A/p15INK4B genes are presented in four scrotal carcinoma cases. The results were correlated with the findings of oncogenic human papilloma viruses (types 16 and 18) in this panel. In two of four case, human papilloma virus type 16 was observed. Homozygous deletion in p16INK4A/p15INK4B genes and a codon 259 missense point mutation (GAC-->TAC; Asp-->Tyr) in the TP53 gene were observed in one human papilloma positive scrotal carcinoma case. The homozygous deletion in p16INK4A/p15INK4B genes was observed in another human papilloma positive scrotal carcinoma case. The cumulation of TP53 mutations and p16INK4A/p15INK4B homozygous deletions in human papilloma virus type 16 positive scrotal carcinoma cases indicate that the alterations of TP53, p16INK4A, and p15INK4B genes have an important role in the progression of scrotal cancers, as well as other factors. The survival rate for the two human papilloma virus type 16 positive patients who had a TP53 mutation or p16INK4A/p15INK4B homozygous deletion or both was lower than that for the human papilloma virus type 16 negative cases who had no TP53, p16INK4A, and p15INK4B mutation. The molecular alteration of TP53, p16INK4A, and p15INK4B genes may be useful as a prognostic marker in scrotal cancer.

Carcinoma, Squamous Cell↗

PubMed2001

TP53 mutation is related to poor prognosis after radiotherapy, but not surgery, in squamous cell carcinoma of the head and neck.

BACKGROUND AND METHODS: TP53 gene-mutation and expression of p53 have been described to influence the radiosensitivity of tumour cells from head and neck carcinomas. The present study was performed to evaluate whether TP53 mutation may influence the clinical outcome of head and neck cancer patients treated with radiotherapy or surgery. MATERIALS AND METHODS: DNA was extracted from formalin-fixed paraffin-embedded tissue sections from primary biopsies taken before radiotherapy. Gene mutations (in exons 5-9) were identified using denaturing gradient gel electrophoresis (DGGE) as the initial scanning procedure and characterized by sequencing. Patients were treated with primary radiotherapy or surgery alone. Treatment was given according to the DAHANCA schedules with 5 or 6 weekly fractions (2 Gy) of radiotherapy (66-68 Gy). Most patients were also treated with the hypoxic radiosensitizer Nimorazole. The results are reported as 5-year actuarial values, and differences estimated by log-rank analysis. RESULTS: The present analysis is based on 114 patients with squamous cell carcinoma of the larynx, pharynx and oral cavity diagnosed between March 1992 and October 1996. Ninety patients received primary radiotherapy alone and 21 were treated with surgery. TP53 mutations were found in 45 patients (39%) and in patients receiving radiotherapy, TP53 mutation was highly associated with poor prognosis. Loco-regional control rates (5-year actuarial values) for TP53 mutation was 29 vs. 54% for TP53 wildtype (P < 0.01). For disease-free survival the corresponding values were 13 and 38% (P < 0.01), respectively. The correlations were not found to be related to specific subtypes of mutations (e.g. missense mutations affecting DNA-contact or Zn-binding regions) but rather to the presence of any mutation at all. In contrast, TP53 mutation did not influence the response to surgery. CONCLUSIONS: A strong relationship was observed between TP53 mutation and poor prognosis (increased risk of loco-regional failure and death) in head and neck cancer patients given primary radiotherapy but not surgery.

Carcinoma, Squamous Cell↗

PubMed1997

Differential binding of nuclear proteins to the TP53 gene promoter in male breast tumour.

It is well established that TP53 regulates the expression of many genes, but the regulation of expression of TP53 itself is poorly understood. Recently, it has been shown that there is a tissue-specific binding of nuclear proteins in the TP53 gene promoter. The aim of this study was to determine the nuclear proteins that bind to the TP53 promoter elements (between -104 and -458) in male breast cancer. The results of our study, using the electrophoretic mobility shift assay (EMSA) and Southwestern analysis, have showed: (1) nuclear proteins or factors other than p53 bind to the TP53 promoter; (2) the levels of at least four nuclear proteins vary between normal and tumour breast tissue; and (3) two newly discovered nuclear proteins bind to the TP53 promoter in tumour tissue but are absent in normal tissue. This differential binding of nuclear proteins to the TP53 gene promoter might play a critical role in TP53 transcription and cancer progression in male breast tumours.

Breast Neoplasms, Male↗

PubMed2002

Oral lichen planus has a high rate of TP53 mutations. A study of oral mucosa in icelanD.

