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PubMed2000

[Genetic diagnosis and construction of its system--importance of the individual characteristics of cancer].

Genetic diagnosis is necessary to correct mistaken cancer therapy. Today, the human genome project is rapidly progressing, and genetic diagnosis is also growing more diversely. To make genetic diagnosis truly useful in the treatment of cancer patients, we need to establish a new system which gives real benefit to the patient. One way to make such a system is based on the idea of focusing on the proper characteristics of individual cancers. In addition, we should never forget that the surgically resected tissue reflects the spirit and life of the patient.

DNA↗
PubMed1980

Genetic counseling, familial breast cancer, and the surgeon's responsibility.

Approximately 20 percent of 75 consecutive breast cancer patients evaluated in our oncology clinic have shown evidence of familial breast cancer. This determination was made on the basis of association with at least two or more affected first-degree relatives. On a national basis, this would project to about 21,000 patients (and their families) for the year 1979. Seven of these patients, whose families are in various stages of completion of detailed cancer genetic evaluations, have been selected to illustrate the logic utilized for genetic counseling and management. Cardinal aspects of familial breast cancer, including its early age of onset, excess of bilaterality, vertical transmission, and occasional familial association with other varieties of cancer, have been emphasized to depict pragmatic utility for its identification. A hypothetical pedigree, based on extensive clinical experience with familial breast cancer, has been constructed to aid the physician in determining which patients have familial cancer tendencies so that he can then integrate this information for employment of strategy in genetic counseling and management. The surgeon must be cognizant of the several crucial characteristics of familial breast cancer. When one or more of these features are present in his patient or family or both, appropriate genetic counseling and management should be provided. Therefore, the surgeon must extent his sphere of responsibility to his patient's high-risk relatives.

Breast Neoplasms↗
PubMed2004

A randomised comparison of UK genetic risk counselling services for familial cancer: psychosocial outcomes.

The aim of the study was to compare psychosocial outcomes for 50 new clinic attendees, referred for cancer genetic counselling to five UK centres. The centres represented England, Scotland and Wales, and were randomly selected from groups ranked by different levels of clinical activity in cancer genetics practice. Questionnaires assessed demographic data, risk perception, mental health and use of health services pre-consultation and at 1 and 12 months follow-up. Satisfaction was measured for attendees and referring doctors at follow-up. A total of 256 unaffected adults fulfilled the study criteria. The five centres varied widely with respect to service organisation and activity, but all had a greater proportion of unaffected attendees with a breast cancer risk (61-91%) than either a bowel cancer risk (0-33%) or ovarian cancer risk (3-25%). There were no significant differences in the psychosocial data between centres pre-counselling. No significant change over time occurred for any of the centres for risk perception or general psychological distress. There were significant differences between centres in reduction of cancer worry from baseline to 12 months and with the number of women who were recommended to have mammographic surveillance who had not received this. Overall, one-third of women for whom mammography had been recommended had not been screened within 1 year of follow-up. Subsequent attendance at the GP, but not at a hospital, was associated with risk level, but differences between centres could not be analysed. Satisfaction differed significantly between centres for 4 : 14 aspects of service provision and with 3 : 17 items concerning communication; satisfaction was high overall. Over 90% of referring doctors were moderately/very satisfied with the service, but 23% were dissatisfied with waiting times and 19% with access to preventive treatment. Results differed significantly between centres for doctor's satisfaction with the provision of referral criteria and prescribing information. In conclusion, there were relatively few significant differences in psychosocial outcomes between centres, considering the wide variation in service organisation and activity. These significant differences were not consistent across the centres, therefore, differences could not be linked to specific aspects of service provision.

Adult↗
PubMed2006

Radiotherapy and genetic predisposition to breast cancer.

Cancer genetics is becoming increasingly integrated into oncological care; particularly in breast cancer management. The recognition of monogenic breast cancer predisposition syndromes, such as BRCA, is critical as there is also a risk of other cancers in addition to a markedly elevated risk of contralateral breast cancer. In individuals with breast cancer due to some predisposition genes, radiation should be avoided, e.g. the ATM and TP53 genes, but there is still controversy as to whether radiation should be used in BRCA1/2 mutation carriers and more follow-up is needed. There are some radiation-sensitive genetic conditions where, if breast cancer occurs (as it may occur in any individual, not necessarily due to an increased risk associated with the condition), radiation should be avoided. These conditions are often associated with dysmorphic features. If such features are noticed then the advice of a geneticist should be sought urgently prior to giving radiation.

Breast Neoplasms↗
PubMed1998

MLH1 and MSH2 constitutional mutations in colorectal cancer families not meeting the standard criteria for hereditary nonpolyposis colorectal cancer.

