Germline TP53 Mutations and Li-Fraumeni Syndrome

Varley, Jenny

doi:10.1002/humu.10218

Cited by 125 publications

(178 citation statements)

References 0 publications

Supporting

Mentioning

173

Contrasting

Unclassified

Order By: Relevance

“…Li-Fraumeni syndrome is usually associated with a variety of different tumour types occurring over a wide age range, including in childhood. Although gastric, pancreatic and colon cancers have been previously found in families with this syndrome, paediatric tumours, such as osteosarcomas and brain tumours, are typical tumours associated with the Li-Fraumeni syndrome [8], which makes this family an atypical Li-Fraumeni kindred with excess of gastric cancer. Our results show that p53 mutations may be involved in a percentage of families with an aggregation of gastric cancer who lack CDH1 mutations.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients

Oliveira

Ferreira

Nabais

et al. 2004

European Journal of Cancer

View full text Add to dashboard Cite

Approximately 30% of all hereditary diffuse gastric cancer (HDGC) families carry CDH1 germline mutations. The other two thirds remain genetically unexplained and are probably caused by alterations in other genes. Using polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP)/sequencing, we screened 32 Portuguese families with a history of gastric cancer and 23 patients with early onset gastric cancer for CDH1 germline mutations. In probands negative for CDH1 mutations, we screened genes involved in hereditary cancer syndromes in which gastric cancer may be one of the component tumours, namely p53 (Li-Fraumeni Syndrome) and hMLH1 and hMSH2 (HNPCC). We also screened in these patients for mutations in Caspase-10, a gene inactivated in sporadic gastric cancer, and SMAD4, a gene whose inactivation in mice is associated with signet-ring cell carcinoma of the stomach. One of the families fulfilling the HDGC criteria harboured a CDH1 germline mutation, and one of the families with incomplete criteria harboured a p53 germline mutation. No mutations were identified in hMLH1 and hMSH2, and only sequence variants were found in SMAD4 and Caspase-10. The present work reports for the first time CDH1 germline mutations in Portuguese gastric cancer families, and highlights the need for p53 mutation screening in families lacking CDH1 germline mutations, in a country with one of the highest incidences of gastric cancer in the world. No evidence was found for a role of germline mutations in SMAD4 and Caspase-10 in families lacking CDH1 mutations.

show abstract

Section: Discussionmentioning

confidence: 97%

“…However, gastric cancer may also be seen as part of the tumour spectrum in other inherited cancer predisposition syndromes, such as: hereditary nonpolyposis colorectal cancer syndrome (HNPCC), LiFraumeni syndrome (LFS), Familial Adenomatous Polyposis (FAP), Cowden syndrome and Peutz-Jeghers syndrome (PJS) [6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients

Oliveira

Ferreira

Nabais

et al. 2004

European Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…There were five breast cancers in relatives of children with soft-tissue sarcoma or adrenocortical carcinoma, typical of Li-Fraumeni syndrome. 31 Germline TP53 mutation carries an increased risk of colorectal cancer, especially at younger ages, 32,33 so some of the cases of colorectal cancer in relatives of children with cancer may represent occurrences of Li-Fraumeni syndrome. Some instances of colorectal cancer in adult relatives could also be attributable to adenomatous polyposis coli (associated with hepatoblastoma and CNS tumors) 34,35 or hereditary nonpolyposis colon cancer (associated with CNS tumors).…”

