scholarly journals p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3148-3157 ◽  
Author(s):  
E Wattel ◽  
C Preudhomme ◽  
B Hecquet ◽  
M Vanrumbeke ◽  
B Quesnel ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Low Dose ◽  
Direct Sequencing ◽  
P53 Gene ◽  
Lymphocytic Leukemia ◽  
Intensive Chemotherapy ◽  
P53 Mutations ◽  
Actuarial Survival ◽  
Survival Difference ◽  
Response To Chemotherapy

We analyzed the prognostic value of p53 mutations for response to chemotherapy and survival in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). Mutations were detected by single-stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene, and confirmed by direct sequencing. A p53 mutation was found in 16 of 107 (15%) AML, 20 of 182 (11%) MDS, and 9 of 81 (11%) CLL tested. In AML, three of nine (33%) mutated cases and 66 of 81 (81%) nonmutated cases treated with intensive chemotherapy achieved complete remission (CR) (P = .005) and none of five mutated cases and three of six nonmutated cases treated by low-dose Ara C achieved CR or partial remission (PR) (P = .06). Median actuarial survival was 2.5 months in mutated cases, and 15 months in nonmutated cases (P < 10(-5)). In the MDS patients who received chemotherapy (intensive chemotherapy or low-dose Ara C), 1 of 13 (8%) mutated cases and 23 of 38 (60%) nonmutated cases achieved CR or PR (P = .004), and median actuarial survival was 2.5 and 13.5 months, respectively (P < 10(-5)). In all MDS cases (treated and untreated), the survival difference between mutated cases and nonmutated cases was also highly significant. In CLL, 1 of 8 (12.5%) mutated cases treated by chemotherapy (chlorambucil and/or CHOP and/or fludarabine) responded, as compared with 29 of 36 (80%) nonmutated cases (P = .02). In all CLL cases, survival from p53 analysis was significantly shorter in mutated cases (median 7 months) than in nonmutated cases (median not reached) (P < 10(-5)). In 35 of the 45 mutated cases of AML, MDS, and CLL, cytogenetic analysis or SSCP and sequence findings showed loss of the nonmutated P53 allele. Our findings show that p53 mutations are a strong prognostic indicator of response to chemotherapy and survival in AML, MDS, and CLL. The usual association of p53 mutations to loss of the nonmutated P53 allele, in those disorders, ie, to absence of normal p53 in tumor cells, suggests that p53 mutations could induce drug resistance, at least in part, by interfering with normal apoptotic pathways in tumor cells.

scholarly journals p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3148-3157 ◽  
Author(s):  
E Wattel ◽  
C Preudhomme ◽  
B Hecquet ◽  
M Vanrumbeke ◽  
B Quesnel ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Low Dose ◽  
Direct Sequencing ◽  
P53 Gene ◽  
Lymphocytic Leukemia ◽  
Intensive Chemotherapy ◽  
P53 Mutations ◽  
Actuarial Survival ◽  
Survival Difference ◽  
Response To Chemotherapy

Abstract We analyzed the prognostic value of p53 mutations for response to chemotherapy and survival in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). Mutations were detected by single-stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene, and confirmed by direct sequencing. A p53 mutation was found in 16 of 107 (15%) AML, 20 of 182 (11%) MDS, and 9 of 81 (11%) CLL tested. In AML, three of nine (33%) mutated cases and 66 of 81 (81%) nonmutated cases treated with intensive chemotherapy achieved complete remission (CR) (P = .005) and none of five mutated cases and three of six nonmutated cases treated by low-dose Ara C achieved CR or partial remission (PR) (P = .06). Median actuarial survival was 2.5 months in mutated cases, and 15 months in nonmutated cases (P < 10(-5)). In the MDS patients who received chemotherapy (intensive chemotherapy or low-dose Ara C), 1 of 13 (8%) mutated cases and 23 of 38 (60%) nonmutated cases achieved CR or PR (P = .004), and median actuarial survival was 2.5 and 13.5 months, respectively (P < 10(-5)). In all MDS cases (treated and untreated), the survival difference between mutated cases and nonmutated cases was also highly significant. In CLL, 1 of 8 (12.5%) mutated cases treated by chemotherapy (chlorambucil and/or CHOP and/or fludarabine) responded, as compared with 29 of 36 (80%) nonmutated cases (P = .02). In all CLL cases, survival from p53 analysis was significantly shorter in mutated cases (median 7 months) than in nonmutated cases (median not reached) (P < 10(-5)). In 35 of the 45 mutated cases of AML, MDS, and CLL, cytogenetic analysis or SSCP and sequence findings showed loss of the nonmutated P53 allele. Our findings show that p53 mutations are a strong prognostic indicator of response to chemotherapy and survival in AML, MDS, and CLL. The usual association of p53 mutations to loss of the nonmutated P53 allele, in those disorders, ie, to absence of normal p53 in tumor cells, suggests that p53 mutations could induce drug resistance, at least in part, by interfering with normal apoptotic pathways in tumor cells.

