BRCA1 germ line mutations in Chinese early-onset breast cancer patients / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the role of disease associated germ line mutations in BRCA1 gene among Chinese early-onset breast cancer patients.</p><p><b>METHODS</b>A total of 188 early-onset breast cancer patients, who were diagnosed with breast cancer before 41-year-old, were enrolled from four breast cancer clinical centers in China. Thirty-nine of them (20.7%) also had family history of breast/ovarian cancer. DNA extracted from lymphocytes was amplified by polymerase chain reaction (PCR) for the entire exons and the splicing sites of BRCA1. Twenty-two of the patients were screened by single strand conformation polymorphism (SSCP), and the other 166 of them were screened by denaturing high performance liquid chromatography (DHPLC). The abnormal fragments recognized were ascertained by DNA direct sequencing. For those samples with the same recurrent mutation, five BRCA1-linked markers (D17S855, D17S1322, D17S1323, D17S1326 and D17S1327) were used for the allelotype analysis.</p><p><b>RESULTS</b>Twelve disease-associated mutations were identified in 15 (8.0%) patients, among which BRCA1 1100delAT and 5589del8 were identified in 3 and 2 patients respectively. Nine (23.1%) of them were identified in those with breast/ovarian cancer family history. The difference of BRCA1 mutation frequency between the patients with and without family history was statistically significant (P=0.001). Allelotype analysis showed the two BRCA1 5589del8 mutation carriers shared the same allelotype in all the 5 STR sites, and two of the three 1100delAT mutation carriers, who came from the northern China, also shared the same allelotype in all the 5 STR sites, which were different from those of the 5589del8 mutation carriers'.</p><p><b>CONCLUSION</b>This is a relatively very large scale multi-hospital-based study of BRCA1 mutations in Chinese early-onset breast cancer patients up to now. It seems reasonable to give genetic consultations and genetic test of BRCA1 gene to early-onset breast cancer patients in China, especially for those with breast/ovarian cancer family history. The two recurrent mutations might be founder mutations of Chinese population. It might be cost-effective to analyze these two mutations before whole gene analysis.</p>

Study on the position of genes responsible for gallstone disease in Chinese population / 中华外科杂志

<p><b>OBJECTIVE</b>To search the susceptibility genes of gallstone disease in Chinese population.</p><p><b>METHODS</b>A genome wide scan was performed in twelve families with gallstone disease using fluorescence-labeled microsatellite markers. Genehunter and Batchlink of Linkage package were used for non- parameter and parameter linkage analysis to search the linkage loci on chromosomes.</p><p><b>RESULTS</b>Four loci of D3S1266, D4S406, D9S1682 and D11S902 showed suggestive evidence for linkage. nonparametric linkage analysis (NPL)-score of D4S406 and D9S1682 was 1.77 (P = 0.05) and 1.92 (P = 0.04) respectively. The corresponding logarithm of the odds ratio (LOD)-score of D3S1266, D9S1682 were 1.35 and 2.07, and showed a rise of LOD-score from 1.35 to 2.71, 2.07 to 2.40 respectively when families with later-found patients or with higher triglyceride level were analyzed alone. Transmitted disequilibrium test of D11S902 showed a P-value of 0.0027.</p><p><b>CONCLUSIONS</b>Chromosome 3, 4, 9 and 11 may contain genes involved in gallstone disease in Chinese population, and chromosome 3, 9 may hide genes that are liked to gallstone disease in families with later-found patients or with higher triglyceride concentration.</p>

