Prenatal substance use in a Western urban community.

To assess the extent of prenatal substance use in a predominantly white population in an urban area of the western United States and to develop a risk profile for this population, a cross-sectional prevalence study was done. Prenatal clinics (10 public and 10 private) anonymously recorded demographic information about and collected aliquots of routinely obtained urine specimens from women during prenatal visits. Urine specimens were screened by enzyme immunoassay for amphetamines, marijuana, cocaine, opiates, and ethanol. Of the 935 women screened, 92 (9.8%) had urine specimens positive for one or more of these substances. Urine screens were positive in 56 (10.0%) of 562 women attending private clinics and 36 (9.6%) of 373 women attending public clinics. Only 7 of the 935 women (0.7%) had screens positive for cocaine. Ethanol was the most frequently detected substance in the private clinic group (6.4%), whereas marijuana was most common among women attending public clinics (5.1%). Although substance use in this group of pregnant women occurs at a lower rate and a different pattern from those found in other more densely populated areas, the rate is high enough to be of concern to all prenatal care professionals, who should incorporate substance use history taking and selective urine drug screening into their routine prenatal practices.     

Screening and genetic counselling for relatives of patients with colorectal cancer in a family cancer clinic.

OBJECTIVE--To introduce and monitor a screening programme for first degree relatives of patients with colorectal cancer based on their calculated lifetime risk. DESIGN--Lifetime risks were calculated for first degree relatives of patients with colorectal cancer and used to offer screening based on estimated risk. SETTING--A family cancer clinic was set up as part of the North East Thames Regional Genetic Service for relatives of patients who had developed colorectal cancer before the age of 45 and members of families in which multiple cancer had occurred. PATIENTS--Self referrals as well as patients referred by general and hospital practitioners. INTERVENTION--Relatives with a lifetime risk of 1 in 10 or greater (high risk group) were offered screening five yearly by colonoscopy, and those whose risk was between 1 in 10 and 1 in 17 were offered yearly screening for faecal occult blood. Women with family histories compatible with Lynch type II cancer family syndrome were offered screening for breast and pelvic tumours. RESULTS--In four years 715 patients were seen. Acceptance of screening was 90% (644 patients). Of 151 patients screened for faecal occult blood, two were found to have polyps. This screening test was unsatisfactory for the high risk group, having a negative predictive value of 78% in 59 patients tested. Regular screening by colonoscopy was offered to 382 high risk patients; 62 patients with polyps and five with colonic cancer were found. One hundred and ten pedigrees were identified with the Lynch type II cancer family syndrome, and four of 35 women screened were found to have breast cancer. Of 14 relatives aged over 65 with a 1 in 2 risk of site specific colonic cancer or Lynch type II cancer family syndrome, seven were found to have polyps, one of whom had carcinoma in situ. CONCLUSIONS--Family history can be used to identify those at risk of colonic cancer and to target appropriate screening. Colonoscopy detected a high number of premalignant colonic polyps, but faecal occult blood testing was unsatisfactory for those at high risk of colorectal cancer.     

Analysis of 5382insC (BRCA1) and 6174delT (BRCA2) mutations in 382 healthy Chilean women with a family history of breast cancer

Breast cancer is the most common malignancy among women. Chilean studies reveal that this cancer presents the third highest mortality rate. A family history of breast cancer is one of the major risk factors for the development of this disease. BRCA1 and BRCA2 are the two main hereditary breast cancer susceptibility genes, and mutations in these genes are related to inherited breast cancer. In specific populations only some mutations have been found to be associated with susceptibility. The purpose of this study was to establish the frequency of 5382insC (BRCA1) and 6174delT (BRCA2) germline mutations in 382 healthy Chilean women with at least two relatives affected with breast cancer and in probands and their relatives from 8 high risk families for breast cancer, using mismatch PCR assay. The results obtained showed that 5382insC and 6174delT mutations were not found in either of the groups studied. The ethnic origin of the contemporary Chilean population and the data reported in the literature suggest that these mutations may be absent or have a very low frequency in this population.. This genetic study is part of a breast cancer screening program that also includes annual mammography and clinical breast examination over a five-year period. Strategies to reduce morbidity and mortality associated with breast cancer lie in early detection in women with genetic risk.     

