Prevalence of Early Onset Colorectal Cancer in 397 Patients With Classic Li–Fraumeni Syndrome

Department of Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Gastroenterology (Impact Factor: 16.72). 01/2006; 130(1):73-9. DOI: 10.1053/j.gastro.2005.10.014
Source: PubMed


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.

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    • "In young adults, breast cancer is the most common malignancy. Other tumours observed in LFS patients include colorectal, lung, gastric, pancreatic and prostate cancers, as well as melanoma and lymphoma [1-3]. Variant forms of the disease, observed in families with tumours of the LFS spectrum, which resemble but do not meet the strict criteria for LFS syndrome, have been collectively named Li-Fraumeni-like (LFL) syndrome [1,4]. "
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    ABSTRACT: Background Adrenocortical carcinomas (ACCs) are among the most common childhood cancers occurring in infants affected with the Li-Fraumeni and Li- Fraumeni-like (LFS/LFL) syndromes, which are caused by dominant germline mutations in the TP53 gene. In Brazil, a particular mutation, occurring in the tetramerisation domain of the gene, p.R337H, is exceedingly common due to a founder effect and is strongly associated with ACC. In this report, we describe the phenotype and long-term clinical follow-up of a female child diagnosed with ACC and homozygous for the TP53 p.R337H founder mutation. Case presentation At age 11 months, the patient was diagnosed with a virilising anaplastic adrenal cortical tumour, which was completely excised without disturbing the adrenal capsule. Family history was consistent with an LFL tumour pattern, and genotyping identified the TP53 p.R337H mutation in both alleles in genomic DNA from lymphocytes and fibroblasts. Haplotype analysis confirmed the occurrence of the mutation in the same founder haplotype previously described in other Brazilian patients. No other germline or somatic TP53 mutations or rearrangements were identified. At age 9 years, the child was asymptomatic and had no evidence of endocrine derangements. Full body and brain magnetic resonance imaging (MRI) failed to detect any suspicious proliferative lesions, and cardiopulmonary exercise testing results were within the normal reference for the child’s age, ruling out a major exercise capacity deficiency. Conclusion This is the first clinical and aerobic functional capacity documentation of a patient who carries two mutant TP53 alleles and no wild-type allele. Our results support the hypothesis that TP53 p.R337H, the most common TP53 mutation ever described in any population, is a conditional mutant. Furthermore, our observations over a long period of clinical follow-up suggest that TP53 p.R337H homozygotes do not have a more severe disease phenotype than do heterozygote carriers of the same mutation. Patients with the homozygous TP53 p.R337H genotype will require careful surveillance for lifetime cancer risk and for effects on metabolic capacity later in life.
    BMC Cancer 04/2013; 13(1):187. DOI:10.1186/1471-2407-13-187 · 3.36 Impact Factor
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    • "Germline TP53 mutations are the underlying genetic defect of Li Fraumeni Syndrome (LFS) and Li-Fraumeni-like Syndrome (LFL), a set of familial syndromes of predisposition to multiple, early cancer, characterized by an excess risk of adrenocortical carcinoma in early childhood, soft tissue sarcoma, bone sarcoma and brain tumors in adolescence, breast cancer in young adult women and multiple other cancers later in life [5]. An excess risk of colorectal cancer in young adults has been reported as well as earlier occurrence of several common cancers as compared to the general population [6,7]. "
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    ABSTRACT: Gastric adenocarcinoma is rare in children and adolescents, with about 17 cases under age 21 in the world's literature. We report a case of invasive well-differentiated metastatic gastric cancer in a Brazilian 12-year-old boy without documented familial history of cancer. The patient, diagnosed with metastatic disease, died seven months after surgery. DNA from intra-surgical specimens revealed a TP53 mutation at codon 337 (p.R337H) in samples with neoplastic cells (dysplasia, tumor and metastasis) but not in non-transformed cells (incomplete intestinal metaplasia and non-involved celiac lymph node). In all mutation-positive tissues, p.R337H occurred on the same background, a founder allele identified by a specific haplotype previously described in Brazilian Li-Fraumeni syndrome patients. The same mutant haplotype, corresponding to a founder mutation present in 0.3% of the general population in Southern Brazil, was found in the genome of the father. Presence of this inherited haplotype in the tumor as well as in the father's germline, suggests a rare case of microchimerism in this patient, who may have harbored a small number of mutant cells originating in another individual, perhaps a dizygotic twin that died early in gestation. This case represents one of the earliest ages at diagnosis of gastric cancer ever reported. It shows that cancer inheritance can occur in the absence of an obvious germline mutation, calling for caution in assessing early cancers in populations with common founder mutations such as p.R337H in Southern Brazil.
    BMC Cancer 10/2011; 11:449. DOI:10.1186/1471-2407-11-449 · 3.36 Impact Factor
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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. "
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    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 ( 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 · 8.46 Impact Factor
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