Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome.
ABSTRACT Hereditary colorectal cancer is associated most commonly with the hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis syndromes. We investigated the prevalence of early onset colorectal cancer and the frequency of p53 germline mutations in 64 families from a Li-Fraumeni syndrome (LFS) registry.
Patients with documented colorectal cancer and a diagnosis at or before age 50 were included. P53 analyses were performed through germline mutational analyses using standard molecular techniques.
Among the 397 patients and 64 families in the classic LFS registry, a total of 11 patients (2.8%) from 10 different families (15.6%) met criteria for classic LFS and had documented colorectal cancer at less than 50 years of age. The mean age at diagnosis in this group was 33 years and of these patients 4 developed colorectal cancer before age 21 (ages, 9, 11, 15, and 20 y). All families that were tested for p53 mutations (8 of 10) had evidence of germline mutations by sequence analysis; therefore, 12.5% of the total number of families in the registry had colorectal cancer at age less than 50 years and a documented germline p53 mutation. Mutations primarily were missense or nonsense and were located between exons 4-10.
LFS patients with germline p53 mutations may have an increased susceptibility to colorectal cancer and present up to several decades earlier than the general population. LFS should be considered when a young patient presents with colorectal cancer.
- SourceAvailable from: Maria Isabel Achatz
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- "TP53 germline mutations have also been reported in individuals with no family history or with a family history not fulfilling LFS or LFL definitions (Olivier et al., 2003). The most frequent cancers associated with TP53 mutations are breast cancer, bone and soft tissue sarcomas, brain tumors and adrenocortical carcinomas (ADC) (Wong et al., 2006). Other less frequent cancers include leukemia, stomach cancer and colorectal cancer. "
ABSTRACT: A large amount of data is available on the functional impact of missense mutations in TP53 and on mutation patterns in many different cancers. New data on mutant p53 protein function, cancer phenotype and prognosis have recently been integrated in the International Agency for Research on Cancer TP53 database (http://www-p53.iarc.fr/). Based on these data, we summarize here current knowledge on the respective roles of mutagenesis and biological selection of mutations with specific functional characteristic in shaping the patterns and phenotypes of mutations observed in human cancers. The main conclusion is that intrinsic mutagenicity rates, loss of transactivation activities, and to a lesser extent, dominant-negative activities are the main driving forces that determine TP53 mutation patterns and influence tumor phenotype. In contrast, current experimental data on the acquisition of oncogenic activities (gain of function) by p53 mutants are too scarce and heterogenous to assess whether this property has an impact on tumor development and outcome. In the case of inherited TP53 mutations causing Li-Fraumeni and related syndromes, the age at onset of some tumor types is in direct relation with the degree of loss of transactivation capacity of missense mutations. Finally, studies on large case series demonstrate that TP53 mutations are independent markers of bad prognosis in breast and several other cancers, and that the exact type and position of the mutation influences disease outcome. Further studies are needed to determine how TP53 haplotypes or loss of alleles interact with mutations to modulate their impact on cancer development and prognosis.Oncogene 04/2007; 26(15):2157-65. DOI:10.1038/sj.onc.1210302 · 8.56 Impact Factor
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ABSTRACT: Matrix metalloproteinase (MMP) is known to be involved in the initial and progressive stages of cancer development, and in the aggressive phenotypes of cancer. This study examines the association of single nucleotide polymorphisms in promoter regions of MMP-1 and MMP-3 with susceptibility to oral squamous cell carcinoma (OSCC). We compared 170 Japanese OSCC cases and 164 healthy controls for genotypes of MMP-1 and MMP-3. The frequency of the MMP-1 2G allele was higher and that of the 1G homozygote was lower in the OSCC cases (p = 0.034). A multivariate logistic regression analysis revealed that subjects who were 45 years old or older had a significantly increased (2.47-fold) risk of OSCC (95%CI 1.47-4.14, p = 0.0006), and those carrying the MMP-1 2G allele had a 2.30-fold risk (95%CI 1.15-4.58, p = 0.018), indicating independent involvement of these factors in OSCC. One of the key discoveries of this research is the apparent reduction of the MMP-1 1G/1G and 1G/2G genotype distributions among the early onset OSCC cases under the ages of 45 years. It should be noted that the tongue was the primary site in 86.2% of these early onset cases. This could suggest the specific carcinogenic mechanisms, i.e. specific carcinogenic stimulations and/or genetic factors in the tongue. Since the 2G allele is a majority of the MMP-1 genotype in the general population, it seems to act as a genetic pre-condition in OSCC development. However this report suggests a crucial impact of the MMP-1 2G allele in the early onset OSCC.BMC Cancer 02/2007; 7(1):187. DOI:10.1186/1471-2407-7-187 · 3.32 Impact Factor
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ABSTRACT: With the development of new approaches to transplantation therapy, such as those building upon the potential found in stem cells, it is vital to pursue a clear understanding of transplantation risks. Allogeneic transplantation presents risk for the transmission of disease of various types, including genetic disease. Predisposition to develop cancer is a feature of numerous genetic disorders, and it may be transmissible by transplantation. Some genetic disorders predisposing to cancer are remarkably common, either worldwide or in specific populations, and they could pose significant risk. Hence, to reduce risk to recipients, there is reason to exclude from donation those potential donors (including embryos) harboring certain germ-line mutations. However, the frequent absence of readily identifiable features might confound the effort to exclude those who harbor mutation. Thus, it is also important to consider the magnitude of risk that they represent. For some disorders, life-threatening cancer is highly likely to develop in those individuals born with germ-line mutation, but whether recipients would face the same risk from transplanted mutation is not always evident. Given the diversity of pathways that lead to cancer, there may be diverse factors that impact the likelihood for cancer to develop in the recipient, with some factors decreasing and others increasing the risk. One factor of special concern is the possibility that manipulation of donor cells, prior to transplantation, might introduce additional genetic or epigenetic abnormality, thereby increasing the risk.Stem Cells and Development 05/2007; 16(2):191-212. DOI:10.1089/scd.2006.0080 · 4.20 Impact Factor