Clinical significance of p53 mutations in newly diagnosed Burkitt's lymphoma and acute lymphoblastic leukemia: a report of 48 cases.

1995 ◽  
Vol 13 (4) ◽  
pp. 812-820 ◽  
Author(s):  
C Preudhomme ◽  
I Dervite ◽  
E Wattel ◽  
M Vanrumbeke ◽  
M Flactif ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Direct Sequencing ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Newly Diagnosed ◽  
P53 Mutations ◽  
Actuarial Survival ◽  
Response To Chemotherapy

PURPOSE To correlate the presence of p53 mutations and initial characteristics, response to chemotherapy, and survival in newly diagnosed Burkitt's lymphoma (BL) and Burkitt's acute lymphoblastic leukemia (L3 ALL). PATIENTS AND METHODS Forty-eight patients with newly diagnosed BL or L3 ALL, most of whom were treated with very intensive regimens, including early CNS disease treatment, were studied. Detection of p53 mutations was made by single-strand conformation polymorphism (SSCP) analysis of exons 5 to 8 of the gene, and mutations were determined by direct sequencing of exons with abnormal SSCP findings. Comparison of outcome between mutated and nonmutated cases was made in all patients and also after excluding five patients who received therapeutic regimens considered as suboptimal and one patient who died of AIDS while in complete remission (CR), as those six patients had no p53 mutations. RESULTS A point mutation was found in nine patients (19%), and consisted of a missense mutation in seven and a chain-terminating mutation in two. SSCP, sequence, and cytogenetic analysis strongly suggested that eight of nine patients with mutations had retained the normal p53 allele, which had been lost in the remaining patient. These findings were confirmed by fluorescence-in-situ hybridization (FISH) with a p53-specific probe in two patients, including the one who had lost the normal p53 allele. Unexpectedly, mutations were significantly less frequent in patients with disseminated disease, ie, L3 ALL or stage IV BL (four of 35, 11%), than in more localized forms, ie, BL stage I, II, or III (five of 13, 38%) (P = .03). CR rates were similar in mutated (78%) and nonmutated cases (78%). The actuarial disease-free interval (DFI) after 12 months and actuarial survival rates after 24 months were 49% and 66%, respectively, in patients with mutations, and 73% and 48%, respectively, those without mutations. The differences were not significant. CONCLUSION Our findings suggest that, contrary to what is seen in most other neoplasias, p53 mutations in newly diagnosed BL and L3 ALL are not associated with extensive tumor mass or poor response to intensive therapeutic regimens. It is hypothesized that this difference with most tumors could be due to the fact that p53 mutations in BL and L3 ALL are generally associated with persistence of a normal residual p53 allele, contrary to what is observed in the majority of tumors.

p53 Alterations Predict Tumor Response to Neoadjuvant Chemotherapy in Head and Neck Squamous Cell Carcinoma: A Prospective Series

2000 ◽  
Vol 18 (7) ◽  
pp. 1465-1473 ◽  
Author(s):  
Arnauld Cabelguenne ◽  
Hélène Blons ◽  
Isabelle de Waziers ◽  
Françoise Carnot ◽  
Anne-Marie Houllier ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Neoadjuvant Chemotherapy ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
P53 Gene ◽  
P53 Mutations ◽  
P53 Antibodies ◽  
Response To Chemotherapy ◽  
P53 Status ◽  
Response To Neoadjuvant Chemotherapy