Colorectal cancer cases and relatives of cases indicate similar willingness to receive and disclose genetic information

Context: Recent developments in genetic testing allow us to detect individuals with inherited susceptibility to some cancers. Genetic testing to identify carriers of cancer-related mutations may help lower risk by encouraging preventive behaviors and surveillance. This study assessed willingness of colon cancer cases and relatives to receive genetic information that may indicate an increased risk for cancer, to whom they would disclose genetic information, and whether receiving genetic test results may influence future prevention behaviors among individuals enrolled in the Seattle Colorectal Cancer Family Registry. Methods: Incident invasive colorectal cancer cases were identified from the Puget Sound Surveillance Epidemiology and End Results (SEER) registry. In 2007, a sequential sample of cases and relatives (n = 147) were asked to respond to a questionnaire addressing study aims. The questionnaire was administered during a baseline or 5-year follow-up interview. Results: Patterns of response to each statement were similar between colorectal cancer cases and relatives. Both colorectal cases (95%) and relatives (95%) reported willingness to receive genetic information. Nearly all participants would tell their doctor the results of a genetic test (99% of cases; 98% of relatives), and all married participants would tell their spouses. Cases (96%) anticipated being slightly more likely than relatives (90%) to change their cancer screening behavior, but this difference was not statistically significant (p = 0.33). Conclusions: A high percentage of both colorectal cancer cases and relatives sampled from the Seattle Colorectal Cancer Family Registry are interested in identifying their genetic status, discussing their genetic status with their family and doctor, and adopting behavioral changes that may reduce cancer risk.     

Active cascade testing for carriers of cystic fibrosis gene.

OBJECTIVE--To examine the acceptability, practicability, efficiency, and application of active screening for carriers of the cystic fibrosis gene in the extended families of those in whom the disease is present (Cascade screening). DESIGN--Paediatricians and physicians provide details of their affected patients, pedigrees are drawn up, and relatives offered tests after initial contact by the affected nuclear families. Affected patients are genotyped in a laboratory with a special interest in the genetics of cystic fibrosis. SETTING--North Western health region. SUBJECTS--Relatives and partners of 607 people with cystic fibrosis. INTERVENTIONS--Genetic counselling by letter for people found to be carriers; formal genetic counselling and when indicated arrangements for prenatal diagnosis for couples discovered to be carriers. MAIN OUTCOME MEASURES--Number of carrier couples detected; action in pregnancy of detected carrier couples; extent of the uptake of screening by relatives. RESULTS--Of 1563 relatives or partners tested, 15 carrier couples were detected; of nine pregnancies undertaken by these 15, eight had prenatal tests and three terminated pregnancies. An average of 16 people per family have come forward for testing so far. CONCLUSIONS--Cascade screening for carriers of cystic fibrosis is well accepted by relatives, especially on the mother''s side of the family; it is 10 times more efficient in detecting carrier couples than unfocused screening. Detected carrier couples make practical use of the information in pregnancy. Active cascade screening for carriers is effective in cystic fibrosis and widespread application is recommended. These principles could be applied to other recessive disorders.     

Cost effectiveness of antenatal screening for cystic fibrosis.