Genetic diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) may have a significant impact on the clinical management of patients and their at-risk relatives. At present, clinical criteria represent the simplest and most useful method for the identification of HNPCC families and for the selection of candidates for genetic testing. However, reports of mismatch repair (MMR) gene mutations in families not fulfilling the minimal diagnostic criteria point out the necessity to identify additional clinical parameters suggestive of genetic predisposition to colorectal cancer (CRC) related to MMR defects. We thus investigated a series of 32 Italian putative HNPCC individuals selected on the basis of one of the following criteria: 1) family history of CRC and/or other extracolonic tumors; 2) early-onset CRC; and 3) presence of multiple primary malignancies in the same individual. These patients were investigated for the presence of MLH1 and MSH2 mutations by single-strand conformation polymorphism analysis. Pathogenetic truncating mutations were identified in 4 (12.5%) cases, 3 of them involving MSH2 and 1 MLH1. In addition, 2 missense MLH1 variants of uncertain significance were observed. All pathogenetic mutations were associated with early age (<40 years) at onset and proximal CRC location. Our results support the contention that constitutional MMR mutations can also occur in individuals without the classical HNPCC pattern. Moreover, evaluation of the clinical parameters associated with MMR mutations indicates that early onset combined with CRC location in the proximal colon can be definitely considered suggestive of MMR-related hereditary CRC and should be included among the guidelines for referring patients for genetic testing.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Progressive genetic aberrations detected by comparative genomic hybridization in squamous cell cervical cancer.

Genetic changes orchestrated by human papillomaviruses are the most important known factors in carcinogenesis of the uterine cervix. However, it is clear that additional genetic events are necessary for tumour progression. We have used comparative genomic hybridization to document non-random chromosomal gains and losses within a subset of 37 cervical carcinomas matched for clinical stage Ib, but with different lymph node status. There were significantly more chromosomal changes in the primary tumours when the lymph nodes were positive for metastases. The most frequent copy number alterations were loss of 3p, 11q, 6q and 10q and gain of 3q. The smallest areas of loss and gain on chromosome 3 were 3p14-22 and 3q24-26. The study identifies progressive DNA copy number changes associated with early-stage invasive cervical cancers with and without lymph node metastases, a factor of potential prognostic and therapeutic value.

Adult↗
PubMed1996

Some public health issues in the current state of genetic testing for breast cancer in Australia.

Two genes associated with a high breast cancer risk (BRCA1 and BRCA2) have been discovered recently from study of large breast-cancer-dense kindreds. It is problematic to make inferences from these atypical families to the general population. Nevertheless, it appears that about 1 to 2 per cent of all breast cancer may be due to rare deleterious mutations in BRCA1 or BRCA2. The majority of breast cancer families with fewer than four cases are likely to have cancers not attributable to these genes. There may be more common mutations in other genes (such as ATM, HRAS1) that confer a moderate risk of breast cancer, and may account for 5 to 15 per cent of cases. At this early stage of cancer genetics, the risks associated with particular mutations are not known, there are no proven and acceptable strategies for women with an inherited susceptibility to ameliorate risk or improve prognosis, and risk estimates appropriate for Australian women with a family history of breast cancer are not established, although data from the United States may overestimate risk. Information is needed from population-based studies, such as the Australian Breast Cancer Family Study (Hopper et al. Breast 1994; 3: 79-86), but 100 per cent mutation detection in large cancer genes is difficult and expensive. Development of a systematic, research-oriented, evidence-based approach to genetic testing in Australia is recommended. Australia could lead the world in having common protocols used in breast cancer clinics across the country, linked to a national research consortium and database.

Australia↗
PubMed1998

Genetics of cancer: current knowledge and future possibilities.

For many years there has been scepticism among clinicians and cancer epidemiologists as to whether cancer was a genetic disease or could be hereditary. It is only in the last 10 years that developments in molecular biology have proven the hereditary nature of a small proportion of certain common cancers. That cancer is now indisputably 'genetic' at the cellular level is beyond dispute.

Breast Neoplasms↗
PubMed2004

Effects of energy balance on cancer in genetically altered mice.

Evidence has accumulated from laboratory-based animal experiments and population-based human epidemiological studies that lifestyle factors that affect energy balance, such as caloric intake, nutritional status, and exercise, act in concert with genetic susceptibility to influence cancer development and progression. The use of animal models with specific genetic alterations, in combination with lifestyle modifications that alter overall energy balance, has contributed to a greater understanding of the mechanistic changes occurring during carcinogenesis and to the identification of points of intervention. Studies in our laboratory focusing on the role of energy balance and genetic susceptibility in mice deficient in one (+/-) or both (-/-) alleles of the p53 tumor suppressor gene and mice with a mutant APC allele (APC(Min)) showed that calorie restriction decreases tumor burden, increases tumor latency, and decreases serum insulin-like growth factor (IGF)-1 and leptin levels. Data from our studies, combined with results from other animal and human studies, have established a role for IGF-1 in carcinogenesis. Studies using genetic models of cancer that have been interbred with mice with abnormal levels of IGF-1 will enable the examination of combined effects of energy balance and genetic alterations on the cancer process. Models that integrate lifestyle and genetic effects in a single system provide a physiologically intact system in which combination interventions and therapies for cancer prevention can be tested and validated, thus building a strong preclinical foundation that will inform the development of clinical trials and add perspective to epidemiological studies.