PURPOSE: The tumor suppressor gene p53 plays a crucial role in cell cycle control and apoptosis in response to DNA damages. p53 gene mutations and allelic losses at 17p are one of the most common genetic alterations in primary head and neck squamous cell carcinoma (HNSCC). Alterations of the p53 gene have been shown to contribute to carcinogenesis and drug resistance. PATIENTS AND METHODS: In this prospective series, patients with HNSCC were treated with cisplatin-fluorouracil neoadjuvant chemotherapy. p53 status was characterized in 106 patients with HNSCC (p53 mutations, allelic losses at p53 locus, and plasma anti-p53 antibodies) to determine the existence of a relationship between p53 gene status and response to neoadjuvant chemotherapy. RESULTS: Exons 4 to 9 of the p53 gene were analyzed, and mutations were found in 72 of 106 patients with HNSCC. p53 mutations were associated with loss of heterozygosity at chromosome 17p (P < .001). The prevalence of p53-mutated tumors was higher in the group of patients with nonresponse to neoadjuvant chemotherapy than in the group of responders (81% v 61%, respectively; P < .04). When compiling p53 mutations and anti-p53 antibodies in plasma, the correlation between p53 status and response to chemotherapy was significant (87% v 57%, respectively; P = .003). A multivariate analysis showed that p53 status is an independent predictive factor of response to chemotherapy. CONCLUSION: This prospective study suggests that p53 status may be a useful indicator of response to neoadjuvant chemotherapy in HNSCC.

A Maintenance Therapy with Differentiating Agents and Low-Dose Chemotherapy Increases Remission Duration and Survival in High Risk AML and MDS Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4614-4614
Author(s):  
Dario Ferrero ◽  
Chiara Dellacasa ◽  
Margherita Bonferroni ◽  
Mariella Grasso ◽  
Elisabetta Campa ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Maintenance Treatment ◽  
Low Dose ◽  
Normal Karyotype ◽  
Intensive Chemotherapy ◽  
Actuarial Survival ◽  
Maintenance Program ◽  
Low Dose Chemotherapy

Abstract Acute myeloid leukemia (AML) patients above the age of 60 or with secondary AML generally have an unfavourable outcome. The same is true for high risk myelodysplastic syndrome (MDS) patients ineligible to bone marrow transplantation. Indeed, in spite of an improved CR rate after intensive chemotherapy (about 60–65%), median CR duration and survival remain short (9–12 months in most studies), due to early relapses. (Sekeres MA et al.: Curr Opin Oncol2002;14:24–30. Verbeek W et al.: Ann Hematol2001;80:499–509). On the basis of our previous clinical trials with differentiative agents + low dose chemotherapy in MDS/AML patients unsuitable to intensive treatments, (Ferrero D et al.: Leuk Res1996;20:867–876; Haematologica2004;89:619–620), we adopted the same strategy as a post-remission maintenance therapy to patients with AML or MDS at high risk of relapse and ineligible to allogeneic transplant. Thirty-six patients (27 AML and 9 high risk MDS) who had obtained a CR after different schemes of intensive chemotherapy were scheduled to receive the maintenance treatment with 13-cis-retinoic acid (20–40 mg/day) + 1,25-di-hydroxy-vitamin D3 (1 microgram /day) in association to intermittent, low dose chemotherapy: 6-thioguanine 40 mg/day x 21 days every 5 weeks, alternated every 2–3 months, in 24 patients, to a 14 day course of ARA-C 8 mg/m2 s.c. x 2/day + 6-mercaptopurine 50 mg/day. Patients’ median age was 64 years (range 27–76), with only 9 below the age of 60. Cytogenetic analysis was performed successfully in 27 cases, and an unfavourable karyotype was found in 10. All patients presented at least one poor prognosis determinant, including age >60 (27), previous AML relapse after autologous BMT (1), therapy-related disease (5), AML secondary to MDS (7), resistance to 1st induction therapy (4), hyperleukocytosis (8), RAEB-2 (8), abnormal karyotype (10). Twenty six had received 1 - 4 courses of consolidation treatment, including autologous stem cell transplantation in 2 MDS patients, before starting the maintenance program. Three patients underwent a very early relapse before maintenance start and 1 patient refused to prosecute the therapy after the first 2 months. The other 32 patients received the treatment as outpatients, with good tolerance and no major toxicity, until relapse, death or 4 years of continuous CR. After a median follow up for alive patients of 23 months (6–76), median disease-free (dfs) and overall survival, based on "intention to treat analysis" are 22 (1–74+) and 23 (5–76+) months, respectively, with a 28% 4 year actuarial survival. Inclusion of ARA-C in the maintenance treatment did not significantly prolong CR duration. The 17 patients with a normal karyotype enjoyed better median dfs (43 months) and overall survival (50,5 months) compared to the 10 patients with abnormal cytogenetics (12,5 and 15,5 months respectively); however, the differences are not significant, probably due to sample exiguity. In conclusion, our patients evidenced quite longer dfs and overall survival than expected from literature data on AML/MDS patients with similar features. However some late relapses (after 3–4 years) occurred. Therefore, our maintenance program seems worthy to be evaluated on larger casistics in randomised trials.