Oral squamous cell carcinoma (OSCC) is a world-wide health problem. In addition to external exposure (smoking and alcohol), certain oral lesions may increase the risk of oral cancer (e.g. leukoplakia, erythroplakia, and oral lichen planus). TP53 has been implicated in OSCC, but there are limited studies of mutations in premalignant oral lesions. In this study, 55 samples from OSCC, 47 from hyperkeratotic (HK) oral mucosa, clinically diagnosed as white patches, 48 samples from oral lichen planus (OLP), and 12 biopsies from normal oral mucosa were studied immunohistochemically for expression of TP53 protein. From all the carcinoma samples and selected non-malignant samples showing moderate or strong TP53 protein expression, malignant cells or TP53-positive nuclei were microdissected and screened for mutations in exons 5-8 by constant denaturation gel electrophoresis. Moderate to strong TP53 protein staining was seen in 56% of OSCC, 32% of OLP but only in 13% of HK. All OLP samples showed a characteristic pattern of positive nuclei confined to the basal layer, whereas TP53 staining was seen in suprabasal nuclei in HK. Mutation rate was 11 out of 52 for OSCC, three out of 20 tested for HK and, remarkably, nine out 27 tested for OLP. There was no correlation between TP53 protein staining and TP53 mutations. No associations were found with anatomical sites or disease progression. The unexpectedly high mutation rate of OLP might explain the premalignant potential of this lesion.

Adult↗

PubMed2003

DNA sequence profile of TP53 gene mutations in childhood B-cell non-Hodgkin's lymphomas: prognostic implications.

OBJECTIVES: The TP53 gene encodes a nuclear protein implicated in the regulation of the cell cycle, DNA repair, and apoptosis. TP53 mutations and other alterations have been described in numerous types of tumors, and some of these have been associated with poor prognosis. The aim of this study was to characterize TP53 mutations in childhood B non-Hodgkin's lymphoma, their correlation with clinical prognostic factors and response to therapy. PATIENTS AND METHODS: Samples from 49 children with B non-Hodgkin's lymphoma were examined for TP53 alterations by single-strand conformation polymorphism analysis (SSCP) of exons 5-9, direct sequencing and by p53 immunohistochemistry. RESULTS: Mutations of TP53 were detected in 11 of 49 (22.5%) patients and more specifically in 20% of Burkitt's lymphoma. The sequence analysis showed missense mutations in 10 cases and an insertion mutation in one case. Mutations of the transition type occurred more frequently than transversions (seven of 11). Analysis of the spectrum of single-nucleotide substitutions showed a 30% frequency of transition mutations in CpG dinucleotide sequences. The overall frequency of p53 immunostaining positivity was 36% (15 of 41). There was a very good agreement between protein expression and the presence of TP53 mutation (P=0.0005). No significant correlation was found regarding age, gender, clinical stage and LDH level and TP53 mutations. Comparison of EFS curves using the log-rank test were also not significant. However, the analysis of the effects of mutations on the core p53 structure identified biological and biochemical mutants with phenotypes probably related to different response to chemotherapy. CONCLUSIONS: Our data suggest that some types of mutants can alter the protein distinctly and may be associated with a more aggressive phenotype. In addition, the impact of TP53 mutations on response to therapy may also be influenced by disruption of other genes.

Adolescent↗

PubMed1993

The TP53 tumour suppressor gene in colorectal carcinomas. II. Relation to DNA ploidy pattern and clinicopathological variables.

Heterozygous loss of the TP53 gene on chromosome arm 17p in colorectal carcinomas was strongly associated with DNA aneuploidy (P < 0.0001). This association was seen only in tumours with loss on both 17p and 17q (P < 0.001), but not for loss on 17p only. DNA near diploid (ND) carcinomas and DNA aneuploid (AN) tumours with DNA index > or = 1.1 and < 1.3 had similar frequencies of TP53 gene loss (49% and 42%, respectively), whereas AN tumours with DNA index > or = 1.3 had a significantly higher frequency of TP53 gene loss (85%) (P < 0.0001 and P < 0.0001, respectively). There was a significant association between loss of the TP53 gene and histological grade (P < 0.01), and there tended to be an association between loss of the TP53 gene and degree of cellular atypia (P < 0.05), with TP53 gene loss being most frequent in moderately differentiated carcinomas, and in carcinomas with severe cellular atypia, respectively. The proportion of tumours with loss of the TP53 gene increased significantly towards the distal part of the large bowel (P < 0.0001). These results indicate that different genetic mechanisms may be involved in the carcinogenesis in colon and rectum carcinomas, and in the two subsets of DNA aneuploid carcinomas. Furthermore, the data may suggest a role for the TP53 gene in the aneuploidisation process, possibly as a 'target' for a whole chromosome loss.