OBJECTIVE--To estimate the cost effectiveness of different antenatal screening programmes for cystic fibrosis. SETTING--Antenatal clinics and general practices in the United Kingdom. DESIGN--Four components of the screening process were identified: information giving, DNA testing, genetic counselling, and prenatal diagnosis. The component costs were derived from the literature and from a pilot screening study in Yorkshire. The cost of a given screening programme was then obtained by summing the components according to the specific screening strategy adopted (sequential and couple), the proportion of carriers detected by the DNA test, and the uptake of screening. Baseline assumptions were made about the proportion with missing information on carrier status from previous pregnancies (20%), the proportion changing partners between pregnancies (20%), and the uptake of prenatal diagnosis (100%). Sensitivity analysis was performed by varying these assumptions. MAIN OUTCOME MEASURE--Cost per affected pregnancy detected. RESULTS--Under the baseline assumptions sequential screening costs between pounds 40,000 and pounds 90,000 per affected pregnancy detected, depending on the carrier detection rate and uptake. Couple screening was more expensive, ranging from pounds 46,000 to pounds 104,000. From the sensitivity analysis a 10% change in the assumed proportion with missing information from a previous pregnancy alters the cost by pounds 4000; a 10% change in the proportion with new partners has a similar effect but only for couple screening; and cost will change directly in proportion to the uptake of prenatal diagnosis. CONCLUSIONS--While economic analysis cannot determine screening policy, the paper provides the NHS with the information on cost effectiveness needed to inform decisions on the introduction of a screening service for cystic fibrosis.     

General practitioner and specialist views on colonoscopic screening of first-degree relatives of colorectal cancer patients

Introduction: Barriers to targeted colonoscopic screening of first-degree relatives of colorectal cancer patients have been the subject of considerable literature, always as seen from the patient's viewpoint. In the specific context of screening individuals with a family history, physicians may also play a predominant role in motivating their colorectal cancer patients to pass on screening information to their relatives. The aim of this study was to examine the views of general practitioners and specialists regarding barriers and facilitators affecting participation of relatives in colonoscopic screening. Methods: A qualitative study was conducted to collect and analyse information from two focus groups of 4 general practitioners and 9 gastroenterologists respectively, and from semi-structured individual interviews with 10 general practitioners, 2 surgeons and 3 oncologists. An extended focus group of 36 gastroenterologists was organized to validate the results. Results: The main barriers to colonoscopic screening of FDRs were associated with lack of direct communication between physicians and FDRs. Physicians needed support in the task of informing index patients and persuading them to transfer information on screening to their FDRs. The general practitioners spoke of their expectations in terms of training in and motivation for promoting screening and the gastroenterologists expressed the wish for patient education material specific to colonoscopy and for systematic post-colonoscopy consultations to inform patients about their results, follow-up and screening their relatives. Conclusion: The findings, notably the need for specific education materials and for training to improve the motivation of physicians, will help to develop effective interventions intended to increase participation in screening.     

Effectiveness of mass screening for endometrial cancer

OBJECTIVE: To investigate the effectiveness of mass screening for endometrial cancer using Endocyte (Laboratoire CCD, Paris, France) endometrial smears. STUDY DESIGN: The study subjects were consecutive patients with documented endometrial cancer diagnosed between January 1, 1989, and December 31, 1997, at 22 hospitals in Japan. One hundred twenty-six cases were detected by mass screening and 1,069 diagnosed in outpatient clinics. We compared the stage of cancer at diagnosis and survival rate of patients in the two groups. RESULTS: Early stage was significantly more frequent in the screening group (P < .001); stage I comprised 88.1% of the screening group as compared with 65.3% of the outpatient group. Well-differentiated adenocarcinoma was significantly more frequent in the screening group (P < .01); grade 1 constituted 74.7% of the screening group as compared with 61.0% of the outpatient group. The five-year survival rate was significantly higher in the screening group than in the outpatient group (94.0% vs. 84.3%, P = .041). The crude hazard ratio (HR) of dying of endometrial cancer for the screening group as compared to the outpatient group was .47 (95% CI .22-.99, P = .048). HR became .96 (95% CI .45-2.08, P = .925) after adjustment for age, study area and cancer stage. CONCLUSION: The results suggest that an endometrial cancer screening program would lead to early detection and improved survival among women with endometrial cancer.     

