Original Article
Germline Mutations of the p53 Tumor-Suppressor Gene in Children and Young Adults with Second Malignant Neoplasms
N Engl J Med 1992; 326:1309-1315May 14, 1992
- Abstract
Background.
Acquired mutations in the p53 tumor-suppressor gene have been detected in several human cancers, including colon, breast, and lung cancer. Inherited mutations (transmitted through the germline) of this gene can underlie the Li—Fraumeni syndrome, a rare familial association of breast cancer in young women, childhood sarcomas, and other malignant neoplasms. We investigated the possibility that p53 mutations in the germline are associated with second primary cancers that arise in children and young adults who would not be considered as belonging to Li—Fraumeni families.
Methods.
Genomic DNA was extracted from the blood leukocytes of 59 children and young adults with a second primary cancer. The polymerase chain reaction, in combination with denaturant-gel electrophoresis and sequencing, was used to identify p53 gene mutations.
Results.
Mutations of p53 that changed the predicted amino acid sequence were identified in leukocyte DNA from 4 of the 59 patients (6.8 percent). In three cases, the mutations were identical to ones previously found in the p53 gene. The fourth mutation was the first germline mutation to be identified in exon 9, at codon 325. Analysis of leukocyte DNA from close relatives of three of the patients indicated that the mutations were inherited, but cancer had developed in only one parent at the start of the study.
Conclusions.
These findings identify an important subgroup of young patients with cancer who carry germline mutations in the p53 tumor-suppressor gene but whose family histories are not indicative of the Li—Fraumeni syndrome. The early detection of such mutations would be useful not only in treating these patients, but also in identifying family members who may be at high risk for the development of tumors. (N Engl J Med 1992;326: 1309–15.)
Article Activity
- Article
THE p53 tumor-suppressor gene, located on the short arm of human chromosome 17,1 , 2 encodes a 53-kd nuclear phosphoprotein involved in the control of cellular proliferation.3 4 5 6 7 Acquired mutations in p53 are the most common tumor-specific genetic changes observed to date, having been identified in most major cancer types.8 , 9 In addition, germline mutations in p53 were recently identified in families with the Li—Fraumeni syndrome, a rare familial cancer syndrome characterized by an unusually high incidence of sarcomas, premenopausal breast cancers, and other diverse neoplasms, particularly brain tumors, leukemias, and adrenocortical carcinomas.10 11 12 13 14 15 Families with Li—Fraumeni syndrome have been described as including a proband with a sarcoma diagnosed early in life and two close relatives with cancers that develop before the age of 45.13 , 14
The overall frequency of germline p53 mutations is unknown, and the age- and site-specific penetrance of these mutations has not been adequately defined. Statistical analysis suggests that 5 to 10 percent of children with soft-tissue sarcomas belong to families with Li—Fraumeni syndrome, in which the distribution of cancer is best explained on the basis of a rare autosomal dominant trait. In carriers of this trait the probability that invasive cancer will develop by the age of 30 is estimated to be 50 percent, as compared with 1 percent in the general population.16 , 17
A review of the cancer phenotypes in families with Li—Fraumeni syndrome reveals a high frequency of second primary tumors in patients who survive their first cancer.10 , 11 , 17 18 19 20 21 Patients with retinoblastoma, which results from the inactivation of another tumor-suppressor gene, also have a high risk of second cancers. Retinoblastoma can occur in either a sporadic fashion, in which mutations occur in both copies of the gene within a single retinal cell, or a hereditary form, in which every cell in the body carries the mutation in one of the two copies of the gene. The only patients with retinoblastoma who are at increased risk for the development of second tumors are those with the hereditary form of the disease. Therefore, the most important risk factor in the development of second malignant neoplasms in patients with retinoblastoma is the presence of a germline mutation in the retinoblastoma tumor-suppressor gene.
The rarity of the Li—Fraumeni syndrome, in contrast with the high frequency of p53 mutations in sporadic (nonfamilial) cancers, suggests that alterations of this gene may be present in the germlines of families without histories of excess cancers. If so, the early identification of persons carrying such mutations would contribute to our understanding of carcinogenesis and to genetic counseling and therapy for young patients with cancer.
To begin the search for germline p53 mutations in such patients outside kindreds known to have Li—Fraumeni syndrome, we evaluated blood-leukocyte DNA from children or young adults who had a second malignant tumor.
Methods
This study included 59 patients, 28 from the M.D. Anderson Cancer Center of the University of Texas, 18 from St. Jude Children's Research Hospital, 7 from the Dana–Farber Cancer Institute, 2 from the Hospital for Sick Children (Toronto), 2 from Massachusetts General Hospital, and 1 each from St. Louis Children's Hospital (St. Louis) and the Universitäts Krankenhaus-Eppendorf (Hamburg, Germany). Each patient had two primary malignant neoplasms; patients were excluded if they had retinoblastoma or a family history of the Li—Fraumeni syndrome. In 27 patients, the second tumor arose within the radiation-therapy field of the first tumor, whereas in the remaining 32 patients, either the second neoplasm developed outside the radiation field or the patient had not received previous radiation therapy. A wide variety of chemotherapeutic drugs and protocols was used to treat the different primary neoplasms.
After written informed consent was obtained according to the protocols of the participating institutions, 10 ml of blood was drawn from each patient into tubes containing EDTA. All the samples, except those obtained at St. Jude Hospital, were shipped either on dry ice or at 4°C to the Molecular Genetics Laboratory at the Massachusetts General Hospital Cancer Center for subsequent analysis. The 18 samples collected at St. Jude Hospital were analyzed at that institution.