scholarly journals p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression

Blood ◽  
1993 ◽  
Vol 82 (11) ◽  
pp. 3452-3459 ◽  
Author(s):  
S el Rouby ◽  
A Thomas ◽  
D Costin ◽  
CR Rosenberg ◽  
M Potmesil ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Gene Mutations ◽  
P53 Gene ◽  
Lymphocytic Leukemia ◽  
P53 Mutations ◽  
P53 Gene Mutation ◽  
P53 Gene Mutations ◽  
Cell Chronic Lymphocytic Leukemia

We studied 53 patients with B-cell chronic lymphocytic leukemia (B-CLL) and found mutations of the p53 gene in 15%. Patients with p53 gene mutations were found to have an aggressive form of B-CLL disease characterized by advanced Rai stage, rapid lymphocyte doubling time (LDT), and resistance to chemotherapy. While 27 of 29 treated patients (93%) without p53 mutations achieved a partial remission, only one of seven treated patients (14%) with p53 mutations achieved a partial remission (P = .00009). Adjusting for prognostic factors (age, sex, race, and Rai stage), patients with p53 gene mutations had a 13-fold greater risk of death than patients without p53 mutations (P = .013). In addition to examining the clinical relevance of p53 gene mutations in B-CLL, we investigated the possible role of p53 gene regulation in the expression of the multidrug resistance genes MDR1 and MDR3. We quantitated MDR1 and MDR3 mRNA expression by reverse transcription- polymerase chain reaction (RT-PCR). Expression of both the MDR1 and MDR3 genes was independent of p53 gene mutation or prior drug treatment, and did not predict for clinical response. Our findings indicate that p53 gene mutations in B-CLL are associated with a poor clinical outcome and may be a prognostic indicator for drug resistance.

Brief intravenous infusions of oblimersen (Genasense; Bcl-2 antisense) alone and in combination with multiple agents are highly effective in human tumor xenografts

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14061-14061
Author(s):  
B. D. Brown ◽  
G. D. Paine-Murietta ◽  
T. N. Julian ◽  
R. P. Warrell
Keyword(s):  
Low Dose ◽  
Safety Data ◽  
Human Tumor ◽  
Lymphocytic Leukemia ◽  
Antisense Oligodeoxynucleotide ◽  
High Dose ◽  
Human Tumor Xenografts ◽  
Tumor Xenografts ◽  
Intravenous Infusions ◽  
Response To Chemotherapy