CHEK2 c.1100delC may not contribute to genetic background of hereditary breast cancer from Shanghai of China / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the prevalence of CHEK2 c.1100delC mutation among non-BRCA1/BRCA2 familial/early-onset breast cancer patients in Shanghai.</p><p><b>METHODS</b>One hundred and fourteen non-BRCA1/BRCA2 hereditary breast cancer patients were analyzed, among whom 76 cases had at least one first-degree relative affected with breast cancer and 38 cases were diagnosed as breast cancer below the age of 40 years without family history. The mutation genotyping of CHEK2 c.1100delC were carried out through long-range PCR amplifying of exons 10-14, and followed by amplification of exon 10 and then DNA direct sequencing.</p><p><b>RESULTS</b>No c.1100delC frame-shift mutation was identified in our studied population. One novel missense mutation 1111C>T (p.His371Tyr), located in kinase catalytic domain, was found in 3 familial breast cancer cases but no one in control group.</p><p><b>CONCLUSION</b>CHEK2 c.1100delC is rare variant for Chinese population and may not contribute to predisposition for hereditary breast cancer in Shanghai. Novel variant -1111C>T could be in association with genetic susceptibility to breast cancer. A further study is needed to confirm the results.</p>

BRCA1 and BRCA2 gene mutations of familial breast cancer from Shanghai in China / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the prevalence of BRCA1 and BRCA2 gene mutations among breast cancer patients with affected relatives in Shanghai of China.</p><p><b>METHODS</b>Thirty-five breast cancer patients who had at least one first-degree relative affected were analyzed, among whom 13 patients suffered from breast cancer at age of less than 40 years. A comprehensive BRCA1 and BRCA2 mutation analysis was performed through denaturing high-performance liquid chromatography (DHPLC) and subsequent DNA direct sequencing.</p><p><b>RESULTS</b>Four mutations in BRCA1 gene, including 2 novel splice-site mutations (IVS17-1G>T, IVS21+1G>C) and 2 frameshift mutations (1100delAT; 5640delA) were identified. One frameshift mutation (5802delAATT) was detected in exon 11 of BRCA2. Additional 12 novel single nucleotide polymorphisms(SNPs) were detected, including a novel unclassified variant and 7 novel intronic variants in BRCA1, and 4 novel intronic variants in BRCA2, with which all caused no alteration of amino acid coding. The mutation frequency of BRCA1 and BRCA2 in patients with family history was 11.4% and 2.9%, respectively.</p><p><b>CONCLUSION</b>Two novel mutations in BRCA1 may be mutations characterized to familial breast cancer of Chinese Shanghai population. The BRCA2 may contribute to mutation less than BRCA1 in familial breast cancer. Our data contribute to information on mutation spectrum of BRCA gene in Chinese population and also offer a recommended screening mode for clinical genetic testing policy in China.</p>

Effect of R264C polymorphism in CYP19A1 gene on BRCA1/2-negative hereditary breast cancer from Shanghai population of China / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>Aromatase, encoded by CYP19A1, play an important role in estrogens biosynthesis from androgens. The present study is to investigate effect of R264C single nucleotide polymorphism in CYP19A1 gene on genetic susceptibility for hereditary breast cancer without BRCA1/2 mutant.</p><p><b>METHODS</b>One hundred and fourteen BRCA1/2 -negative hereditary breast cancer patients from independent families and 121 age-matched healthy control subjects were analyzed. Genotype analysis was performed through polymerase chain reaction (PCR) and then DNA direct sequencing. The odd-ratios (OR) and 95% confidence intervals (CI) were calculated by unconditional Logistic regression model.</p><p><b>RESULTS</b>The frequency of R264C single nucleotide polymorphism CC, CT and TT genotype in case group and controls was 84(77.8%), 22(20.4%), 2(1.8%) and 87(77.7%), 24(21.4%), 1(0.9%), respectively. CT genotype (OR=1.16, 95%CI: 0.53-2.55) and TT genotype (OR=1.44, 95%CI: 0.12-17.15) did not confer a significantly increased risk for breast cancer. No significant association was found between T allele and susceptibility for breast cancer under analysis according to menopausal status and body mass index.</p><p><b>CONCLUSION</b>R264C polymorphism in CYP19A1 gene is not a candidate locus for low penetrance breast cancer susceptibility in Shanghai group of Chinese population and not recommended in clinical genetic test. Homozygous T allele of R264C is not common in Shanghai group of Chinese population.</p>

Prevalence of Val158Met polymorphism in COMT gene on non-BRCA1/2 hereditary breast cancer / 中华外科杂志