DNA was extracted by standard methods from a 0.5-ml sample of whole blood from each subject. The DNA pellet was resuspended in TRIS—EDTA (10 mM TRIS–hydrochloric acid and 1 mM EDTA; pH 7.5) to a final concentration of 100 to 500 ng per microliter. All 59 samples were amplified by the polymerase chain reaction, and mutations were analyzed by nucleotide sequencing. Twenty-eight of the samples were analyzed by both constant denaturant-gel electrophoresis (CDGE) and sequencing, and the other 31 samples were studied by sequencing only, without electrophoresis. CDGE analysis has been shown to have a sensitivity of more than 90 percent in identifying p53 mutations.22 , 23 To obtain sufficient DNA for this analysis, which relies on the strand dissociation of DNA fragments in discrete sequence-dependent melting domains, we amplified template DNA (100 to 300 ng in a 100-μl reaction) in a Perkin—Elmer Thermocycler (Cetus) for 35 cycles, using a protocol described elsewhere.22 Four sets of primers were generated on the basis of the theoretical melting profiles of the amplified fragments.23 These sequences spanned the four conserved regions of the p53 gene, which contain more than 80 percent of the mutations previously identified in sporadic tumors.22 Wild-type and mutant fragments were distinguished from each other in the CDGE analysis with use of acrylamide gels stained with ethidium bromide.22 , 24
DNAs from the blood samples were amplified with two primers that generated a 1.9-kb fragment containing exons 5 through 9 of the p53 gene. The fragments were subcloned into pBSK vector (Stratagene) and sequenced by the Sanger dideoxynucleotide method with a Sequenase 2.0 kit (U.S. Biochemical). For the samples studied at St. Jude Hospital, sequence analysis was performed on pools of at least 100 clones.25 For all the other samples, multiple clones were sequenced individually, according to a protocol described elsewhere.10 Multiple primers were used to sequence the relevant exonic region on both strands. The material obtained from duplicate polymerase chain reactions was cloned and sequenced independently to eliminate the possibility of interpreting misincorporations of bases caused by the polymerase chain reaction as actual point mutations.
Results
Each of the 59 patients in this study had been treated for a primary malignant neoplasm and had subsequently had a second malignant tumor. The patients ranged in age from 0.5 to 37 years (mean, 12.1; median, 14) at the time of the initial diagnosis, and they were from 4 to 54 years old (mean, 22.9; median, 23) when the second tumor was found. None had a family history indicative of the Li—Fraumeni syndrome. Table 1Table 1
Type and Frequency of Tumors, Especially Those Associated with Li—Fraumeni Syndrome, in 59 Patients. shows the various combinations of first and second tumors found in this cohort. In 25 of the 59 patients, both cancers were of types associated with the Li—Fraumeni syndrome; in another 25, either the first or the second tumor was associated with the syndrome; and in 9, neither tumor was of a type statistically associated with Li—Fraumeni kindreds.Four of the 59 patients (6.8 percent) were found to have mutations of the p53 gene that changed the predicted sequence of amino acids. Because these mutations were found in leukocyte DNA, they were assumed to be present in the germline. One mutation occurred in codon 248 of exon 7 (arginine to tryptophan), one each in codons 273 and 282 of exon 8 (arginine to histidine and arginine to tryptophan, respectively), and the fourth in codon 325 of exon 9 (glycine to valine) (Fig. 1Figure 1
Mutations of the p53 Gene Found in Four Families.). The patients' ages, the histologic features of the tumors, and the specific mutational changes, as well as the times to the development of the second cancer, differed widely (Table 2Table 2
Characteristics of Patients with Germline p53 Gene Mutations.). This heterogeneity was consistent with the random acquisition of secondary alterations that ultimately lead to the full expression of cancer.26 Genomic DNA from the blood leukocytes of family members was also screened to ascertain whether the germline p53 mutations detected in the clinical samples had arisen spontaneously or were inherited. The pedigrees shown in Figure 2Figure 2
Abridged Pedigrees of Four Families with Germline p53 Mutations in Which the Probands Had Second Malignant Neoplasms. Panels at left show the findings at the time of diagnosis of the first cancer in the probands (arrows); those at right, findings for the same families at the conclusion of the study. The malignant phenotypes are indicated, followed by the patients' ages at the time of diagnosis of the tumors. Solid symbols denote subjects with two cancers, hatched symbols subjects with a single cancer, diagonal lines dead subjects, and wt wild-type p53 allele. The subjects' ages, cancers, and the codons at which the p53 mutation appears are shown. The numbers inside the symbols are the numbers of unaffected subjects. ChC denotes ovarian choriocarcinoma, LS liposarcoma, OS osteosarcoma, NB neuroblastoma, BC breast carcinoma, BT brain tumor, STS soft-tissue sarcoma, GaC gastric carcinoma, NHL non-Hodgkin's lymphoma, CoC colon carcinoma, and UC ureteral carcinoma. In Family 49, Patient I-5 had a hysterectomy at the age of 32 and had breast and ovarian cystic disease at the conclusion of the study, whereas Patient II-1 has had multiple abnormal cervical Pap smears; neither patient has had signs of malignant disease. represent the patients' families both at the time of diagnosis of the primary tumor in the proband and at the conclusion of the study.Patient 6 was given a diagnosis of retromediastinal neuroblastoma in 1957 at the age of one year; she was treated with radiation therapy. At the time of the diagnosis, there was no history of cancer in her family. Breast carcinoma developed when she was 32, and we identified a germline p53 mutation in codon 248. The patient's mother subsequently had breast cancer at the age of 57. Blood leukocyte DNA from the patient's parents and sister was screened by CDGE analysis for the presence of a p53 mutation (Fig. 3Figure 3
Analysis of the p53 Gene in Family 6, by Constant Denaturant-Gel Electrophoresis.). Both the proband and her mother were found to have bands with similar patterns of aberrant migration and the formation of heteroduplexes (hybrid DNA) after gel electrophoresis of fragments of exon 7 generated by polymerase chain reaction, indicating that they carried identical mutations in that region of the gene. The father and unaffected sister were found to have patterns identical to that of the wild-type sample used as a control.A liposarcoma was diagnosed in Patient 15 at the age of seven. Her mother had choriocarcinoma of the ovary at the age of 18. Although ovarian germ-cell tumors have been associated with Li—Fraumeni syndrome,27 this family contained no other members with cancer. Five years after the diagnosis of the proband's primary tumor, she had a chondroblastic osteosarcoma of the left clavicle, which appeared within the radiation field of the first tumor. Analysis of her leukocyte DNA revealed a germline p53 mutation at codon 282. Her mother was subsequently shown to have an identical mutation.