Study of the duplication of 17p11.2-12 chromosome region in the patients with hereditary motor and sensory neuropathy type 1A

Charcot-Marie-Tooth neuropathy (CMT) is one of the most common hereditary disorders, affecting 1:2500 individuals. CMT is a heterogeneous group of disorders characterized by chronic peripheral motor and sensory neuropathy. We have performed the detection of 1.5 Mb CMT1A tandem duplication in 17p11.2-12 chromosome region for autosome-dominant CMT1 patients and their relatives using the analysis of two (CA)n polymorphic microsatellite loci: 17S921 and 17S1358 localised in the duplication region. CMT1A duplication was found in three of five autosome-dominant CMT1 families. It has been shown that CMT1A duplication analysis is important for early differential diagnosis of CMT including prenatal diagnosis and genetic consulting in high risk families.     

Cystic fibrosis heterozygote screening in 5,161 pregnant women.

A screening program for cystic fibrosis (CF) heterozygotes was conducted in a large HMO prenatal population, to evaluate the level of interest among eligible patients, the effectiveness of prescreening education, attitudes toward the screening process, psychological effects, and utilization of prenatal diagnosis and its outcomes. The heterozygote identification rate and frequency of specific CFTR mutations were also assessed. Identified carriers were offered genetic counseling and testing of male partners. Prenatal diagnosis was offered if both parents were identified as carriers. A total of 5,161 women underwent carrier testing; 947 others completed survey instruments only. The acceptance rate of screening was high (78%), and pretest education by videotape was generally effective. Adverse psychological effects were not reported. Participants generally found screening to be desirable and useful. Screening identified 142 female heterozygotes, 109 couples in which the male partner was not a carrier, and 7 high-risk couples. The incidence of R117H mutations was much higher than expected. The number of identified carriers was much lower in Hispanics than in Caucasians. We conclude that large-scale prenatal screening for CF heterozygotes in the absence of a family history of CF is an acceptable method for identifying couples at risk for affected fetuses. Sufficient pretest education can be accomplished efficiently, test insensitivity is well accepted, adverse psychological events are not observed, and general patient satisfaction is high.     

Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan

The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution that genetic factors make to these high rates, we have conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from two major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7% (95% confidence interval [CI] 4.1%-9.4%), and that among case subjects with ovarian cancer was 15.8% (95% CI 9.2%-22.4%). Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. The majority of detected mutations are unique to Pakistan. Five BRCA1 mutations (2080insA, 3889delAG, 4184del4, 4284delAG, and IVS14-1A-->G) and one BRCA2 mutation (3337C-->T) were found in multiple case subjects and represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 is comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1-mutation-positive case subjects was 48% and was 37% for first-degree relatives of the BRCA2-mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio [OR] 2.1; 95% CI 1.4-3.3; P=.001). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age <40 years) (OR=2.7; 95% CI 1.5-4.9; P=.0008) and case subjects with ovarian cancer (OR=2.4; 95% CI 1.4-4.2; P=.002). These results suggest that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan.     

Application of a closely linked polymorphism of restriction fragment length to counselling and prenatal testing in families with myotonic dystrophy.

The close genetic linkage between the loci for apolipoprotein CII (ApoC2) and myotonic dystrophy makes ApoC2 the closest fully validated marker for prediction of myotonic dystrophy. Application to genetic counselling and presymptomatic and prenatal prediction is reported in seven families with myotonic dystrophy, including one case in which the disorder was excluded prenatally. Only one of the families did not have members with ApoC2 genotypes that allowed prediction, but careful clinical study of older family members was found to be an important factor. ApoC2 typing of families with myotonic dystrophy should be of practical help both in prediction for asymptomatic relatives and for prenatal diagnosis in pregnancies of an affected parent.     

