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PubMed1989

p53: a frequent target for genetic abnormalities in lung cancer.

Allele loss is a hallmark of chromosome regions harboring recessive oncogenes. Lung cancer frequently demonstrates loss of heterozygosity on 17p. Recent evidence suggests that the p53 gene located on 17p13 has many features of such an antioncogene. The p53 gene was frequently mutated or inactivated in all types of human lung cancer. The genetic abnormalities of p53 include gross changes such as homozygous deletions and abnormally sized messenger RNAs along with a variety of point or small mutations, which map to the p53 open reading frame and change amino acid sequence in a region highly conserved between mouse and man. In addition, very low or absent expression of p53 messenger RNA in lung cancer cell lines compared to normal lung was seen. These findings, coupled with the previous demonstration of 17p allele loss in lung cancer, strongly implicate p53 as an anti-oncogene whose disruption is involved in the pathogenesis of human lung cancer.

Base Sequence↗

PubMedDate not supplied

Efficacy of risk-reducing salpingo-oophorectomy in women with BRCA-1 and BRCA-2 mutations.

Recognizing the emerging role of genetics in clinical care, in 1996 the American Society of Clinical Oncology established a Task Force on Cancer Genetics Education to develop educational opportunities and resources for its members. These efforts, and recent advances in the understanding of genetic predisposition to breast and ovarian cancers, have resulted in growing numbers of women participating in genetic testing protocols. The first prospective clinical trial involving women with known BRCA-1 and BRCA-2 mutations was recently published. In a prospective study involving 170 BRCA-1 and BRCA-2 mutation carriers and a mean follow-up of 2 years, the estimated 5-year cancer-free estimates were 96% for the 98 women choosing prophylactic bilateral salpingo-oophorectomy and 69% for the 72 women choosing intensive surveillance (p=0.006). Three cases of stage I ovarian cancers were diagnosed at the time of prophylactic surgery. These results are consistent with published literature and data from the Prevention and Observation of Surgical Endpoints (PROSE) study group, which reported a 96% reduction in ovarian cancer risk and a 53% reduction in breast cancer risk among BRCA-1 and BRCA-2 mutation carriers who had prophylactic bilateral oophorectomy compared to matched controls. Thus prophylactic bilateral salpingo-oophorectomy can be regarded as an effective risk-reducing procedure that permits early diagnosis of ovarian cancer at the time of surgery and significantly reduces the risk of breast and ovarian cancer in women with germ-line mutations in the BRCA-1 and BRCA-2 genes.

Breast Neoplasms↗

PubMed1998

Genetics of pancreatic cancer. From genes to families.

Cancer of the pancreas is a genetic disease. Sporadic cancers of the pancreas are frequently associated with the activation of an oncogene, K-ras, and the inactivation of multiple tumor suppressor genes, including p53, DPC4, p16, and BRCA2. An improved understanding of the genetics of pancreas cancer should lead to new tests to screen for this disease and novel rational gene-based therapies.

Genes, Suppressor↗

PubMed1997

[Genetic predispositions to breast cancer].

NEW DATA: Genetic epidemiology and position cloning techniques have made it possible to estimate the risk women with a family history of breast cancer have of developing a breast tumor. THREE PREDISPOSITION GENES: Three BReast CAncer genes (BRCA1, BRCA2 and BRCA3) have been localized on chromosomes 17 13 and 8. It is highly likely that other genes also have an influence. GENETIC TESTING: When an altered BRCA1 or BRCA2 gene is identified in a family, a gene test can be proposed to recognize predisposition in relatives. A negative test means the subject is not predisposed to breast cancer and that transmission to offspring is not possible. Inversely, the risk of breast cancer is high if the mutation is detected, raising the difficult problem of counselling, particularly in young subjects. PROBLEMS RELATED TO SCREENING TESTS: Screening tests can only be undertaken if the "candidate" is aware of the consequences of the screening results and has had enough time to make a fully informed decision. Confidentiality must be particularly strict, particularly in the field of employment and insurance.

Breast Neoplasms↗

PubMed2006

Genetic Susceptibility to Prostate Cancer: Prostate-specific Antigen and its Interaction with the Androgen Receptor (United States).

