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PubMed1994

The use of loss of constitutional heterozygosity data to ascertain the location of predisposing genes in cancer families.

A method is described to investigate the inheritance of disease predisposition in cancer families. It is an extension of classic genetic linkage analysis, which enables information on loss of constitutional heterozygosity (LOCH) to be incorporated into the model. This adapted model treats LOCH data as additional observations on the disease phenotype. One of the major benefits of this approach is that isolated parent-offspring pairs are now potentially informative for linkage analysis. Examples are presented.

Alleles↗
PubMed1992

p53 mutations in breast cancer.

We have identified and analyzed 41 mutations in p53 in sporadic breast tumors from 136 unselected breast cancer patients and estimate that approximately 40% of such tumors contain p53 mutations. The frequency of G-T transversions and the incidence of guanosine mutations in the nontranscribed strand of the p53 gene were found to be higher than expected, and we suggest, therefore, that exogenous carcinogens have an etiological role in sporadic breast cancers. Mutations were recorded in 44 codons of the p53 gene, with no obvious mutational hot-spots, although mutations at codons 175, 194, 273, and 280 accounted for 25% of the changes. One germ-line mutation was found in 136 patients and so we conclude that constitutional mutation of p53 may be an uncommon etiological factor in breast cancer.

Base Composition↗
PubMed1994

The molecular biology of childhood rhabdomyosarcoma.

Rhabdomyosarcomas comprise a biologically heterogeneous group of childhood malignancies that are histologically characterized by varying degrees of differentiation, ranging from uncommitted primitive mesenchymal cells to fetal myotubes. This differentiation pattern is reflected in the behavior of the tumor cells in vitro and can be manipulated by the addition of various biological and chemical agents to the intercellular milieu. Recent studies have documented some of the genetic and phenotypic events that occur under these conditions. In addition, the use of cell lines has facilitated the identification of characteristic karyotypic abnormalities and DNA transcriptional activators that are of potential diagnostic importance. Alterations of tumor-suppressor and multidrug-resistance genes have also been described, and they portend identification of susceptible families and potential therapeutic strategies to deal with this clinically aggressive family of childhood neoplasia. These developments herald an increasing utility of molecular biology in the diagnosis and treatment of pediatric sarcomas and necessitate pathologists' familiarity with this subject.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Inherited susceptibility to breast cancer.

Four genes are now known to be responsible for inherited susceptibility to breast cancer: the BRCA1 gene on chromosome 17q21, the ataxia-telangiectasia (AT) gene (11q22-q23), the TP53 gene (17p13.1) and the androgen receptor (AR) (Xq11.2-q12). These genes, however, differ dramatically in terms of the risk of breast cancer that they confer, the proportion of breast cancer incidence that they account for and the other cancers and other phenotypes with which they are associated. Genetic linkage studies have shown that some high risk breast cancer families, particularly those where breast cancer occurs in association with ovarian cancer, are due to a gene on chromosome 17q known as BRCA1. The BRCA1 gene is estimated to confer a breast cancer risk of about 70% by age 70, and may account for about 2% of overall breast cancer incidence, although a higher proportion of younger cases. Germline mutations in the TP53 gene are responsible for a high proportion of LI-Fraumeni families, in which breast cancer occurs in association with childhood sarcomas and other cancers. In such families, the risk of breast cancer is over 50% by age 50, and the risk of all cancers is nearly 100%; germline TP53 mutations are, however, probably responsible for much less than 1% of all breast cancer. By contrast, heterozygotes for the AT gene carry a much more moderate risk of breast cancer. This gene, however, is much more common in the population and may account for 7% or more of breast cancer incidence. Finally, germline mutations in the androgen receptor are known to cause male breast cancer, but this has only been demonstrated in two families. Evidence from linkage and population based studies suggests that these genes may account for about one half of the observed familial clustering of breast cancer; other breast cancer susceptibility genes therefore remain to be identified.

Aged↗
PubMed1991

Tumorigenic transformation of spontaneously immortalized fibroblasts from patients with a familial cancer syndrome.

Immortal cell lines arose spontaneously during in vitro culture of initially normal fibroblasts, MDAH041 and MDAH087, from patients with Li-Fraumeni familial cancer syndrome. Fibroblasts from a control donor, MDAH170, maintained a normal morphology and senesced at 31 population doublings. The immortal fibroblasts have several properties of transformed cells. In addition to having acquired an altered morphology and chromosomal anomalies, MDAH041 and MDAH087 have escaped from senescence, growing beyond 300 and 100 population doublings (pd), respectively. As early as 50 pd, these cells can be transformed by an activated H-ras oncogene to form tumors in nude mice. However, MDAH041 immortal cells were resistant to tumorigenic transformation by transfection with the v-abl oncogene.

Animals↗
PubMed1991

Genetic epidemiology of childhood brain tumors.

