食管癌遗传病因的研究：Ⅴ.林县食管癌高癌家族成员淋巴...

The chromosome fragile sites of cultured peripheral lymphocytes from 40 members of 4 high risk cancer families and 10 members of 4 low risk cancer families in Linxian County were analysed. The results showed that 46 fragile sites in 7045 lymphocytes expression at 502 times (7.13%) were found in high risk cancer families and 8 fragile sites in 1053 lymphocytes expression at 26 times (2.47%) were found in low risk cancer families. There was a significant difference between the two groups (P less than 0.01). In 46 fragile sites carried by 40 members of high risk cancer families, 27 were common, 5 rare, 12 provisional and 2 new fragile sites. Among them, the fragile sites at 1p22-p36 and 4q21-q31 were detected in members of high risk cancer families and in patients with esophageal cancer, meanwhile, uniform breakpoint in chromosome deletion and rearrangement was also found in 4 esophageal cancer cell lines. Therefore, the author conjectures that these fragile sites at 1p13-p36 and 4q21-q31 may be fragile site-specific for high risk cancer families and patients with esophageal cancer, and they may be breakpoint-specific for esophageal cancer cells. These fragile sites may play an important role in esophageal carcinogenesis in high risk cancer families.     

Genetic etiology of esophageal cancer--III. The spontaneous and mitomycin-C (MMC) induced sister chromatid exchanges (SCE) and chromosome aberrations in cultured lymphocytes from members of "high risk" and "low risk" esophageal cancer families in Linxian County

The spontaneous and mitomycin-c (MMC) induced sister chromatid exchanges (SCE) and chromosome aberrations in cultured lymphocytes from members of "high risk" and "low risk" esophageal cancer families in Linxian County were studied. The results showed that the frequencies of the spontaneous SCE of "high risk" and "low risk" esophageal cancer groups were 7.8 +/- 0.25 and 8.3 +/- 0.25/per cell. There were no difference between these two groups (P greater than 0.5). The frequencies of the SCE induced by MMC in "high risk" and "low risk" esophageal cancer groups were 43.8 +/- 2.4 and 21.6 +/- 1.1/per cell. There were noteworthy difference (P less than 0.001). However, the frequencies of the spontaneous and MMC induced chromosome aberrations in "high risk" cancer families were higher than those of the "low risk" ones.     

O6-methyldeoxyguanosine in DNA of the adjacent epithelium in human esophageal cancer in Linxian County

Radioimmunoassay of monoclonal antibodies against O6-methyldeoxyguanosine (O6-MedG) was used to detect the presence of these DNA adducts in the human esophageal epithelium. The analysis comprised 48 adjacent epithelial specimens of the esophageal and cardiac cancer resected in Linxian County and 30 specimens of the fetal esophageal epithelium and 4 of the normal esophageal epithelium from autopsy as collected from the hospital in Beijing. The results show that O6-MedG was detected in all the specimens from the esophageal and cardiac cancer patients. In 7 samples in the adjacent epithelium of esophageal cancer, the level of O6-MedG ranged from 0.5 to 1.0 pmol/mgDNA. 19 showed higher levels up to 37.4 pmol/mgDNA with a mean of 4.72 +/- 6.08 pmol/mgDNA. 5 samples of gastric mucosa showed the level of O6-MedG ranging 0.3-1.0 pmol/mgDNA and the remaining 6 showed a higher level of 1.2-13.4 pmol/mgDNA. The mean was 3.31 +/- 3.97. In all the 11 patients, O6-MedG was detected in the para-cancerous gastric mucosa of the cardiac cancer. 4 normal autopsied esophageal epithelial samples were too low for detection. Samples from the fetal esophageal epithelium showed lower level of O6-MedG, the mean was 0.4 +/- 0.57 pmol/mgDNA. The results mentioned above give us the new evidence that the effect of N-nitrosamines is most likely a causative factor in the carcinogenesis of human esophageal cancer.     