A spindle-cell sarcoma of the forehead developed in Patient 38 at the age of 22, and eight years later a gastric adenocarcinoma appeared. Other than his maternal grandmother, who had died of a brain tumor, the patient had no close relatives with cancer. We identified a germline p53 mutation of codon 273. While we were completing our analysis and obtaining samples of leukocyte DNA from family members, the patient's 11-year-old son was found to have a pleomorphic rhabdomyosarcoma of the thigh. He was later found to carry the same mutation as his father.
Patient 49 was given a diagnosis of non-Hodgkin's lymphoma in 1973, at which time cancer had been diagnosed in several distant relatives but not in any first-degree relatives. The patient subsequently had colon cancer, as did one maternal uncle. The patient's parents, who are second cousins, did not have cancer. This patient had a germline p53 mutation at codon 325 of exon 9, a codon that is conserved in mammals but not in lower vertebrates. Mutations at this codon have not been reported in patients with sporadic tumors. Family studies have shown that the proband's mother and one of his sisters have the same mutation. Although neither has had cancer, they have each had cystic changes in the breast or ovary, and the patient's sister has recently had evidence of cervical dysplasia. The patient has a number of café au lait spots suggestive of neurofibromatosis.
Thus, five carriers of p53 mutations were identified in the probands' families, and cancer has not yet developed in two of them. According to the pedigree analysis, there are at least 16 other potential carriers, only 1 of whom has had cancer to date. Unfortunately, blood samples from these family members were not available for study.
Discussion
The hypothesis that constitutional genetic defects underlie the development of tumors in many organ systems is based in part on the increased frequency of second malignant neoplasms in survivors of childhood cancer.18 , 21 We have described the detection of germline mutations of the p53 tumor-suppressor gene in leukocyte DNA from 59 patients who had second cancers but did not have family histories consistent with the Li—Fraumeni syndrome. Four of these patients had germline p53 mutations that most likely contributed to the genesis of both cancers. One change, a missense mutation (causing the substitution of a single amino acid) involving codon 248 in exon 7, was identical to mutations previously implicated in the Li—Fraumeni syndrome.10 Two others were mutations in codons 273 and 282 in a highly conserved region of exon 8, where p53 mutations occur frequently in sporadic tumors but have not been previously reported in the germline. The fourth change, in Family 49, involved a germline p53 mutation in exon 9, affecting an amino acid residue that is conserved among mammals but not lower vertebrates.28 Until the biologic function of this mutation is determined, we must be cautious in interpreting its meaning. This mutation represents the unusual situation of a germline p53 mutation that is associated with both colon cancer and non-Hodgkin's lymphoma, although somatic p53 mutations have frequently been identified in such tumors.25 , 29 , 30
Attempts to explain the higher risk of second cancers in survivors of childhood cancer have been hindered by uncertainty over the various contributions of the primary tumor, associated immunodeficiencies, underlying genetic factors, and treatment. The importance of germline mutations in tumor-suppressor genes was first indicated by studies of the retinoblastoma gene.31 It is important to note that the only patients with retinoblastoma who have an increased risk of a second tumor, frequently osteosarcoma, are those with the hereditary form of the disease.32 33 34 35 The mutated p53 alleles we identified also encode altered proteins that in all likelihood predispose carriers to the development of one or more cancers at an early age. The mechanism by which these abnormal proteins lead to the induction of cancer is not clear. Evidence suggests that mutant p53 protein fails to perform its normal function as a negative regulator of the cell cycle, setting the stage for cellular transformation due to the accumulation of other genetic and cellular alterations.36
Germline p53 mutations were not identified in 55 of the 59 patients in our study, suggesting that other mechanisms contributed to their second cancers. One possibility is that some of these patients had germline p53 mutations located outside exons 5 to 9, the region screened in this study. A more likely explanation for the large number of negative cases is that second cancers reflect a complex interaction between the underlying treatment and the inactivation of numerous tumor-suppressor genes, along with other genetic factors, including DNA-repair genes and immunodeficiencies. As these additional genes are identified, it will be important to evaluate their roles in contributing to second cancers.
Our results demonstrate that patients with germline p53 mutations cannot be identified solely by reviewing the family's history of cancer. As shown by the pedigrees of Patients 6 and 49, and possibly that of Patient 38, a p53 mutation may be inherited from a parent who has no clinical evidence of cancer at the time the disease is diagnosed in the child. The time of onset of a malignant tumor in a person who has a mutation of one p53 allele is thought to depend on the stochastic acquisition of one or more additional genetic abnormalities within the cell that give rise to the malignant clone. Thus, cancer may develop in a child before a tumor arises in the child's affected parent or in other affected first-degree relatives. This scenario is exemplified by the fact that malignant tumors were recently diagnosed in relatives of three of the patients with germline p53 mutations in our study (Patients 6, 38, and 49), none of whom were known to have a family history of cancer when they were enrolled in the study.
In some genetic disorders, such as Huntington's disease, germline mutations are largely inherited. By contrast, germinal mutations of the retinoblastoma gene occur spontaneously in over 80 percent of cases. This study afforded the opportunity for an indirect assessment of the frequency of spontaneous mutations of the p53 gene. Our results suggest that germinal p53 mutations identified in children with no family history of cancer are most often inherited, in that all three sets of parents whom we could evaluate carried the mutations.
The high relative risk of invasive tumors in persons with germline p53 mutations suggests that there is an extremely low carrier rate in the general population.16 , 17 The inability of one group of investigators to detect germline p53 mutations in more than 100 unaffected control patients supports this hypothesis.37 Furthermore, no germline mutations were found in the leukocyte DNA of several hundred adults with cancer10 (and unpublished data). Thus, research efforts to determine the frequency of such mutations should focus on young patients with malignant tumors.