The study goal was to determine the genetic (heritable) contribution to childhood brain tumors (CBT) which cause nearly one quarter of all childhood cancer deaths. Their etiology remains unknown, but previous studies have suggested a proportion of CBT may be heritable. In this study we collected family histories of 243 confirmed CBT patients referred to The University of Texas M. D. Anderson Cancer Center between the years 1944 and 1983, diagnosed before age 15, and residents of the United States or Canada. Family histories were obtained for all the probands' first degree relatives (parents, siblings, and offspring) and extended to include selected second degree relatives (aunts, uncles, grandparents) using sequential sampling. To determine if these CBT families exhibited excess cancer, we compared their cancer experience to age-, race-, sex-, and calendar-year specific rates from the Connecticut Tumor Registry. No cancer excess was observed among 1,099 first and second degree relatives [39 cancers observed (O) and 44 expected (E) for a standardized incidence ratio (SIR) of 0.88]. For colon cancer, although small numbers, five cases were observed among the probands' first degree relatives with 1.6 expected, for a significant SIR of 3.10. Segregation analysis demonstrated that chance alone could not account for the observed cancer distribution with a multifactorial model providing the best overall explanation of the data. Overall, heredity played a role in the etiology of CBT in 4% of the study families: four (1.7%) due to known hereditary syndromes (nevoid basal cell carcinoma syndrome and von Recklinghausens neurofibromatosis--NF-1), four (1.7%) with multifactorial inheritance, and two additional families with cancers aggregating similar to the clinical criteria described for the Li-Fraumeni cancer family syndrome.

Adolescent↗
PubMed1989

A review of astrocytoma in childhood.

Between 1954 and 1984, 282 children with astrocytoma were included in the Manchester Children's Tumour Registry (MCTR), giving an overall incidence of 9.3 per million person-years. There were 110 children with adult astrocytoma and 172 children with juvenile astrocytoma. The five-year survival for adult astrocytoma was 15% and 75% for juvenile astrocytoma. There were no significant improvements in survival with time. There were 21 children with neurofibromatosis (NF) and 4 children had tuberous sclerosis. Some children had other recognized syndromes and others had major or minor abnormalities. Nine children had second tumors, mainly associated with NF, and seven siblings had malignant tumors. A number of mothers of these children were found to have breast cancer. Some of these families may represent examples of the Li-Fraumeni cancer family syndrome. We conclude that astrocytomas is an important problem in childhood and that a proportion of cases may have a genetic origin.

Adolescent↗
PubMed1995

Absence of significant germ line p53 mutations in ovarian cancer patients.

Germ line mutations of the p53 gene have been described in the Li-Fraumeni Cancer Family Syndrome and occur in patients with multifocal gliomas, particularly those with a history of a metachronous cancer or a family history of cancer. p53 dysfunction is often associated with ovarian cancer. Patients with ovarian carcinoma frequently develop synchronous or metachronous cancers and may have a family history of this or related cancers. Thus, we hypothesized that germ line p53 mutations might be associated with a significant proportion of ovarian cancers. Germ line DNA isolated from peripheral leukocytes of 73 patients with ovarian carcinoma was screened for p53 sequence abnormalities utilizing single-strand conformation polymorphism analysis and direct PCR sequencing techniques. As many as 40% of this cohort of ovarian cancer patients from 67 families may represent familial phenotypes. Synchronous and metachronous cancers occurred in 19% of the cohort. Only two intron-based polymorphisms were found. Neither has been previously reported. One of these, in intron 6, occurred in three unrelated patients all of whom had a history of metachronous breast cancer. A polymorphism in intron 10 occurred in a patient with synchronous endometrial cancer. No classic germ line mutations of p53 were found.

Base Sequence↗
PubMed1991

Cancer risk in second degree relatives of children with soft tissue sarcoma.

The risk of cancer in the second degree relatives of a population-based series of children with soft tissue sarcoma was studied in relation to (i) various characteristics in these relatives, (ii) certain clinical features in the index children previously identified as risk factors for cancer in their first degree relatives. Overall there was a non-significant deficit of cancers in the second degree relatives (RR = 0.88) and cancer risk was unrelated to type or site of cancer, type of relative, or to risk factors in the index case. The findings indicate that although the families investigated may include a proportion with the Li-Fraumeni cancer family syndrome, the increased cancer risk already reported in the first degree relatives does not extent to second degree relatives in general.

Adolescent↗
PubMed1992

A significant proportion of patients with osteosarcoma may belong to Li-Fraumeni cancer families.

We studied the pedigrees of 17 index patients with osteosarcoma, recording malignant disease and cause of death for first- and second-degree relatives. There were seven cancers and five cancer deaths per 2151.5 person-years in first-degree relatives of osteosarcoma patients under the age of 50 years, a significantly greater incidence than in an age- and sex-matched population group (p < 0.001). This excess of malignancy was largely due to two families which fulfilled the criteria for the Li-Fraumeni cancer family syndrome. Both of these families were shown to have the genetic alterations in the p53 gene which have been implicated in this syndrome. Our study suggests that orthopaedic surgeons seeing new cases of osteosarcoma should arrange screening for familial malignancy.

Adolescent↗
PubMed1992

Abnormal expression of wild type p53 protein in normal cells of a cancer family patient.

Mutations in the p53 gene are the commonest specific genetic change in human cancer. In normal tissues, p53 protein is present in such low quantities that it is not readily detectable by immunochemical techniques. However, in many tumour cells large amounts of p53 protein accumulate and can be seen by simple immunohistochemical staining; this is generally attributed to the accumulation of stabilised, mutant protein. We have found a mother and daughter, who both have a history of breast cancer, who show strong immunohistochemical staining of p53 in most of their normal epithelial and mesenchymal cells. Their family has a history of multiple cancers developing at an early age. Detailed protein analysis and gene sequencing of material obtained from cultured cells, grown from a skin biopsy taken from the daughter, suggest that her cells contained large quantities of normal (unmutated) p53. We suggest that this phenotype defines a new inherited cancer susceptibility syndrome that is distinct from the germ-line mutations in p53 found in some Li-Fraumeni families. This new syndrome affects p53 tumour suppressor function through an indirect mechanism that stabilises normal p53. It remains to be established whether this mechanism also contributes to the accumulation of p53 in sporadic cancers.

Adult↗