Comparison of nucleolar organizer regions (NORs) on chromosomes of cultured lymphocytes from cancer patients, high risk cancer family members and normal subjects

Using the technique of AG-NORs, the number of silver-stained NORs on chromosomes of the peripheral lymphocytes from 10 cancer patients, 10 high risk cancer family members and 10 normal individuals was compared. It was found that the total mean value of AG-NORs was 5.46 +/- 0.00/per cell in cancer patients, 5.62 +/- 0.01/per cell in high risk cancer family members and 7.03 +/- 0.07/per cell in normal subjects. The total mean value of AG-NORs was markedly lower in the first two groups than in the third group (P less than 0.001). It seems to be due to the decrease of the transcribed activity of rRNA gene on chromosomes of the cultured lymphocytes in the first two groups. A probable relation between the carcinogenesis and decrease of NORs is shown. The transcribed activity of rRNA gene gives the expression to AG-NORs numbers with which the relation to carcinogenesis is briefly discussed with a review of the literature.     

Nitrosamines and nitrosamine precursors in foods from Linxian, China, a high incidence area for esophageal cancer

Nitrosamines and precursor secondary amines were assayed infoods from families in four villages of the esophageal cancerhigh incidence area of Linxian, Henan Province, People's Republicof China. Amines (as tosyiamides) and nitrosamines were readilydetected at p.p.m. and p.p.b. levels, respectively, in all samples.In this small preliminary survey (25 families, four villages),however, there were no strong correlations between the levelsof the carcinogenic nitrosamines or the precursor secondaryamines with the incidence of esophageal cancer in the individualfamilies. The success of the analytical procedures suggeststhat a more extensive study is warranted.     

Mammographic density and breast cancer in women from high risk families

Introduction

Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype.

Methods

The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants’ density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (<10 %, 10-25 %, 25-50 %, 50-75 %, >75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype.

Results

We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes.

Conclusions

Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context.     

Tailoring communication in consultations with women from high risk breast cancer families

This multicentre study examined the influence of patient demographic, disease status and psychological variables on clinical geneticists/genetic counsellors (consultants) behaviours in initial consultations with women from high-risk breast cancer families. One hundred and fifty-eight women completed a pre-clinic self-report questionnaire. The consultations were audiotaped, transcribed verbatim and coded. Consultants did not vary their behaviour according to women's expectations. However, significantly more aspects of genetic testing were discussed with women who were affected with breast cancer (P<0.001), screening and management with unaffected women (P=0.01) and breast cancer prevention with younger women (P=0.01). Prophylactic mastectomy was discussed more frequently with women with medical and allied health training (P=0.02), and prophylactic oophorectomy with women affected with breast cancer (P=0.03), those in non-professional occupations (P=0.04) and with a family history of breast and ovarian cancer (P<0.001). Consultants used significantly more behaviours to facilitate understanding with women who were in non-professional occupations (P=0.04); facilitated active patient involvement more with women affected with breast cancer (P<0.001) and used more supportive and counselling behaviours with affected women (P=0.02). This study showed that patient demographics were more likely to predict consultants' communication behaviours than the woman's psychological status. Methods to facilitate assessment of psychological morbidity are needed to allow more tailored communication.     

Identification and referral of families at high risk for cancer susceptibility.

PURPOSE: Obtainment of family history and accurate assessment is essential for the identification of families at risk for hereditary cancer. Our study compared the extent to which the family cancer history in the physician medical record reflected that entered by patients directly into a touch-screen family history computer program. PATIENTS AND METHODS: The study cohort consisted of 362 patients seen at a comprehensive cancer center ambulatory clinic over a 1-year period who voluntarily used the computer program and were a mixture of new and return patients. The computer entry was assessed by genetics staff and then compared with the medical record for corroboration of family history information and appropriate physician risk assessment. RESULTS: Family history information from the medical record was available for comparison to the computer entry in 69%. It was most often completed on new patients only and not routinely updated. Of the 362 computer entries, 101 were assigned to a high-risk category. Evidence in the records confirmed 69 high-risk individuals. Documentation of physician risk assessment (ie, notation of significant family cancer history or hereditary risk) was found in only 14 of the high-risk charts. Only seven high-risk individuals (6.9%) had evidence of referral for genetic consultation. CONCLUSION: This study demonstrates the need to collect family history information on all new and established patients in order to perform adequate cancer risk assessment. The lack of identification of patients at highest risk seems to be directly correlated with insufficient data collection, risk assessment, and documentation by medical staff.     