The detection of germline p53 mutations in young patients at the time of a cancer diagnosis may permit treatment protocols to be modified in order to reduce the risk of a second cancer. The recognition that a patient has a mutant p53 gene could also influence reproductive decisions and focus efforts on clinical programs for the early diagnosis of second tumors. Knowing that asymptomatic relatives carry the mutation could lead to the early detection and prevention of primary tumors in them. Because the frequency and implications of germline p53 mutations are unknown at present, it is essential to begin multicenter research surveys to define their frequency in young patients with malignant tumors of the types shown in Table 1. As new index cases are discovered, relatives who carry the defective gene but have not yet had cancer will be identified in increasing numbers. The availability of this privileged genetic information will raise legal, social, and ethical questions that will need to be addressed in view of the potential benefits of screening.
Supported in part by a grant (RD3Y0) from the American Cancer Society, grants (CA-20180, CA-23099, and CA-21765) from the Public Health Service, a grant from the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital, grants (CA-34936 and CA-38929) from the National Cancer Institute, Department of Health and Human Services, and a grant from SunLife of Canada. Dr. Malkin is the recipient of a Medical Research Council of Canada Fellowship. Dr. Friend is a Lucille P. Markey Trust Scholar and was supported by the John Merck Fund.
We are indebted to Jayne Kassel, Karen Jahiel, Jennifer Zallen, Juan Sebastian Saldivar, Phyllis Begin, Joann Cook, Darlene Mc-Naughton, Margaret Sharp, and Anne Sinclair for their excellent laboratory assistance; to John Gilbert and Drs. Elizabeth Yang and Thierry Frebourg for editorial assistance and critical comments; and to Drs. Mark Greenberg, Hartmut Kabisch, Charles Pratt, Joann L. Ater, Richard S. Benjamin, Sue Cohn, Francisco H. Dexeus, Norman Jaffe, Christopher J. Logothesis, Nicholas E. Papadopoulos, Carl Plager, Hubert L. Reid, Margaret Sullivan, Jan van Eys, Lolie Chua Yu, Edwin Douglass, Warren W. Nichols, Beppino C. Giovanella, Marc F. Hansen, Jack vanHoff, and Elizabeth Yang for referring patients and providing laboratory assistance.
Source Information
From the Division of Molecular Genetics, Massachusetts General Hospital Cancer Center (D.M., N.B., S.H.F.), the Department of Epidemiology, Dana–Farber Cancer Institute (F.P.L., J.G.), the Departments of Orthopedic Surgery, Massachusetts General Hospital and Children's Hospital (M.C.G.), and the Division of Hematology and Oncology, Children's Hospital, and the Department of Pediatrics, Harvard Medical School (S.H.F.), all in Boston; the Department of Hematology and Oncology, St. Jude Children's Research Hospital, and the Department of Pediatrics, University of Tennessee College of Medicine, Memphis (K.W.J., A.T.L.); the Department of Experimental Pediatrics and Genetics, University of Texas, M.D. Anderson Cancer Center, Houston (L.C.S.); and the Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway (T.I.A., A.-L.B.). Address reprint requests to Dr. Friend at the Massachusetts General Hospital Cancer Center, Bldg. 149, 13th St., Charlestown, MA 02129.
- References
References
1
McBride
CrossRef | Web of Science | Medline2
Isobe
CrossRef | Web of Science | Medline3
Harlow
Web of Science | Medline4
Diller
Web of Science | Medline5
Baker
CrossRef | Web of Science | Medline6
Finlay
CrossRef | Web of Science | Medline7
Lamb
Web of Science | Medline8
Nigro
CrossRef | Web of Science | Medline9
Hollstein
CrossRef | Web of Science | Medline10
Malkin
CrossRef | Web of Science | Medline11
Srivastava
CrossRef | Web of Science | Medline12
Li
CrossRef | Web of Science | Medline13
Li
Web of Science | Medline14
Li
Web of Science | Medline15
Li
Web of Science | Medline16
Young JL Jr, Perry CL, Asire AJ, eds. Surveillance, epidemiology, and end results: incidence and mortality data, 1973–1977. National Cancer Institute monograph 57. Washington, D.C.: Government Printing Office, 1977:70–3.
17
Williams WR, Strong LC. Genetic epidemiology of soft tissue sarcomas in children. In: Müller H, Weber W, eds. Familial cancer. Basel, Switzerland: S. Karger, 1985:151–3.
18
Strong
Web of Science | Medline19
Burke
CrossRef | Web of Science | Medline20
de Vathaire
CrossRef | Web of Science | Medline21
Meadows
Web of Science | Medline22
Børresen
CrossRef | Web of Science | Medline23
Fischer
CrossRef | Web of Science | Medline24
Hovig
CrossRef | Web of Science | MedlineErratum, Mutat Res 1991;263:61.
CrossRef | Web of Science | Medline25
Nishisho
CrossRef | Web of Science | Medline26
Knudson
CrossRef | Web of Science | Medline27
Hartley
CrossRef | Web of Science | Medline28
Soussi
Web of Science | Medline29
Baker
CrossRef | Web of Science | Medline30
Farrell
Web of Science | Medline31
Friend
CrossRef | Web of Science | Medline32
Cavenee
CrossRef | Web of Science | Medline33
Yandell
Full Text | Web of Science | Medline34
Draper
CrossRef | Web of Science | Medline35
Wiggs
Full Text | Web of Science | Medline36
Levine
CrossRef | Web of Science | Medline37
Toguchida
Web of Science
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CrossRef2
Jing Dong, Binhui Ren, Zhibin Hu, Jiaping Chen, Lingmin Hu, Juncheng Dai, Guangfu Jin, Lin Xu, Hongbing Shen. (2011) MDM2 SNP309 contributes to non-small cell lung cancer survival in Chinese. Molecular Carcinogenesis 50:6, 433-438
CrossRef3
John A. DʼOrazio. (2010) Inherited Cancer Syndromes in Children and Young Adults. Journal of Pediatric Hematology/Oncology 32:3, 195-228
CrossRef4
A. P. Kyritsis, M. L. Bondy, J. S. Rao, C. Sioka. (2010) Inherited predisposition to glioma. Neuro-Oncology 12:1, 104-113
CrossRef5
Yasmin Jayasinghe, Patricia S. Simmons. (2009) Occurrence of Two Rare Malignant Neoplasms (Breast and Ovarian) in an Adolescent Female. Journal of Pediatric and Adolescent Gynecology 22:5, e99-e103
CrossRef6
Isabel Soto-Cruz, Martha Legorreta-Herrera. (2009) Analysis of a p53 mutation associated with cancer susceptibility for biochemistry and genetic laboratory courses. Biochemistry and Molecular Biology Education 37:4, 236-242
CrossRef7
LAWRENCE M. WEISS. 2009. Soft Tissues. , 1717-1783.