14061 Background: Oblimersen (OBL; Genasense®) is a phosphorothioate-modified antisense oligodeoxynucleotide (ODN) that down-regulates Bcl-2 and may enhance the response to chemotherapy in patients with melanoma and chronic lymphocytic leukemia (CLL). Extensive safety data for Genasense and other systemically administered ODNs have been obtained using low-dose continuous intravenous infusions (CIVI). However, this method is inconvenient and unsuitable for drug combinations that employ frequent or discontinuous dosing. We have now established that OBL can be effectively administered by high-dose, short IV infusions. Methods: We tested multiple treatment schedules of OBL, alone and in combination with paclitaxel, paclitaxel albumin nanoparticles, imatinib, sorafenib, sunitinib, and erlotinib against human tumor xenografts (melanoma A375, NSCLC A549 and H460, colon HT29 and SW620) grown in C.B-17/SCID mice. Results: Periodic OBL monotherapy (high dose IV Q2–3d) yielded consistently superior antitumor efficacy when compared with low- dose daily IV injections. These results have been obtained against all tumor models evaluated to date. This increased efficacy was also observed when OBL was combined with any other therapeutic agent. For combination treatments that included taxanes, efficacy was shown to be schedule dependent. Conclusions: These results, and recent clinical observations, suggest that brief high-dose IV infusions of OBL may significantly increase antitumor activity, and may obviate the need for CIVI. Brief high-dose IV infusions are being incorporated into ongoing clinical trials to evaluate the safety and efficacy of OBL in combination with other agents. No significant financial relationships to disclose.

Low-dose radiation therapy and reduced chemotherapy in childhood Hodgkin's disease: the experience of the French Society of Pediatric Oncology.

1992 ◽  
Vol 10 (10) ◽  
pp. 1602-1608 ◽  
Author(s):  
O Oberlin ◽  
G Leverger ◽  
H Pacquement ◽  
M A Raquin ◽  
A Chompret ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Hodgkin's Disease ◽  
Low Dose ◽  
Hodgkin’S Disease ◽  
Disease Free Survival ◽  
National Study ◽  
Actuarial Survival ◽  
Free Survival ◽  
Response To Chemotherapy ◽  
Localized Disease

PURPOSE With the aim of decreasing undesirable side effects of therapy, we investigated the reduction of both chemotherapy and radiation therapy (RT) in children with Hodgkin's disease, and compared Adriamycin (doxorubicin; Farmitalia Carlo Erba, Rueil-Malmaison, France), bleomycin, vinblastine, and dacarbazine (ABVD) alone to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and ABVD in favorable cases and assessed the effectiveness of low-dose RT (20 Gy) after good response to chemotherapy. PATIENTS AND METHODS A French national study began in 1982 that included 238 pediatric patients with Hodgkin's disease. Initial staging was clinical and without laparotomy. In patients with localized disease (IA-IIA), an equivalence trial compared the effectiveness of four cycles of ABVD with two cycles of ABVD that were alternated with two cycles of MOPP. Patients with more advanced disease (IB-IIB-III-IV) received three courses of MOPP that was alternated with three courses of ABVD. All of the patients who achieved a good remission after chemotherapy were administered 20 Gy RT, which was limited to the initially involved areas for localized disease, and encompassed the paraaortic nodes and the spleen as well for more advanced stages. When a good remission was not obtained, 40 Gy RT was administered. RESULTS At the completion of chemotherapy, 227 patients (97%) were considered good responders, whereas 11 did not achieve a good remission. With a median follow-up of 6 years, the 6-year actuarial survival was 92% and the disease-free survival was 86%. The relapse-free survival in favorable stages was 90% in the ABVD arm and was 87% in the MOPP and ABVD arm. In June 1987, inclusion of stage IV patients was discontinued because of poor results. CONCLUSIONS Present findings indicate that (1) in favorable stages, ABVD alone and alternating MOPP and ABVD are equivalent, and (2) chemotherapy followed by 20 Gy RT represents a valid therapeutic approach in the vast majority of children with Hodgkin's disease.

scholarly journals p53 mutations are associated with histologic transformation of follicular lymphoma

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2289-2295 ◽  
Author(s):  
F Lo Coco ◽  
G Gaidano ◽  
DC Louie ◽  
K Offit ◽  
RS Chaganti ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
Low Grade ◽  
Diffuse Type ◽  
P53 Mutations ◽  
Clinical Progression ◽  
Hodgkin's Lymphomas