中国近缘野生大麦醇溶蛋白的遗传多态性研究

随机选取来源于中国西藏24个不同行政县的181份近缘野生大科材料,其中包括47份六棱野生大麦,134份二棱野生大麦,选用青藏高原的二棱野生大麦（W2）,欧洲的代表品种Betzes大麦及以色列的二棱野生大麦（Is)作对照。利用A-PAGE（Acidic-polyacrylamide gel electrophoresis)法进行了醇溶蛋白遗传多态性的研究。结果表明,184份供试材料共得到60种不同的电泳图谱,说明西藏近缘野生大麦醇溶蛋白遗传多态性非常丰富,其中有38种图谱为单一材料所独有,以ZYM0019和ZYM1488材料为代表的2种醇溶蛋白图谱占供试材料的29.3%,在西藏分布较为普遍,聚类分析表明地理环境相似的地区有着相似的图谱类型,图谱类型与地理生态环境具有一定的相关性。讨论了中国近缘野生大麦醇溶蛋白的多态性与地理分布的关系。以及栽培大麦的起源中心等问题。     

Impact of genetic testing for breast-ovarian cancer susceptibility

Previously, we have reported a clinical trial in which any woman in a defined geographic region who had a qualifying family history and who was referred by her physician or who was identified through a regional cancer registry was offered free genetic counseling, BRCA testing, and recommendations based on test results. Each family was represented by one affected and one unaffected person. Of the 87 families actually tested, 13 were found to have deleterious mutations. To assess the impact of the counseling and testing process, we contacted the tested individuals 1 month and 1 year after receiving the test result and those with an abnormal test result after 4 years. Index subjects, we found, differed significantly from relatives. Before coming for counseling, index subjects perceived both their general health and emotional health as worse than did their relatives. After counseling and testing, index subjects continue to worry more about breast cancer than do relatives. Affected subjects, we found, differed significantly from unaffected subjects. Before counseling, affected subjects knew more about breast cancer, perceived their general health as poorer, and reported greater adherence to recommended breast cancer surveillance than did unaffected subjects. After counseling and testing, affected subjects were less satisfied than unaffected subjects with having been tested. This study indicates that the group most prone to distress by cancer risk genetic counseling and testing is not the recruited relatives, nor even those affected with cancer, but rather the index patients themselves. The index patients, i.e., the ones who want the risk information most, appear to undergo the most stress in obtaining it.     

Does genetic counseling have any impact on management of breast cancer risk?

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.     

Screening for 185delAG in the Ashkenazim.

A study was initiated to assess interest, educational effectiveness, and implications of genetic testing for the common BRCA1 mutation, 185delAG, in the Ashkenazim. Of 333 individuals who attended group sessions, 309 (92%) participated in the study. Participants were categorized as having negative family history (67%), positive family history (defined, by a relaxed criterion, as one first-degree relative or two second-degree relatives with breast [premenopausal] or ovarian cancer) (22%), positive personal history (7%), and both positive personal history and positive family history (4%). Group education was effective, as shown by the improvement in participant scores from pre- to posteducation tests. For the 289 individuals (94%) who requested testing, the major reasons included concern for their own risk, concern for the risk of their children, and desire to learn about surveillance options. The most common reason given by participants who declined testing was concern about health insurance. Six participants found to be heterozygous for the 185delAG mutation received results and were offered genetic counseling. Participants had consented for additional testing without receiving results and were screened for the 6174delT mutation in BRCA2, and seven were found to be positive. All identified carriers reported at least one first- or second-degree relative with a history of breast or ovarian cancer, although they did not all meet our study criteria for positive family history. Given these outcomes, we conclude that screening for breast and ovarian cancer susceptibility is most appropriate for individuals with a positive personal or positive family cancer history. We propose a guideline for future studies designed to identify individuals who may benefit from genetic testing for inherited breast and ovarian cancer.     

BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer

Ovarian cancer is a component of the autosomal-dominant hereditary breast-ovarian cancer syndrome and may be due to a mutation in either the BRCA1 or BRCA2 genes. Two mutations in BRCA1 (185delAG and 5382insC) and one mutation in BRCA2 (6174delT) are common in the Ashkenazi Jewish population. One of these three mutations is present in approximately 2% of the Jewish population. Each mutation is associated with an increased risk of ovarian cancer, and it is expected that a significant proportion of Jewish women with ovarian cancer will carry one of these mutations. To estimate the proportion of ovarian cancers attributable to founding mutations in BRCA1 and BRCA2 in the Jewish population and the familial cancer risks associated with each, we interviewed 213 Jewish women with ovarian cancer at 11 medical centers in North America and Israel and offered these women genetic testing for the three founder mutations. To establish the presence of nonfounder mutations in this population, we also completed the protein-truncation test on exon 11 of BRCA1 and exons 10 and 11 of BRCA2. We obtained a detailed family history on all women we studied who had cancer and on a control population of 386 Ashkenazi Jewish women without ovarian or breast cancer. A founder mutation was present in 41.3% of the women we studied. The cumulative incidence of ovarian cancer to age 75 years was found to be 6.3% for female first-degree relatives of the patients with ovarian cancer, compared with 2.0% for the female relatives of healthy controls (relative risk 3.2; 95% CI 1.5-6.8; P=.002). The relative risk to age 75 years for breast cancer among the female first-degree relatives was 2.0 (95% CI 1.4-3.0; P=.0001). Only one nonfounder mutation was identified (in this instance, in a woman of mixed ancestry), and the three founding mutations accounted for most of the observed excess risk of ovarian and breast cancer in relatives.     

Cystic fibrosis carrier population screening in the primary care setting.

To determine the receptivity of prenatal care providers and their patients to carrier testing for cystic fibrosis (CF), we offered free carrier screening, followed by genetic counseling of carriers, to all prenatal care providers in Rochester, NY, for all their female patients of reproductive age, pregnant or not. Of 124 prenatal care providers, only 37 elected to participate, but many of these offered screening only to pregnant women. The acceptance rate among pregnant women was approximately 57%. The most common reasons for accepting screening were to obtain reassurance (50.7%) and to avoid having a child with CF (27.8 %). The most common reasons for declining screening were not intending to terminate a pregnancy for CF (32.4%) and believing that the chance of having a CF child was very low (32.2%). Compared with decliners, acceptors were more likely to have no children, regarded having a child with CF as more serious, believed themselves more susceptible to having such a child, knew more about CF, would be more likely to terminate a pregnancy if the fetus were shown to have CF, and more strongly supported offering CF screening to women of reproductive age. Of 4,879 women on whom results were obtained, 124 were found to be carriers. Of these 124 carriers, the partners of 106 were tested. Of the five at-risk couples, four requested prenatal diagnosis and one requested neonatal diagnosis. No woman found to be a carrier whose partner tested negative requested prenatal diagnosis. Except for the imperfect knowledge of those testing negative, none of the adverse outcomes predicted for CF carrier testing in the general population were observed in this study.     

Screening for carriers of cystic fibrosis--a general practitioner's perspective.

The identification of the gene for cystic fibrosis has led to the possibility of population based screening for carriers of cystic fibrosis to identify couples at risk of having an affected child. Pilot studies have shown that screening is feasible and does not cause untoward anxiety, though the uptake of testing varies considerably with the setting and method of invitation. Screening offered at times when individuals (and health professionals) perceive it as directly relevant will probably gradually become established in the United Kingdom. This review examines the role of general practice in genetic carrier screening as exemplified by cystic fibrosis. General practice has a pivotal role from the beginning in providing individuals and couples with information, facilitating testing of patients'' relatives and of carriers identified by screening elsewhere (such as antenatal clinics), and offering testing in the context of reproduction. Screening for the cystic fibrosis gene will probably be followed by other genetic screening programmes.