OBJECTIVE: To determine whether directly observed prostate-specific antigen (PSA) promoter diploid haplotype, either alone or in conjunction with androgen receptor (AR) genotype, is associated with prostate cancer risk. METHODS: We conducted a case-control study nested within the US population-based Cardiovascular Health Study cohort. Incident prostate cancers were identified by linkage to cancer registry records for the years 1989-2000. We genotyped 193 cases and 391 controls for the PSA -252 G/A and -158 G/A SNPs and the AR CAG microsatellite, and developed methods to directly determine proximal PSA promoter haplotypes. Exact logistic regression was used to estimate odds ratios and significance levels. RESULTS: No significant associations were observed between PSA diplotype and prostate cancer overall. Short (< 20) AR CAG repeat lengths were associated with modest increases in the risk of prostate cancer (OR, 1.46; 95% CI, 0.97-2.19; p = 0.071) that were significant for advanced disease (OR, 1.82; 95% CI, 1.02-3.26; p = 0.044). Men who possessed two copies of the PSA*2 (-252G/-158G) haplotype and short AR CAG repeat lengths had a 4-fold (95% CI, 1.05-20.75; exact p = 0.040) increased risk of prostate cancer, and a 7-fold (95% CI, 1.25-39.78; exact p = 0.026) increased risk of advanced disease. CONCLUSIONS: We found evidence that the PSA*2*2 diplotype in combination with short AR CAG alleles increases a man's risk of developing prostate cancer. These findings support an etiologic role in prostate cancer of genetic interactions between polymorphisms that increase AR transactivation strength and those that alter the regulatory regions of target genes such as PSA that are responsive to androgen stimulation.

Aged↗

PubMed1990

A physical map around the retinoblastoma gene.

The gene predisposing to retinoblastoma, RB1, has been mapped to 13q14 and a cDNA clone has been isolated. Alterations of this chromosomal region are found not only in retinoblastoma, but in other tumor types including bone and soft tissue sarcomas, gastric tumors, small cell lung cancer, hematologic malignancies, rhabdomyosarcoma, and breast cancer. Genetic alterations implicating RB1 in some of these cancers have been observed. A long-range, overlapping restriction map around RB1 has been derived to provide a basis for study of rearrangements in tumors. Putative CpG islands closely linked to RB1 were identified, the effect of methylation was investigated, and RB1 transcriptional direction was determined. Using data in the literature, the map was oriented with respect to the centromere and it was determined that the distance between esterase D, a nearby gene, and RB1 was greater than 200 kb.

Carboxylesterase↗

PubMed2001

[Genetic diagnosis of cancers? Which cancers should be screened?].

Our knowledge in the genetic basis of hereditary human cancer has improved over the last 10 years. Molecular diagnoses have become feasible in major hereditary cancer-prone syndromes, as well as in other hereditary diseases in which cancer appears as symptoms or complications. The major cancer-prone syndromes are described here with a table summarizing the links between various cancer types and the genetic syndromes to which they could belong. Clinicians should be aware of these new diagnostic tools. Specific consultations in oncogenetics are being settled to help clinicians and patients in the course of establishing molecular diagnoses, and providing guidelines for a better surveillance of high-risk persons.

Genetic Predisposition to Disease↗

PubMed2002

When is molecular genetic testing for colorectal cancer indicated?

The genetic mutations causing many of the syndromes which confer a high inherited risk of colorectal cancer have now been identified. These include familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, Peutz-Jeghers syndrome, Cowden's syndrome and juvenile polyposis. In all these diseases, the precise mutation is nearly always unique to a particular family; there are few mutation hot spots. This means that mutation detection is technically demanding. Nonetheless, genetic testing can now be used clinically to confirm the diagnosis in affected individuals, and to predict whether an "at risk" family member has inherited the disease and should therefore have endoscopic screening. Because current technology does not detect all mutations, a negative result in a definitely affected individual is diagnostically unhelpful and does not allow predictive testing of other family members. When a mutation can be detected, it is diagnostically very useful, and allows better management of all family members.

Adenomatous Polyposis Coli↗

PubMed1998

Genetics of colorectal cancer.

Recent years have brought great advances in the understanding of the pathogenesis of colorectal cancers. The elucidation of the underlying genetic alterations that produce these cancers has made it possible to broadly categorize this disease into two major types, hereditary and sporadic. The hereditary cancers have been divided further into recognized syndromes, mainly familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. These syndromes have unique clinical pictures and different prognoses in addition to their different genetic bases. Sporadic cancers have been found to have analogous genetic alterations which propel them along the progression from normal tissue to benign adenoma/dysplasia to malignancy. These advances in genetics can potentially lead to clinically useful advances in detection, treatment, and, ultimately, prevention of colorectal cancer.

Adenoma↗

PubMed1991

The genetic basis of cancer.