Section: Discussionmentioning

confidence: 99%

Familial aggregation of childhood and adult cancer in the Utah genealogy

Neale

Stiller

Bunch

et al. 2013

Intl Journal of Cancer

View full text Add to dashboard Cite

A small proportion of childhood cancer is attributable to known hereditary syndromes, but whether there is any familial component to the remainder remains uncertain. We explored familial aggregation of cancer in a population-based case-control study using genealogical record linkage and designed to overcome limitations of previous studies. Subjects were selected from the Utah Population Database. We compared risk of cancer in adult first-degree relatives of children who were diagnosed with cancer with the risk in relatives of children who had not had a cancer diagnosed. We identified 1,894 childhood cancer cases and 3,788 controls; 7,467 relatives of cases and 14,498 relatives of controls were included in the analysis. Relatives of children with cancer had a higher risk of cancer in adulthood than relatives of children without cancer [odds ratio (OR) 1.31, 95% confidence interval (CI) 1.11-1.56]; this was restricted to mothers and siblings and was not evident in fathers. Familial aggregation appeared stronger among relatives of cases diagnosed before 5 years of age (OR 1.48, 95% CI 1.13-1.95) than among relatives of cases who were older when diagnosed (OR 1.22, 95% CI 0.98-1.51). These findings provide evidence of a generalized excess of cancer in the mothers and siblings of children with cancer. The tendency for risk to be higher in the relatives of children who were younger at cancer diagnosis should be investigated in other large data sets. The excesses of thyroid cancer in parents of children with cancer and of any cancer in relatives of children with leukemia merit further investigation.The causes of childhood cancer are largely unknown. A small proportion of cases are attributable to known hereditary cancer syndromes, but whether there is any familial component to the remainder remains uncertain. Understanding familial risks may help to further elucidate etiology and/or identify the need to screen family members.Little 1 reviewed much of the already extensive literature published to 1997 on aggregation of cancer among firstdegree relatives of children with cancer. Many of these studies involved a relatively small number of cases, and Little concluded that there was no strong evidence of familial risks in parents or siblings for most of the common types of childhood cancer. Since then, several large studies of cancer risk in first-degree relatives of children with cancers of all types have emerged from the Nordic countries, 2 the United Kingdom, 3 the United States 4 and Italy. 5,6 Analyses of risk for many types of childhood cancer have also been published from the Swedish Family Cancer Database. 7-9 There has been broad agreement that overall the risk of childhood cancer in the siblings of children with cancer is moderately increased. 2,10,11 In a population-based study in the Nordic countries, there was a small increase in the risk of cancer in siblings of all ages combined, but this was entirely accounted for by known familial cancer syndromes. 2 Conversely, a North American study of the siblings of 5-y...

show abstract

“…63,64 p53 mutations are common in RMS with nearly 50% of cases exhibiting a lesion in the p53 gene. 63,65 p53 mutations are not as common in ES with frequencies of 3-16%; 31,66 however, the subset of ES patients with mutant p53 have a markedly poorer outcome.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

et al. 2004

View full text Add to dashboard Cite

Sarcomas, or tumors of connective tissue, represent roughly 20% of childhood cancers. Although the cure rate for sarcomas in general has significantly improved in the last 10 years, there continue to be subgroups that are difficult to treat. High-grade or metastatic soft-tissue sarcomas and rhabdomyosarcomas (RMS) of the extremities remain therapeutic challenges and their prognosis is often poor. The future of sarcoma therapy will likely include molecular approaches including gene/protein expression profiling and gene-based therapy. Most sarcomas harbor defects in the p53 or pRb pathways. The tumor suppressor p53 is central to regulation of cell growth and tumor suppression and restoring wild-type p53 function in pediatric sarcomas may be of therapeutic benefit. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. Studies of this approach, however, remain limited in pediatric cancers, including sarcomas. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (C135S) and lacZ, we studied the effect of adenoviralmediated gene therapy in four pediatric sarcoma cell lines, RD and Rh4 (RMS), Rh1 (Ewing's sarcoma) and A204 (undifferentiated sarcoma). Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, we have shown a dose-dependent decrease in cell viability 72 h post-treatment that occurs with Ad-wtp53 but not with Ad-mutp53. Cells treated with Ad-wtp53 show upregulation of the p53 downstream targets, p21 CIP1/WAF1 and bax. Growth curves demonstrate suppression of cell growth over a period of 4 days and cells treated with Ad-wtp53 demonstrate a significant increase in sensitivity to the chemotherapeutic agents, cisplatin and doxorubicin. Our results indicate that restoration of wild-type p53 function in pediatric sarcoma cells could provide a basis for novel approaches to treatment of this disease.

show abstract

Germline TP53 Mutations and Li-Fraumeni Syndrome

Cited by 125 publications

References 0 publications

E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients

E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients

Familial aggregation of childhood and adult cancer in the Utah genealogy

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

Contact Info

Product

Resources

About