CrossRef8
E C Pietsch, S M Sykes, S B McMahon, M E Murphy. (2008) The p53 family and programmed cell death. Oncogene 27:50, 6507-6521
CrossRef9
Hany Ariffin, Ghyslaine Martel-Planche, Siti Sarah Daud, Kamariah Ibrahim, Pierre Hainaut. (2008) Li–Fraumeni syndrome in a Malaysian kindred. Cancer Genetics and Cytogenetics 186:1, 49-53
CrossRef10
Chalotte W. Stecher, Kirsten Grønbæk, Henrik Hasle. (2008) A novel splice mutation in theTP53 gene associated with Leydig cell tumor and primitive neuroectodermal tumor. Pediatric Blood & Cancer 50:3, 701-703
CrossRef11
A. Salmon, D. Amikam, N. Sodha, S. Davidson, L. Basel-Vanagaite, R.A. Eeles, D. Abeliovich, T. Peretz. (2007) Rapid Development of Post-radiotherapy Sarcoma and Breast Cancer in a Patient with a Novel Germline ‘De-Novo’ TP53 Mutation. Clinical Oncology 19:7, 490-493
CrossRef12
Sergey Postovsky, Eugene Vlodavsky, Ayelet Eran, Joseph Guilburd, Myriam Weyl Ben Arush. (2007) Secondary Glioblastoma Multiforme After Treatment for Primary Choroid Plexus Carcinoma in Childhood. Journal of Pediatric Hematology/Oncology 29:4, 248-252
CrossRef13
Richard C. Chao, Urszula Pyzel, Jane Fridlyand, Yien-Ming Kuo, Lewis Teel, Jennifer Haaga, Alexander Borowsky, Andrew Horvai, Scott C. Kogan, Jeannette Bonifas, Bing Huey, Tyler E. Jacks, Donna G. Albertson, Kevin M. Shannon. (2005) Therapy-induced malignant neoplasms in Nf1 mutant mice. Cancer Cell 8:4, 337-348
CrossRef14
Catherine M. Khayat, Donna L. Johnston. (2004) Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. Pediatric Blood & Cancer 43:6, 683-686
CrossRef15
Sharon A. Savage, Stephen J. Chanock. (2004) Using germ-line genetic variation to investigate and treat cancer. Drug Discovery Today 9:14, 610-618
CrossRef16
Robert E Steward, Malcolm W MacArthur, Roman A Laskowski, Janet M Thornton. (2003) Molecular basis of inherited diseases: a structural perspective. Trends in Genetics 19:9, 505-513
CrossRef17
Anna T. Meadows. (2003) Pediatric cancer survivors: past history and future challenges. Current Problems in Cancer 27:3, 112-126
CrossRef18
Daniel M. Green. (2003) Late effects of treatment for cancer during childhood and adolescence. Current Problems in Cancer 27:3, 127-142
CrossRef19
Shih-Jen Hwang, Guillermina Lozano, Christopher I. Amos, Louise C. Strong. (2003) Germline p53 Mutations in a Cohort with Childhood Sarcoma: Sex Differences in Cancer Risk. The American Journal of Human Genetics 72:4, 975-983
CrossRef20
Nilgun Yari
, Tezer Kutluk, Haluk Topaloğlu, Zuhal Akçören, Münevver Büyükpamukçu. (2002) Disseminated Alveolar Rhabdomyosarcoma in a Child With Spinal Muscular Atrophy. Journal of Pediatric Hematology/Oncology 24:6, 508-509
CrossRef21
Anna Patrikidou, Jon Bennett, Patrick Abou-Sleiman, Joy D.A. Delhanty, Malcolm Harris. (2002) A novel, de novo germline TP53 mutation in a rare presentation of the Li-Fraumeni syndrome in the maxilla. Oral Oncology 38:4, 383-390
CrossRef22
Agnès Chompret. (2002) The Li–Fraumeni syndrome. Biochimie 84:1, 75-82
CrossRef23
Toshinari Minamoto, Ze'ev Ronai. (2001) Gene mutation as a target for early detection in cancer diagnosis. Critical Reviews in Oncology/Hematology 40:3, 195-213
CrossRef24
Chu-Xia Deng, Steven G Brodie. (2001) Knockout mouse models and mammary tumorigenesis. Seminars in Cancer Biology 11:5, 387-394
CrossRef25
Ruth Warren. (2001) Screening women at high risk of breast cancer on the basis of evidence. European Journal of Radiology 39:1, 50-59
CrossRef26
Kari Hemminki, Xinjun Li. (2001) A population-based study of familial soft tissue tumors. Journal of Clinical Epidemiology 54:4, 411-416
CrossRef27
Ofer Merimsky, Yehuda Kollender, Josephine Issakov, Jacob Bickels, Gideon Flusser, Mordechai Gutman, Dina Lev-Chelouche, Moshe Inbar, Isaac Meller. (2001) Multiple primary malignancies in association with soft tissue sarcomas. Cancer 91:7, 1363-1371
CrossRef28
M. Reincke, F. Beuschlein, M. Slawik, K. Borm. (2000) Molecular adrenocortical tumourigenesis. European Journal of Clinical Investigation 30:S3, 63-68
CrossRef29
Cabot, Richard C.Scully, Robert E., Mark, Eugene J., McNeely, William F., Ebeling, Sally H.Ellender, Stacey M.Peters, Christine C., Larsen, Ericde Leval, Laurence. (2000) Case 33-2000. New England Journal of Medicine 343:17, 1249-1257
Full Text30
Amanda L. Kim, Conrad V. Fernandez, Wenda L. Greer, David Hogg, Norman J. Lassam, Lothar Resch. (2000) Concurrent Acute Lymphoblastic Leukemia and Juvenile Pilocytic Astrocytoma in a Pediatric Patient. Journal of Pediatric Hematology/Oncology 22:5, 451-453
CrossRef31