Cancer is essentially a genetic disease resulting from congenital or acquired alterations in some cells of the patient. Such changes may occur in particular oncogenes and are responsible for the tumour phenotype of the affected population of cells. Oncogenes function by continuous positive action in the mitogenic pathway, and may become activated by point mutations, chromosomal rearrangements, gene amplification or viral insertion events. In contrast, unaltered tumour-suppressor genes are responsible for suppressing the neoplastic phenotype, and their inactivation by deletion or mutation permits cancerous development in the affected cells. The genetic model of carcinogenesis is thus based on the idea that mutations at the DNA level create a functional imbalance between the oncogenes and the tumour-suppressor genes, resulting in uncontrolled clonal proliferation. It is likely that the clinical importance of these recent findings will soon be realised and utilised in the development of therapies and diagnostic procedures that will directly benefit the patient.

Colorectal Neoplasms↗

PubMed1989

Multiple genetic alterations in distal and proximal colorectal cancer.

Multiple genetic alterations were investigated in colorectal cancer, including changes in DNA content, mutations in ras oncogenes, and deletions involving chromosomes 5, 17, and 18. A non-random association of deletions and mitotic abnormalities by site was seen, with both types of alterations occurring significantly more frequently in distal tumours. In contrast, the frequency of c-Ki-ras mutations did not differ between proximal and distal cancers. In addition, deletions were significantly associated with each other and with change in DNA content. The data provide strong support for the hypothesis that proximal and distal colon carcinoma might differ in the genetic mechanisms in their initiation and/or progression.

Adenocarcinoma↗

PubMed2005

Molecular epidemiology of non-small cell lung cancer.

Although smoking is the primary risk factor for most lung cancers, genetic predisposition may play an important role. Familial aggregation studies suggest a greater genetic component in the risk for younger individuals developing lung cancer, for lifetime nonsmokers, and possibly for women. Low-penetrance, high-prevalence polymorphic genes may explain part of this genetic predisposition. Functional polymorphisms of xenobiotic metabolism may alter the total exposure of tobacco carcinogens in the host. Subtle alterations in the DNA repair, inflammatory, and cell cycle pathways may also alter lung cancer susceptibility. The role of individual polymorphisms has been evaluated for several genes including the CYP and glutathione s-transferase superfamilies, and the NAT genes; DNA repair genes such as XPD (nucleotide excision pathway), XRCC1 (base excision pathway), and MGMT; and tumor suppressor or cell cycle genes such as p53. Molecular epidemiological studies are now focused on building larger databases from existing smaller studies and developing strategies to simultaneously evaluate multiple polymorphisms and genes within the same pathway.

Carcinoma, Non-Small-Cell Lung↗

PubMed2000

[Not Available].

Along with the detection of several genetic mutations that are associated with increased susceptibility for hereditary cancer syndromes, e. g. hereditary breast/ovarian and colorectal cancer, genetic tests are available for members of families at risk. Until now, the benefit in terms of prevention still needs to be confirmed. Furthermore, a variety of legal, ethical and psychosocial risks has to be considered, unless predictive genetic testing results in additional härm for individuals and families. Guidelines including Standards for genetic analyses and comprehensive counseling have been established worldwide aiming at the prevention of negative consequences for persons at risk. The knowledge collected in Psychooncology is applicable to the field of genetic counseling. During the pre-test-phase counseling aims at supporting the process of decision-making, both in individuals and in families. After disclosure of test results psychosocial support aims to enhance adjustment and communication within families. A small subgroup at risk for increased psychosocial distress warrants additional support. Efforts in research are needed to evaluate psychosocial issues during the process of decision-making and outcome, with adequate length of follow-up. Risk factors indicating poor psychosocial outcome need to be identified in order to develop appropriate ways of support.

Cancer↗

PubMed1990

Lessons from the genetics of colon cancer.

Remarkable advances in the understanding of specific inherited and acquired genetic events that are important in colonic carcinogenesis have occurred in the last several years. Studies of the population genetics of colon cancer have determined that the gene responsible for familial adenomatous polyposis (FAP), and Gardner's syndrome has been localized on the long arm of chromosome 5 and have more clearly defined the importance of genetic influences in 'sporadic' colon cancer. Studies of the molecular genetics of colon cancer have identified acquired alterations in oncogenes such as the K-ras gene and in putative tumor suppressor genes such as the FAP gene on chromosome 5, the p53 gene on chromosome 17, and the DCC gene on chromosome 18, which appear to mediate important steps in the adenoma-dysplasia-carcinoma sequence. Some of these research advances (FAP gene carriage) are already being used clinically to identify individuals at risk for colon cancer, and they offer great promise for the future of both prevention and therapeutic programs.