Adenocarcinoma↗

PubMed2004

TP53 mutations in early-stage ovarian carcinoma, relation to long-term survival.

We conducted the present study to evaluate the frequency and prognostic importance on long-term survival of TP53 mutations and TP53 protein accumulation in a cohort of 178 patients with early-stage ovarian carcinomas. TP53 mutations scored as aberrant temporal temperature gradient gel electrophoresis pattern from all exons were observed in 39.9% of the tumours. Full screening of exons 5-8, followed by sequencing, was successful in 135 cases, and 48 mutations altering the protein were detected in 39 cases (28.9%). TP53 mutations were slightly less common in the Federation of Gynecologists and Obstetricians stage IA than in IB/IC (P=0.05). No significant correlations with histological type, grade of differentiation, DNA ploidy status or age at diagnosis were found. TP53 protein accumulation analysed by immunohistochemistry was found in 32.6% of all tumours, and was a poor predictor of TP53 mutations with 56.4% sensitivity, 77.1% specificity, 50% positive predictive value and 81.3% negative predictive value. Neither TP53 mutations nor TP53 protein accumulation influenced the prognosis significantly in this group of patients.

Aged↗

PubMed2005

Modulation of retrovirally driven therapeutic genes by mutant TP53 in anaplastic thyroid carcinoma.

We previously demonstrated that restoration of TP53 activity in anaplastic thyroid carcinoma inhibits cell growth and induces expression of thyroid differentiation markers. Here, we investigated whether TP53 status may condition the expression of therapeutic genes driven by retroviral LTR or tissue-specific enhancer elements. The TP53-defective ARO anaplastic thyroid carcinoma cells were transfected with TP53(Val135), which exhibits wild-type activity at 32 degrees C, and transduced with retroviral vectors, in which therapeutic genes were driven either by wild-type LTR or by a reshuffled LTR containing thyroglobulin (TG) enhancer. Both at 37 and 32 degrees C, expression of transgenes driven by TG enhancer was 10-fold lower than that obtained with wild-type LTR retroviral vector. TP53(Val135) transfer into ARO cells repressed transcription from wild-type LTR but increased expression of TG-driven therapeutic genes. This effect was markedly enhanced by cell culture at 32 degrees C and by TSH treatment. Cytotoxic effects shown after ganciclovir treatment paralleled therapeutic gene expression levels. In conclusion, TP53 status in the tumor cell can influence expression of therapeutic genes. When using retroviral-vector-based gene therapy, wild-type LTR vectors should be employed to target TP53-defective tumors, whereas thyroid-specific promoters should be used for transcriptional targeting of thyroid carcinomas carrying wild-type TP53.

Animals↗

PubMed2003

P21WAF1, P27KIP1, TP53 and C-MYC analysis in 204 ovarian carcinomas treated with platinum-based regimens.

BACKGROUND: The prognostic and predictive value of cell cycle regulatory proteins in ovarian cancer has not been established. We evaluated the clinical and biological significance of P21(WAF1), P27(KIP1), C-MYC, TP53 and Ki67 expressions in ovarian cancer patients. MATERIALS AND METHODS: Immunohistochemical analysis was performed on 204 ovarian carcinomas of International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV treated with platinum-based chemotherapy. Multivariate analysis with Cox and logistic regression models was performed in the whole group, and in the TP53-negative and TP53-positive subgroups. RESULTS: High P21(WAF1) labeling index (LI) was an independent positive predictor of platinum-sensitive response (P = 0.02). Overall survival was positively influenced by P21(WAF1) LI (P = 0.02) or by P21(WAF1) plus P27(KIP1) LI (P = 0.004) in the TP53-negative group only. Ki67 LI showed borderline association with disease-free survival (P = 0.05). Growth fraction was negatively associated with P21(WAF1) and P27(KIP1) indices in the TP53-negative group (P = 0.023 and 0.008, respectively), and these associations were borderline or lost in the TP53-positive group. Endometrioid and clear cell carcinomas differed from other carcinomas by having a low incidence of TP53 accumulation, a high incidence of C-MYC overexpression (70%) and a low median Ki67 LI (all with P <0.001). CONCLUSIONS: We have shown an independent predictive value of P21(WAF1) LI in ovarian carcinoma patients. The prognostic value of P21(WAF1) and P21(WAF1) plus P27(KIP1) LI was determined by TP53 status. A high frequency of C-MYC overexpression in endometrioid and clear cell carcinomas may suggest its role in the development of these tumor types.