Brita Arver, Quan Du, Jindong Chen, Liping Luo, Annika Lindblom. (2000) Hereditary breast cancer: a review. Seminars in Cancer Biology 10:4, 271-288
CrossRef32
Chu-Xia Deng, Steven G. Brodie. (2000) Roles of BRCA1 and its interacting proteins. BioEssays 22:8, 728-737
CrossRef33
Adnan Aydiner, Ahmet Karadeniz, Kazim Uygun, Siirsel Tas, Faruk Tas, Rian Disci, Erkan Topuz. (2000) Multiple Primary Neoplasms at a Single Institution. American Journal of Clinical Oncology: Cancer Clinical Trials 23:4, 364-370
CrossRef34
Ching-Hon Pui, Mary V. Relling. (2000) TOPOISOMERASE II INHIBITOR-RELATED ACUTE MYELOID LEUKAEMIA. British Journal of Haematology 109:1, 13-23
CrossRef35
Alexander Powers, Charles Cox, Douglas S. Reintgen. (2000) Breast cancer screening in childhood cancer survivors. Medical and Pediatric Oncology 34:3, 210-212
CrossRef36
Henry T. Lynch, Rodney D. McComb, Neal K. Osborn, Paul A. Wolpert, Jane F. Lynch, Zbigniew K. Wszolek, David Sidransky, Robert E. Steg. (2000) Predominance of brain tumors in an extended Li-Fraumeni (SBLA) kindred, including a case of Sturge-Weber syndrome. Cancer 88:2, 433-439
CrossRef37
Claudia P
tzsch, Hans-Eckart Schaefer, Michael L
CrossRef38
Mark L. Bernstein, Sylvain Baruchel, Susan Devine, Nektaria Markoglou, Irving W. Wainer, Marion Williams, Susan Blaney, Albert Moghrabi, Naomi Winick, Teresa Vietti. (1999) Phase I and Pharmacokinetic Study of CI-980 in Recurrent Pediatric Solid Tumor Cases. Journal of Pediatric Hematology/Oncology 21:6, 494-500
CrossRef39
Kevin M. Lin, Charles A. Ternent, Dean R. Adams, Alan G. Thorson, Garnet J. Blatchford, Mark A. Christensen, Patrice Watson, Henry T. Lynch. (1999) Colorectal cancer in hereditary breast cancer kindreds. Diseases of the Colon & Rectum 42:8, 1041-1045
CrossRef40
S.J. Ham, W.T.A. van der Graaf, E. Pras, W.M. Molenaar, E. van den Berg, H.J. Hoekstra. (1998) Soft tissue sarcoma of the extremities. A multimodality diagnostic and therapeutic approach. Cancer Treatment Reviews 24:6, 373-391
CrossRef41
S.J. Ham, H. Schraffordt Koops, W.T.A. van der Graaf, J.R. van Horn, L. Postma, H.J. Hoekstra. (1998) Historical, current and future aspects of osteosarcoma treatment. European Journal of Surgical Oncology (EJSO) 24:6, 584-600
CrossRef42
Kathleen J. Smith, Terry L. Barrett, William F. Smith, Henry M. Skelton. (1998) A Review of Tumor Suppressor Genes in Cutaneous Neoplasms With Emphasis on Cell Cycle Regulators. The American Journal of Dermatopathology 20:3, 302-313
CrossRef43
MAKOTO AKASHI, H. PHILLIP KOEFFLER. (1998) Li-Fraumeni Syndrome and the Role of the p53 Tumor Suppressor Gene in Cancer Susceptibility. Clinical Obstetrics and Gynecology 41:1, 172-199
CrossRef44
Kim E. Nichols, Frederick P. Li, Daniel A. Haber, Lisa Diller. (1998) Childhoood cancer predisposition: Applications of molecular testing and future implications. The Journal of Pediatrics 132:3, 389-397
CrossRef45
Richard M. Terek, John H. Healey, Pilar Garin-Chesa, Solida Mak, Anthony P. Albino, Andrew Huvos. (1998) p53 Mutations in Chondrosarcoma. Diagnostic Molecular Pathology 7:1, 51-56
CrossRef46
Federico Antillon, Sue C. Kaste, Jesse J. Jenkins, Sheila A. Shurtleff, Thomas E. Merchant, James R. Downing, Alberto S. Pappo. (1997) Primitive Neuroectodermal Tumor of Bone as a Second Malignant Neoplasm in a Child Previously Treated for Acute Lymphoblastic Leukemia. Journal of Pediatric Hematology/Oncology 19:5, 473-476
CrossRef47
Sabine J Kony, Florent de Vathaire, Agnès Chompret, Akthar Shamsaldim, Emmanuel Grimaud, Marie-Anne Raquin, Odile Oberlin, Laurence Brugières, Jean Feunteun, François Eschwège, Jean Chavaudra, Jean Lemerle, Catherine Bonaïti-Pellié. (1997) Radiation and genetic factors in the risk of second malignant neoplasms after a first cancer in childhood. The Lancet 350:9071, 91-95
CrossRef48
I Heide. (1997) The status of p53 in the metastatic progression of colorectal cancer. European Journal of Cancer 33:8, 1314-1322
CrossRef49
Malkin, David, , Friend, Stephen H., , Li, Frederick P., , Strong, Louise C., . (1997) Germ-Line Mutations of the p53 Tumor-Suppressor Gene in Children and Young Adults with Second Malignant Neoplasms. New England Journal of Medicine 336:10, 734-734
Full Text50
Eleftherios P Diamandis. (1997) Clinical applications of tumor suppressor genes and oncogenes in cancer. Clinica Chimica Acta 257:2, 157-180
CrossRef51
Paul L. Baron, Christopher E. Gates, Carolyn E. Reed, Roberta L. D. Dikeman, Jay J. Drosieko, Roger N. Passmore, Jonathan S. Bromberg, Mark C. Willingham. (1997) p53 Overexpression in squamous cell carcinoma of the esophagus. Annals of Surgical Oncology 4:1, 37-45
CrossRef52