Genetic polymorphisms of XRCC1 and risk of the esophageal cancer

A variety of environmental factors were identified to be associated with the risk of esophageal cancer. The variation in capacity of DNA repair might influence environmental chemical-associated carcinogenesis. We hypothesized that the polymorphic XRCC1 genes might modify cancer susceptibility of the esophagus. To investigate the effect of XRCC1 genetic polymorphisms on codons 194, 280 and 399, we evaluated data from 105 patients of esophageal squamous cell carcinoma and 264 healthy controls, matching with age (+/-3 years), gender and ethnicity. The distribution of the 3 genotypes were not significantly different among patients and controls. However, among alcohol drinkers, the XRCC1399 Arg/Arg genotype was more frequently found in patients with esophageal cancer. After adjustment with other environmental confounders, the OR for the genotype of XRCC1399 Arg/Arg was 2.78 (95% CI =1.15-6.67) as compared with the XRCC1(399) Arg/Gln and XRCC1(399) Gln/Gln genotypes in the alcohol drinkers. Similar trends were observed among cigarette smokers and areca chewers. However, they did not reach a statistical significance. Our findings suggest that the polymorphic XRCC1 genes might modify the risk of alcohol-associated esophageal cancers.     

Expression of cripto and amphiregulin in colon mucosa from high risk colon cancer families

We assessed the expression of the epidermal growth factor (EGF)-related peptides, cripto-I (CR-I) and amphiregulin (AR), in a small panel of human colon adenomas and carcinomas. CR-I immunoreactivity was found in 17/31 (55%) of colon adenomas, and in 33/39 (84%) colon carcinomas. AR immunostaining was observed in 16/26 adenomas (61%) and in 20/26 carcinomas (77%). CR-I and AR staining were also assessed in 29 specimens from 24 individuals that belong to families with high incidence of colorectal carcinoma, and in 5 non-high risk individuals. Expression of CR-I was detected in 18/29 (62%) of high risk colon mucosa specimens, but only in 1/5 (20%) specimens from non-high risk individuals, while AR staining was found in 20/29 (69%) and in 4/5 (80%) of colon mucosa samples from high and low risk individuals, respectively. A majority (21/29; 72%) of the specimens from the high risk individuals had a high proliferative rate, as measured by Ki-67 staining. A statistically significant correlation was found between high proliferative rate, increased expression of CR-I and reduced expression of AR in the mucosa specimens from high risk individuals, suggesting that these might represent early events in colon tumorigenesis.     

Genetic testing and first presymptomatic diagnosis in Moroccan families at high risk for breast/ovarian cancer

Germline mutations in the BRCA1 and BRCA2 genes highly predispose to breast and ovarian cancers and are responsible for a substantial proportion of familial breast and ovarian cancers. No female individuals from families from Morocco affected by breast cancer with mutations of these genes have previously been reported, and clinicians in Morocco are unaccustomed to dealing with healthy female individuals carrying mutations in the BRCA genes. This study aimed to report the initial experience of a group of Moroccan investigators carrying out predictive genetic testing to detect a known familial mutation in healthy Moroccan females with a high risk of developing breast cancer and to introduce supervision of these asymptomatic female carriers as a new approach in the prevention and early diagnosis of breast and ovarian cancers in Morocco. Presymptomatic diagnosis was carried out using DNA genetic testing in 5 healthy Moroccan female individuals from three families with an elevated risk of developing breast cancer. These are the first Moroccan families reported to be affected by breast cancers associated with BRCA mutations. Presymptomatic diagnosis was carried out for breast cancer in 5 female individuals from three Moroccan families with BRCA mutations. Two of the families are the first reported incidence of the founder mutation Ashkenazi BRCA1-185_186delAG in Moroccan patients. The third family carried the known BRCA2 mutation c.5073dupA/p.trp1692metfsX3. We tested the presence of these mutations in 5 asymptomatic healthy females from the three families. Two sisters from family 1 carried the BRCA1-185_186delAG mutation, whereas the third female individual from family 2 carried the c.5073dupA/p.trp1692metfsX3 mutation. However, one healthy female individual and her mother from family 3 did not carry the familial mutation of the BRCA1 gene. This study found BRCA mutations in three asymptomatic subjects, suggesting that this is the first step towards the development of persistent medical monitoring of females from families with a history of breast and ovarian cancers. Consequently, it is crucial for oncologists in Morocco to initiate the supervision of healthy female individuals with genetic defects which may lead to hereditary cancers.     