Adult↗

PubMed2004

Simultaneous mutations in K-ras and TP53 are indicative of poor prognosis in sporadic colorectal cancer.

Despite the fact that the mutations in K-ras codon 12 and TP53 are common abnormalities in colorectal cancer, the determination of K-ras mutation combined with TP53 gene mutation, with diagnostic and prognostic purposes is still controversial. We have analyzed K-ras and TP53 mutations in 77 sporadic colorectal adenocarcinomas by means of polymerase chain reaction and sequencing. We observed a negative correlation between both K-ras and TP53 mutations. Patients with mutations in K-ras but not in TP53 exhibited worse survival rates than those with mutations in TP53 and not in K-ras. Moreover, we found the worst outcome in patients with mutations in both K-ras and TP53. These results may relate to the previously published data about primary human and rodent cells, in which transformation by Ras require either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. In conclusion, simultaneous mutations in K-ras and TP53 are indicative of a worse prognosis in sporadic colorectal cancer.

Adenocarcinoma↗

PubMed2000

Impact of KRAS and TP53 mutations on survival in patients with left- and right-sided Dukes' C colon cancer.

OBJECTIVE: It has been suggested that KRAS and TP53 mutated tumors might influence the phenotypic behavior of left- and right-sided colon tumors. We investigated the incidence of these mutations in left- and right-sided colon tumors and their possible influence on survival in a homogeneous group of patients with Dukes' C colon cancers. METHODS: The primary tumors of 55 patients with a sporadic Dukes' C colon cancer, all treated with adjuvant chemotherapy were analyzed for the presence of KRAS and TP53 mutations. Mutation detection of the KRAS and TP53 genes was performed on paraffin-embedded tumor material, using denaturating gradient gel electrophoresis. The 5-yr survival rates of KRAS and TP53 mutated tumors were analyzed regarding right-sided tumors (defined as tumors up to the splenic flexure) and left-sided tumors (defined as tumors from the splenic flexure to the rectosigmoid peritoneal reflection). RESULTS: KRAS mutations occurred more frequently in the right colon compared to the left colon (R = 38% (10/26); L = 10% (3/29); chi2 test: p = 0.014). KRAS mutations did not influence survival in patients with right-sided colon tumors. Patients with KRAS mutation-negative tumors in the right colon, however, had a significantly worse survival than patients with left-sided KRAS mutation-negative tumors (5-yr survival; R: 34% vs L: 65%, log-rank test: p = 0.007). TP53 mutations of a possible causative nature were found in 24 tumors (44%). Neither the incidence (R = 42% (11/26); L = 45% (13/29)) nor the survival of TP53 mutated tumors differed significantly between left- and right-sided tumors. Furthermore, survival of patients with TP53 mutation-negative tumors did not differ significantly between left- and right-sided tumors. CONCLUSIONS: There seems to be no difference in survival rate between patients with KRAS mutated and KRAS negative Dukes' C colon tumors; however, KRAS mutations are more frequently found in the right colon compared to the left colon. TP53 mutations do not have predominance for either side of the colon, and there are no differences in survival in patients with left-sided versus right-sided tumors. Patients with KRAS-nonmutated tumors in the right colon did have a worse survival compared to those with such tumors in the left colon. This suggests that other genetic factors may play a role in tumor genesis in this subgroup of patients.

Adenocarcinoma↗

PubMed2006

The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer.

To investigate the clinical value of somatic TP53 mutations in breast cancer, we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing. TP53 mutations were more frequent in tumors of ductal and medullar types, aggressive phenotype (high grade, large size, node positive cases, and low hormone receptor content) and in women <60 years old. TP53 mutations within exons 5 to 8 conferred an elevated risk of breast cancer-specific death of 2.27 (relative risk >10 years; P < 0.0001) compared with patients with no such mutation. The prognostic value of TP53 mutation was independent of tumor size, node status, and hormone receptor content, confirming and reconciling previous findings in smaller series. Moreover, an interaction between TP53 mutation and progesterone receptor (PR) status was revealed, TP53 mutation combined with the absence of progesterone receptor being associated with the worst prognosis. Whereas previous studies have emphasized the fact that missense mutations in the DNA-binding motifs have a worse prognosis than missense mutations outside these motifs, we show that non-missense mutations have prognostic value similar to missense mutations in DNA-binding motifs. Nonetheless, specific missense mutants (codon 179 and R248W) seem to be associated with an even worse prognosis. These results, obtained on the largest series analyzed thus far, show that TP53 mutations identified by gene sequencing have an independent prognostic value in breast cancer and could have potential uses in clinical practice.