RS Cornelis, M van Vliet, MJ van de Vijver, HFA Vasen, PA Voute, B Top, P. Meera Khan, P Devilee, CJ Cornelisse. (1997) Three germline mutations in theTP53 gene. Human Mutation 9:2, 157-163
CrossRef53
Steven A. Narod. (1996) Genetic epidemiology of childhood cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1288:3, F141-F150
CrossRef54
Céline Moutou, Christine Le Bihan, Agnès Chompret, Nicole Poisson, Laurence Brugières, Brigitte Bressac, Jean Feunteun, Jean Lemerle, Catherine Bonaïti-Pellié. (1996) Genetic transmission of susceptibility to cancer in families of children with soft tissue sarcomas. Cancer 78:7, 1483-1491
CrossRef55
S Moore. (1996) Absence of germline mutations in exons 5–9 of the p53 gene in patients with Li-Fraumeni-like (SBLA) and familial adenomatous polyposis heritable cancer syndromes. Cancer Genetics and Cytogenetics 90:2, 125-129
CrossRef56
Frederick P. Li. (1996) Hereditary cancer susceptibility. Cancer 78:3, 553-557
CrossRef57
Tanya M. Gottlieb, Moshe Oren. (1996) p53 in growth control and neoplasia. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1287:2-3, 77-102
CrossRef58
(1996) Evidence of a hereditaryp53 syndrome in cancer-prone families. International Journal of Cancer 65:4, 554-557
CrossRef59
D.Mark Pritchard, Alastair J.M. Watson. (1996) Apoptosis and gastrointestinal pharmacology. Pharmacology & Therapeutics 72:2, 149-169
CrossRef60
C.J. Cornelisse, R.S. Cornelis, P. Devilee. (1996) Genes Responsible for Familial Breast Cancer. Pathology - Research and Practice 192:7, 684-693
CrossRef61
Carolyn A. Felix, Irene Slavc, Michael Dunn, Eric A. Strauss, Peter C. Phillips, Lucy B. Rorke, Leslie Sutton, Greta R. Bunin, Jaclyn A. Biegel. (1995) p53 gene mutations in pediatric brain tumors. Medical and Pediatric Oncology 25:6, 431-436
CrossRef62
Adriano Aguzzi, Sebastian Brandner, Stefan Isenmann, Joachim P. Steinbach, Ulrich Sure. (1995) Transgenic and gene disruption techniques in the study of neurocarcinogenesis. Glia 15:3, 348-364
CrossRef63
P Chen. (1995) Constitutional p53 mutations associated with brain tumors in young adults. Cancer Genetics and Cytogenetics 82:2, 106-115
CrossRef64
Hannah R. Krigman, Rex C. Bentley, Donald K. Strickland, Cindy R. Miller, Louis P. Dehner, Kay Washington. (1995) Anaplastic renal cell carcinoma following neuroblastoma. Medical and Pediatric Oncology 25:1, 52-59
CrossRef65
Eleftherios P. Diamandis. (1995) Clinical applications of the p53 tumor suppressor gene. Clinica Chimica Acta 237:1-2, 79-90
CrossRef66
Benedikt L. Ziegler, Melanie Weiss, Stefan Thoma, Christa Lamping, Theodor M. Fliedner. (1995) Chapter 8: Perspectives for the use of biological indicators for the assessment of radiation induced responses and impairments: Biologic indicators of exposure: Are markers associated with oncogenesis useful as biologic markers of effect?. Stem Cells 13:S1, 326-338
CrossRef67
U. A. PATEL, M. PERRY, C. CRANE-ROBINSON. (1995) Screening for germline mutations of the p53 gene in familial breast cancer patients. European Journal of Clinical Investigation 25:2, 132-137
CrossRef68
Jerry W. Shay, Woodring E. Wright. (1995) Mechanisms of escaping cellular senescence. Radiation Oncology Investigations 3:6, 284-289
CrossRef69
Joseph B. Martin. (1995) Gene therapy and pharmacological treatment of inherited neurological disorders. Trends in Biotechnology 13:1, 28-35
CrossRef70
Christine Le Bihan, Céline Moutou, Laurence Brugières, Jean Feunteun, Catherine Bonaïti-Pellié. (1995) ARCAD: A method for estimating age-dependent disease risk associated with mutation carrier status from family data. Genetic Epidemiology 12:1, 13-25
CrossRef71
L. E. Becker. (1995) Central neuronal tumors in childhood: relationship to dysplasia. Journal of Neuro-Oncology 24:1, 13-19
CrossRef72
Willemina M Molenaar, John Q. Trojanowski. (1994) Primitive neuroectodermal tumors of the central nervous system in childhood: tumor biological aspects. Critical Reviews in Oncology/Hematology 17:1, 1-25
CrossRef73
H. W. Taylor, D. Adam, A. M. Thompson, J. Dunn, J. R. Farndon. (1994) Correlation between p53 mutations and antibody staining in breast carcinoma. British Journal of Surgery 81:7, 1080-1081
CrossRef74
Massimo Loda. (1994) Polymerase chain reaction-based methods for the detection of mutations in oncogenes and tumor suppressor genes. Human Pathology 25:6, 564-571
CrossRef75
Lorenzo Tomatis. (1994) Transgeneration Carcinogenesis: A Review of the Experimental and Epidemiological Evidence. Cancer Science 85:5, 443-454
CrossRef76