Adenomatous Polyposis Coli↗

PubMed1999

Risk communication in genetic testing for cancer susceptibility.

Risk communication is an integral part of genetic counseling and testing for cancer susceptibility. This paper reviews the emerging literature on this topic. Three relevant aspects of risk communication are addressed: communication of individual risk, communication of the risks inherent in genetic testing, and family communications related to risk. These studies suggest that (a) most individuals with some family history of cancer, including those at low to moderate risk, overestimate their personal cancer risk; (b) awareness of the risks of genetic testing is limited; (c) decision making about genetic testing is influenced strongly by exaggerated perceptions of personal cancer risk and less so by perceptions of the risks of genetic testing; (d) perceptions of personal risk of cancer are resistant to standard education and counseling approaches; (e) psychologic distress and coping processes influence the processing of risk information and subsequent decision making in genetic testing; and (f) family influences play an important role in risk awareness, genetic testing decisions, and outcomes. To study these issues further, new theoretical models and measures of risk perceptions need to be developed. Both observational and experimental methods should be used to examine both the content and process of risk communication in cancer genetic counseling and testing. Emotional, familial, and sociocultural influences on the risk communication process require special attention.

Communication↗

PubMed2003

[The role of molecular genetics in childhood cancer].

In the last few years molecular genetic studies of childhood cancer have acquired great importance. Advances in these techniques have increased knowledge of the various genes involved in tumoral development. Genetic alterations can occur in three large groups of genes: oncogenes, tumor suppressor genes, and DNA repair genes. Cytogenetic analyses (karyotyping) are complemented by various molecular techniques, such as fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR) and spectral karyotyping (SKY). These are the most reliable techniques and improve the sensitivity of karyotyping. The present article reviews the most representative and best characterized genes involved in the molecular etiology of childhood cancer, both hematologic malignancies (leukemia and lymphoma) and solid tumors (brain tumors, neuroblastoma, Wilms' tumor, hepatoblastoma, rhabdomyosarcoma, Ewing's sarcoma and retinoblastoma). Molecular techniques have enabled more precise diagnosis as well as identification of new prognostic factors and the development of more effective treatments. These techniques can also be useful in identifying minimal residual disease during and after treatment for leukemias, neuroblastomas and sarcomas, with the aim of predicting recurrence.

Child↗

PubMed2005

The use of preventive measures among healthy women who carry a BRCA1 or BRCA2 mutation.

PURPOSE: The purpose of this study was to assess women's knowledge about tamoxifen, to examine the frequency of tamoxifen usage and other preventive measures in BRCA1/2 mutation carriers, and to document women's concerns about taking tamoxifen for chemoprevention. METHODS: One hundred and twenty five women with known BRCA1 or BRCA2 mutation and with no prior diagnosis of breast or ovarian cancer were identified through the records of two large cancer genetics clinics. These women had been counseled about their cancer risk and various preventive options were discussed. At a time from two to 110 months following disclosure session, a questionnaire was sent by mail. Women were asked about their current and past use of tamoxifen, their knowledge of risks and benefits, their desire for additional information, and their experience with other preventive measures. RESULTS: Eighty-one of 125 eligible women returned the questionnaire (64.8%). Ten women (12.3%) had used tamoxifen and eight women had used raloxifene (9.9%). Twenty-two women (27.2%) had undergone prophylactic mastectomy and 54 women (66.7%) had had an oophorectomy. Twelve women (14.8%) did not recall discussing tamoxifen. Thirty-five women (58.3%) said that their doctors had not provided them with sufficient information about tamoxifen to consider its use. Fear of side-effects was the most common reason for not taking tamoxifen. CONCLUSION: Although tamoxifen appears to be effective in preventing breast cancer in women with a BRCA1 or BRCA2 mutation, few women now take the drug compared to those who choose other preventive measures including surgery. Health care providers should provide accurate information about the risks and benefits of tamoxifen to allow women to make informed decisions.

Adult↗

PubMed1994

Towards cloning the familial breast-ovarian cancer gene on chromosome 17.

The past year has seen a great deal of excitement in the field of breast cancer genetics. Since linkage of the familial breast-ovarian cancer gene (BRCA1) to chromosome 17, the critical region has been narrowed to 1.0-1.5 Mb by recombination studies, a detailed physical map has been constructed and much of the region has been cloned in yeast artificial chromosome, bacteriophage P1 and cosmid vectors. The focus now lies on identifying the genes housed within the BRCA1 region and scanning them for oncogenic mutations.

Breast Neoplasms↗