<p><b>OBJECTIVE</b>To explore the prevalence of Val158Met polymorphism in Catechol-O-methyltransferase (COMT) gene and its effect on genetic susceptibility for breast cancer in Shanghai population.</p><p><b>METHODS</b>A total of 114 patients with BRCA1/BRCA 2 negative hereditary breast cancer from independent families and 121 age-matched healthy controls were analyzed. Genotype analysis was conducted by polymerase chain reaction (PCR) and then DNA direct sequencing. The odd ratios (OR) and 95% confidence intervals (CI) were calculated by unconditional logistic regression model.</p><p><b>RESULTS</b>The frequency of Val158Met polymorphism GG, GA and AA genotype in case group and control was 0.58 (65), 0.32 (36), 0.10 (11) and 0.60 (66), 0.35 (41), 0.03 (3), respectively. The frequency of allele-containing genotypes is significantly higher in early-onset breast cancer patients (0.57) than in familial ones (0.35). Compared with GG (Val/Val) genotype, AA (Met/Met) genotype confers a significantly increased risk for breast cancer (adjusted OR = 3.15; 95% CI, 0.70 - 14.19), especially among premenopausal women (adjusted OR = 9.98; 95% CI, 1.00 - 99.64). Borderline significantly association was found between AA genotype (adjusted OR = 7.57; 95% CI, 0.57 - 101.28) and susceptibility for breast cancer in BMI < or = 23 kg/m(2) group.</p><p><b>CONCLUSIONS</b>Val158Met polymorphism in COMT gene could be a candidate for low penetrance breast cancer susceptibility in Shanghai population, especially among premenopausal women and early-onset breast cancer patients.</p>

A polymorphism of kynureninase gene in a hypertensive candidate chromosomal region is associated with essential hypertension / 中华心血管病杂志

<p><b>OBJECTIVE</b>To identify single nucleotide polymorphisms (SNP) in the regulatory and coding regions of human kynureninase (KYNU) gene in a hypertensive candidate chromosomal region 2q14-q23 of Han Chinese, and to investigate the relationship between polymorphisms in KYNU and essential hypertension.</p><p><b>METHODS</b>The SNPs in the promoter region and exons of the KYNU gene were detected by direct DNA sequencing. Genotyping of the nonsynonymous Lys412Glu (A/G) polymorphism was performed by DHPLC technology in 456 hypertensive patients and 430 normal controls.</p><p><b>RESULTS</b>Sixteen SNP were identified in the KYNU gene, including 6 in the regulatory region and 2 in the coding region (both of them lead to substitution of amino acid). Significant differences between hypertensive patients and normal controls were observed for the distribution of alleles (chi(2) = 6.693, P = 0.035) and genotypes (chi(2) = 4.188, P = 0.041) of the Lys412Glu polymorphism in all subjects, and for the distribution of alleles in the subgroup of men (chi(2) = 4.424, P = 0.035).</p><p><b>CONCLUSION</b>The Lys412Glu polymorphism of the KYNU gene in a hypertensive candidate chromosomal region is associated with essential hypertension in Han Chinese.</p>

The relationship between haplotypes of multilocus markers and ankylosing spondylitis / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the relationship between haplotypes of multilocus markers and ankylosing spondylitis (AS).</p><p><b>METHODS</b>Five families with AS were recruited from Shanghai area. Eleven microsatellite markers around D6S276 were analyzed by Linkage package and by Cyrillic package.</p><p><b>RESULTS</b>Fine linkage analysis showed the significant Lod score values with D6S276 was 3.8821, Lod score values with D6S1691 and D6S1618 near D6S276 were larger than 1.5. The crossover value in 5 pedigrees was 14%. The haplotype analysis showed that the regions between D6S1691 and D6S1618 were associated with AS.</p><p><b>CONCLUSION</b>The regions of D6S1691-D6S276-D6S1618 may harbor a susceptible gene of AS. The specific haplotypes of different pedigrees may play an important role in the presymptomatic diagnosis for AS.</p>