Alleles↗
PubMed1993

Genetic polymorphism of cytochrome P4502E1 in a Swedish population. Relationship to incidence of lung cancer.

Genetic polymorphism of CYP2E1 was investigated among 195 Swedish patients with lung cancer and 206 controls. Three different polymorphic sites were found, all in introns, using RFLP and the restriction enzymes DraI, RsaI and TaqI. The frequencies of the rare alleles were 0.08-0.18 and much lower than previously described among Japanese. No significant difference in distribution of the polymorphic alleles between controls and lung cancer patients was evident, in contrast to results of a previous Japanese study. However, examination of a polymorphic site in the 5'-flanking region, within a putative binding motif for the hepatic transcription factor HNF-1, revealed a significantly less frequent distribution of the mutated allele (c2) among the lung cancer patients as compared to controls. It is concluded that major interethnic differences exist in the genetic polymorphism of CYP2E1 and that people carrying the c2 allele might be at lower risk for developing lung cancer.

Base Sequence↗
PubMed1995

Genetics in cancer prediction, screening, and counseling: Part II, The nurse's role in genetic counseling.

PURPOSE/OBJECTIVES: To describe an expanded role for oncology nurses in genetic counseling for cancer. DATA SOURCES: Published professional articles, computerized data bases, lay publications. DATA SYNTHESIS: A description of the availability of genetic counseling, of motivation for undergoing genetic counseling, and of the basic components of genetic counseling for cancer. CONCLUSIONS: The need for genetic counseling will increase as more families with inherited cancer are identified, more cancer genes are isolated, and genetic analysis becomes more available. IMPLICATIONS FOR NURSING PRACTICE: Advances in genetic technology provide nurses with the opportunity for an expanded role in genetic counseling for cancer. Oncology nurses also can act as case finders of families with inherited cancers and conduct research in this area.

Genetic Counseling↗
PubMed2026

Integrating genetic predictors into subsequent breast cancer risk prediction in survivors of childhood cancer.

PURPOSE: Female survivors of childhood cancer are at high risk for developing breast cancer. The contributions of most general population primary breast cancer genetic predictors to this risk have not been explored. METHODS: Analyses included females who survived &#x2265;5 years after their childhood cancer diagnosis with available array (N&#x2009;=&#x2009;2096, subsequent breast cancer [SBC]=218) or whole-genome sequencing (WGS; N&#x2009;=&#x2009;3292, SBC=101) data from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. We computed 99 externally-validated primary breast cancer polygenic risk scores (PRS). Using deep-coverage WGS, ClinVar-annotated pathogenic/likely pathogenic (P/LP) variants in breast cancer susceptibility genes were identified. Cox proportional hazards models assessed associations with SBC risk, adjusting for treatments and genetic ancestry. RESULTS: Among 5388 female survivors (genetic ancestry, European: N&#x2009;=&#x2009;4,752; African: N&#x2009;=&#x2009;444; East Asian: N&#x2009;=&#x2009;192), 319 developed SBC. Most (90.9%) PRSs were nominally associated with SBC risk (P&#x2009;<&#x2009;0.05), but effect sizes varied substantially. PRSs with superior discriminatory ability had greater genome-wide coverage (e.g., 6.4 million-variant PRS, HR per SD&#x2009;=&#x2009;1.71, 95% CI&#x2009;=&#x2009;1.43 to 2.05; P&#x2009;=&#x2009;4.2x10-9) and 7.7-fold higher odds (P&#x2009;=&#x2009;7.0x10-4) of including variants in multiple DNA damage repair pathways compared with PRSs with weaker risk associations. Among survivors with WGS, 1.6% carried P/LP variants in clinical testing panel genes, which was associated with a 7.4-fold greater risk (95% CI&#x2009;=&#x2009;3.16 to 17.19). Including genetic factors improved SBC risk prediction by age 40 (P&#x2009;<&#x2009;0.001) compared to treatment exposures alone. CONCLUSIONS: Externally-validated primary breast cancer genetic susceptibility predictors are relevant for SBC risk prediction and should be prioritized for risk stratification in survivors.

Journal Article↗
PubMed2002

Current understanding of the epidemiology and clinical implications of BRCA1 and BRCA2 mutations for ovarian cancer.

Genetic testing for susceptibility to ovarian cancer is rapidly becoming integrated into the clinical practice of oncology. Genetic testing for BRCA1 and BRCA2 is now recommended to most women with invasive ovarian cancer. Approximately 10% of these women will have a positive test, including 4% of women without a family history of cancer. Currently, the treatment of hereditary ovarian cancer is the same as for non-hereditary ovarian cancer. It appears that women with ovarian cancer and a BRCA mutation experience better survival than women without a mutation, possibly due to enhanced susceptibility to chemotherapy. Strategies for prevention of ovarian cancer among carriers include oral contraceptives, tubal ligation and prophylactic oophorectomy.

Biomarkers, Tumor↗