食管癌高发区上消化道恶性肿瘤死亡趋势分析

目的分析河北省食管癌高发区磁县、涉县29年（1974-2002年）上消化道恶性肿瘤的死亡情况,为肿瘤防治提供依据。方法对比分析磁县、涉县同时期20世纪70年代（1974-1976年）、90年代（1990-1992年）、21世纪初（2000-2002年）全人群肿瘤登记的食管癌、贲门癌、非贲门胃癌的死亡率。结果自20世纪70年代到21世纪初,磁县、涉县食管癌粗死率均呈现明显下降趋势,磁县食管癌粗死率下降了40.96/10万,下降了32.21%;而同时期涉县下降了65.74/10万,下降了50.06%。磁县贲门癌和非贲门胃癌的粗死率呈现曲线波动,变化不大,20世纪70年代贲门癌死亡占上消化道恶性肿瘤死亡的5.67%,到90年代占4.58%,21世纪初占8.15%。而涉县贲门癌呈现明显上升趋势,非贲门胃癌呈现明显下降趋势,发现贲门癌在上消化道恶性肿瘤死亡中所占比重越来越大,由20世纪70年代的6.28%上升到新世纪的30.17%。磁县、涉县人群中男性贲门癌的死亡率高于女性。磁县山区贲门癌死亡率高于丘陵和平原,年平均死亡率达到11.61/10万,且有上升趋势。结论29年来磁县、涉县食管癌死亡呈显著下降趋势,磁县贲门癌、非贲门胃癌死亡均呈曲线波动;涉县贲门癌死亡率呈明显上升趋势,非贲门胃癌死亡率呈下降趋势。     

Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China

Esophageal cancer incidence and mortality rates in Linxian, China are among the highest in the world. We examined risk factors for esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC), and gastric noncardia cancer (GNCC) in a population-based, prospective study of 29,584 adults who participated in the Linxian General Population Trial. All study participants completed a baseline questionnaire that included questions on demographic characteristics, personal and family history of disease, and lifestyle factors. After 15 years of follow-up, a total of 3,410 incident upper gastrointestinal cancers were identified, including 1,958 ESCC, 1,089 GCC and 363 GNCC. Cox proportional hazard models were used to estimate risks. Increased age and a positive family history of esophageal cancer (including ESCC or GCC) were significantly associated with risk at all 3 cancer sites. Additional risk factors for ESCC included being born in Linxian, increased height, cigarette smoking and pipe smoking; for GCC, male gender, consumption of moldy breads and pipe smoking; and for GNCC, male gender and cigarette smoking. Protective factors for ESCC included formal education, water piped into the home, increased consumption of meat, eggs and fresh fruits and increased BMI; for GCC, formal education, water piped into the home, increased consumption of eggs and fresh fruits and alcohol consumption; and for GNCC, increased weight and BMI. General socioeconomic status (SES) is a common denominator in many of these factors and improving SES is a promising approach for reducing the tremendous burden of upper gastrointestinal cancers in Linxian.     

Breast cancer risk estimation in families with history of breast cancer.

Among 288 breast cancer patients (118 with bilateral disease and 165 with diagnosis before 40 years of age), we identified 26 families with a history of breast cancer, including a minimum of three first- or second-degree relatives. Complete pedigrees with verified malignancy data from the Finnish cancer registry were constructed for 22 families. The median age at breast cancer diagnosis of the young probands (< 40 years of age) was 35 years and of bilateral probands was 54 years. The relatives of the young probands were diagnosed with breast cancer at a younger age (median age 54 years) than the relatives of the older (bilateral) probands (median age 60 years). Standard life-table methods were used to compare the risk of breast cancer in the family members with that of the general population. Among the relatives of the young probands, the increased breast cancer risk occurred in the early post-menopausal period, whereas the risk estimate for the relatives of the bilateral probands closely followed that of the general population. In both groups, however, those family members reaching the age of 80 years had a cumulative probability of over 50% of developing breast cancer. The standard life-table method proved useful when assessing the age-specific risk for familial breast cancer, taking into account numerous family members as well as their age at disease onset. This kind of analysis can be performed in populations for which reliable cancer registry data are available. It provides a useful tool for selecting individuals for imaging and mutation screening, counselling and experimental chemoprevention programmes.     

PREVENTIVE DETECTION OF FUNGI AND MYCOTOXINS IN CORN FROM HIGH RISKAREA OF ESOPHAGEAL CANCER IN CIXIAN COUNTY

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