Winand N. M. Dinjens, Marcel M. Van Der Weiden, Fritz H. Schroeder, Fred T. Bosman, Jan Trapman. (1994) Frequency and characterization of p53 mutations in primary and metastatic human prostate cancer. International Journal of Cancer 56:5, 630-633
CrossRef77
W. Alexandra Hoogerwerf, Anita L. Hawkins, Constance A. Griffin, Elizabeth J. Perlman. (1994) Chromosome analysis of nine osteosarcomas. Genes, Chromosomes and Cancer 9:2, 88-92
CrossRef78
Daniel M. Green, Michael A. Zevon, Peter A. Reese, Geoffrey S. Lowrie, John F. Gaeta, John I. Pearce, Arthur M. Michalek, Elizabeth A. Stephens. (1994) Second malignant tumors following treatment during childhood and adolescence for cancer. Medical and Pediatric Oncology 22:1, 1-10
CrossRef79
Carolyn L. Russo, James McIntyre, Allen M. Goorin, Michael P. Link, Mark C. Gebhardt, Stephen H. Friend. (1994) Secondary breast cancer in patients presenting with osteosarcoma: Possible involvement of germline p53 mutations. Medical and Pediatric Oncology 23:4, 354-358
CrossRef80
Daniela Seminara, G. Iris Obrams. (1994) Genetic epidemiology of cancer: A multidisciplinary approach. Genetic Epidemiology 11:3, 235-254
CrossRef81
Michele Harvey, Mark J. McArthur, Charles A. Montgomery, Janet S. Butel, Allan Bradley, Lawrence A. Donehower. (1993) Spontaneous and carcinogen–induced tumorigenesis in p53–deficient mice. Nature Genetics 5:3, 225-229
CrossRef82
Harris, Curtis C.Hollstein, Monica. (1993) Clinical Implications of the p53 Tumor-Suppressor Gene. New England Journal of Medicine 329:18, 1318-1327
Full Text83
Chikashi Ishioka, Thierry Frebourg, Yu-Xin Yan, Marc Vidal, Stephen H. Friend, Susanne Schmidt, Richard Iggo. (1993) Screening patients for heterozygous p53 mutations using a functional assay in yeast. Nature Genetics 5:2, 124-129
CrossRef84
Crispian Scully. (1993) Oncogenes, tumour suppressors and viruses in oral squamous carcinoma. Journal of Oral Pathology and Medicine 22:8, 337-347
CrossRef85
Masayuki Shiseki, Ryo Nishikawa, Hiroshi Yamamoto, Atsushi Ochiai, Haruhiko Sugimura, Nobuyuki Shitara, Yuichi Sameshima, Hideaki Mizoguchi, Takashi Sugimura, Jun Yokota. (1993) Germ-line p53 mutation is uncommon in patients with triple primary cancers. Cancer Letters 73:1, 51-57
CrossRef86
Lawrence A. Donehower, Allan Bradley. (1993) The tumore suppressor p53. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1155:2, 181-205
CrossRef87
Ann L. Hartley, Jillian M. Birch, Val Blair, Anna M. Kelsey, Martin Harris, Patricia H. Morris Jones. (1993) Patterns of cancer in the families of children with soft tissue sarcoma. Cancer 72:3, 923-930
CrossRef88
Theresa M. Cheng, Robert J. Coffey, Benjamin R. Gelber, Bernd W. Scheithauer. (1993) Simultaneous Presentation of Symptomatic Subependymomas in Siblings. Neurosurgery 33:1, 145???150
CrossRef89
Ju Chen, Amrik Sahota, Glenn F. Martin, Masayuki Hakoda, Naoyuki Kamatani, Peter J. Stambrook, Jay A. Tischfield. (1993) Analysis of germline and in vivo somatic mutations in the human adenine phosphoribosyltransferase gene: Mutational hot spots at the intron 4 splice donor site and at codon 87. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 287:2, 217-225
CrossRef90
Sang Wook Choi, Prodromos Hytiroglou, Stephen A. Geller, Sun Moo Kim, Kyu Won Chung, Doo Ho Park, Neil D. Theise, Swan N. Thung. (1993) The expression of p53 antigen in primary malignant epithelial tumors of the liver: an immunohistochemical study. Liver 13:3, 172-176
CrossRef91
Louise C. Strong. (1993) Genetic implications for long-term survivors of childhood cancer. Cancer 71:S10, 3435-3440
CrossRef92
Ketil Heimdal, Ragnhild A. Lothe, Sigrid Lystad, Ruth Holm, Sophie D. Fosså, Anne-Lise Børresen. (1993) No germlineTP53 mutations detected in familial and bilateral testicular cancer. Genes, Chromosomes and Cancer 6:2, 92-97
CrossRef93
(1993) REVIEW. Biological Chemistry Hoppe-Seyler 374:1-6, 227-236
CrossRef94
Birgitte Smith-Sørensen, Mark C. Gebhardt, Peter Kloen, Jim McIntyre, Fernando Aguilar, Peter Cerutti, Anne-Lise Børresen. (1993) Screening for TP53 mutations in osteosarcomas using constant denaturant gel electrophoresis (CDGE). Human Mutation 2:4, 274-285
CrossRef95
Orna Mor, Zehava Grossman, Orit Jakobovitz, Frida Brok-Simoni, Gideon Rechavi. (1992) Artifactual p53 point mutations: possible effect of gene secondary structure on PCR and direct sequence analysis. The Lancet 340:8829, 1236
CrossRef96
Carole Hennessy Martz. (1992) Introduction. Seminars in Oncology Nursing 8:4, 227-228
CrossRef97
Levine, Arnold J.. (1992) The p53 Tumor-Suppressor Gene. New England Journal of Medicine 326:20, 1350-1352
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