Aged↗

PubMed2003

Clinical application of oligonucleotide probe array for full-length gene sequencing of TP53 in colon cancer.

OBJECTIVE: TP53 mutations are the most frequent genetic alterations in colon cancer. We studied whether the recently developed oligonucleotide microarray technique, GeneChip p53 assay, can be applied to sensitive detection of TP53 gene mutations in surgical specimens from colon cancer patients. METHODS: TP53 gene mutations in exons 2-11 in 20 colon cancers and the corresponding histopathologically normal mucosa at the surgical margins were assessed by GeneChip p53 assay, and the results were further evaluated by direct sequencing of the involved exon or by mutant-allele-specific amplification (MASA). The expression of TP53 protein was also evaluated immunohistochemically and the result was compared with the gene alteration. RESULTS: The GeneChip p53 assay detected TP53 mutations in 65% of primary cancers; 61% of the mutations were within the evolutionarily conserved regions, and 46% of the mutations were within the zinc-binding domains (regions of loop 2 and loop 3). Direct sequencing confirmed these mutations. Immunohistochemical examination detected TP53 protein overexpression in 47% of primary cancers, but this protein did not accumulate with all types of TP53 mutations. In addition, the GeneChip assay detected a mutation identical to that in the primary tumor in 2 samples from the surgical margins, and MASA confirmed both mutations, implying the presence of occult cancer cells. CONCLUSION: The GeneChip p53 assay is sufficiently sensitive to detect TP53 mutations in surgical specimens from colon cancers and may be applicable to screening examination in clinical laboratories as a routine procedure.

Adult↗

PubMed2005

TP53 mutations in ovarian carcinomas from sporadic cases and carriers of two distinct BRCA1 founder mutations; relation to age at diagnosis and survival.

BACKGROUND: Ovarian carcinomas from 30 BRCA1 germ-line carriers of two distinct high penetrant founder mutations, 20 carrying the 1675delA and 10 the 1135insA, and 100 sporadic cases were characterized for somatic mutations in the TP53 gene. We analyzed differences in relation to BRCA1 germline status, TP53 status, survival and age at diagnosis, as previous studies have not been conclusive. METHODS: DNA was extracted from paraffin embedded formalin fixed tissues for the familial cases, and from fresh frozen specimen from the sporadic cases. All cases were treated at our hospital according to protocol. Mutation analyses of exon 2-11 were performed using TTGE, followed by sequencing. RESULTS: Survival rates for BRCA1-familial cases with TP53 mutations were not significantly lower than for familial cases without TP53 mutations (p = 0.25, RR = 1.64, 95% CI [0.71-3.78]). Median age at diagnosis for sporadic (59 years) and familial (49 years) cases differed significantly (p < 0.001) with or without TP53 mutations. Age at diagnosis between the two types of familial carriers were not significantly different, with median age of 47 for 1675delA and 52.5 for 1135insA carriers (p = 0.245). For cases > or = 50 years at diagnosis, a trend toward longer survival for sporadic over familial cases was observed (p = 0.08). The opposite trend was observed for cases < 50 years at diagnosis. CONCLUSION: There do not seem to be a protective advantage for familial BRCA1 carriers without TP53 mutations over familial cases with TP53 mutations. However, there seem to be a trend towards initial advantage in survival for familial cases compared to sporadic cases diagnosed before the age of 50 both with and without TP53 mutations. However, this trend diminishes over time and for cases diagnosed > or = 50 years the sporadic cases show a trend towards an advantage in survival over familial cases. Although this data set is small, if confirmed, this may be a link in the evidence that the differences in ovarian cancer survival reported, are not due to the type of BRCA1 mutation, but may be secondary to genetic factors shared. This may have clinical implications for follow-up such as prophylactic surgery within carriers of the two most frequent Norwegian BRCA1 founder mutations.

Adult↗