Abstract The majority of low-grade non-Hodgkin's lymphomas (NHL) undergo clinical progression toward intermediate- and high-grade lymphomas. This progression is often associated with histologic transformation from follicular to diffuse-type NHL. The pathogenetic mechanisms underlying this evolution are presently unknown. In this study, we have analyzed the role in NHL progression of relevant genetic lesions affecting proto-oncogenes and tumor suppressor genes. Sequential biopsies from 21 patients with clinical progression with (5 cases) or without (16 cases) evidence of histologic transformation were analyzed for karyotypic changes, c-myc rearrangements and deletions affecting 6q27 by Southern blot analysis, and p53 mutations by single-strand conformation polymorphism (SSCP) analysis coupled with direct sequencing of polymerase chain reaction-amplified products. No novel cytogenetic aberration was detected in association with progression, and all samples analyzed displayed a normal c-myc gene. Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL and in none of the 16 cases displaying clinical progression in the absence of histologic transformation. In 1 of these positive cases, the same mutation was also present in the pretransformation biopsy, correlating with the presence of diffuse-type areas within a predominant follicular pattern. In 1 of these cases, a deletion of 6q27 was also detected in the posttransformation biopsy along with a p53 mutation. These findings indicate that p53 mutations are associated with and may be responsible for histologic transformation of follicular lymphoma.

scholarly journals p53 mutations are associated with histologic transformation of follicular lymphoma

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2289-2295 ◽  
Author(s):  
F Lo Coco ◽  
G Gaidano ◽  
DC Louie ◽  
K Offit ◽  
RS Chaganti ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
Low Grade ◽  
Diffuse Type ◽  
P53 Mutations ◽  
Clinical Progression ◽  
Hodgkin's Lymphomas

The majority of low-grade non-Hodgkin's lymphomas (NHL) undergo clinical progression toward intermediate- and high-grade lymphomas. This progression is often associated with histologic transformation from follicular to diffuse-type NHL. The pathogenetic mechanisms underlying this evolution are presently unknown. In this study, we have analyzed the role in NHL progression of relevant genetic lesions affecting proto-oncogenes and tumor suppressor genes. Sequential biopsies from 21 patients with clinical progression with (5 cases) or without (16 cases) evidence of histologic transformation were analyzed for karyotypic changes, c-myc rearrangements and deletions affecting 6q27 by Southern blot analysis, and p53 mutations by single-strand conformation polymorphism (SSCP) analysis coupled with direct sequencing of polymerase chain reaction-amplified products. No novel cytogenetic aberration was detected in association with progression, and all samples analyzed displayed a normal c-myc gene. Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL and in none of the 16 cases displaying clinical progression in the absence of histologic transformation. In 1 of these positive cases, the same mutation was also present in the pretransformation biopsy, correlating with the presence of diffuse-type areas within a predominant follicular pattern. In 1 of these cases, a deletion of 6q27 was also detected in the posttransformation biopsy along with a p53 mutation. These findings indicate that p53 mutations are associated with and may be responsible for histologic transformation of follicular lymphoma.

scholarly journals Assessment of sequence-based p53 gene analysis in human breast cancer: messenger RNA in comparison with genomic DNA targets

1998 ◽  
Vol 44 (3) ◽  
pp. 455-462 ◽  
Author(s):  
Cecilia Williams ◽  
Torbjörn Norberg ◽  
Afshin Ahmadian ◽  
Fredrik Pontén ◽  
Jonas Bergh ◽  
...  
Keyword(s):  
Comparative Study ◽  
Messenger Rna ◽  
Genomic Dna ◽  
Direct Sequencing ◽  
P53 Gene ◽  
Missense Mutations ◽  
P53 Mutations ◽  
Gene Encoding ◽  
Therapeutic Consequences ◽  
One Stop

Abstract The high prevalence of p53 mutations in human cancers and the suggestion from several groups that the presence or absence of p53 mutations might have both prognostic and therapeutic consequences point to the importance of optimal methods for p53 determination. Several strategies exploring this have been described, based either on mRNA or genomic DNA as a template. However, no comparative study on the reliability of the two templates has been performed. The principal aim of this study was to study the concordance of RNA- and DNA-based direct sequencing methods in detecting p53 mutations in breast tumors. In 100 tumors, 22 mutations were detected by both methods. Furthermore, one stop mutation, two splice-site mutations, and one intron alteration were found only by genomic sequencing. In addition, the comparative study suggests that cells with missense mutations have increased steady-state concentrations of p53-specific mRNA, in contrast to cells with a gene encoding a truncated protein.

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