Sex hormone-binding globulin polymorphisms in familial and sporadic breast cancer

Ovarian steroids are one of the strongest risk factors for breast cancer. Sex hormone-binding globulin (SHBG) binds and transports sex steroids in the blood, regulating their bioavailable fraction and access to target cells. It can also inhibit the estradiol-induced proliferation of breast cancer cells through its membrane receptor. Three coding-region polymorphisms, which lead to an amino acid change, have been reported. We studied the influence of these three polymorphisms on breast cancer risk in three different populations: Polish familial breast cancer cases, 27% of them carrying a BRCA1/BRCA2 mutation, Nordic familial and sporadic breast cancer cases. The reported G to A polymorphism in exon 1 was not found in the 423 analyzed samples. Instead, we found a C to T transition causing an arg to cys amino acid change within the same codon in one Polish breast cancer patient and her daughter. Both of them were heterozygotes for the exon 8 G to A polymorphism as well. They were diagnosed for bilateral breast cancer and carried a BRCA1 mutation (5382insC). Analysis of the tumor samples showed that they had lost the wild-type allele both at exons 1 and 8 of the SHBG gene. Analysis of the other Polish samples showed no correlation of the exon 8 polymorphism to breast cancer, bilateral breast cancer, BRCA1/BRCA2 mutations or age at diagnosis. No association of the exon 8 polymorphism with breast cancer in the Nordic familial or sporadic cases was found. The C to T polymorphism located in exon 4 was rare in all the studied populations (overall allele frequency 0.011). However, in each of the study populations there was a trend for a lower variant allele frequency in cancer cases than in controls. Variant allele frequency in all the breast cancer cases was significantly lower than in all the controls (chi(2) = 5.27, P-value 0.02; odds ratio = 0.23, 95% confidence interval 0.05-0.84).     

Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer.

Previous studies suggest that enzymes involved in the androgen metabolic pathway are susceptibility factors for prostate cancer. Estrogen metabolites functioning as genotoxins have also been proposed as risk factors. In this study, we systematically tested the hypothesis that common genetic variations for those enzymes involved in the androgen and estrogen metabolic pathways increase risk for sporadic and familial prostate cancer. From these two pathways, 46 polymorphisms (34 single nucleotide polymorphisms, 10 short tandem repeat polymorphisms, and 2 null alleles) in 25 genes were tested for possible associations. Those genes tested included PRL, LHB, CYP11A1, HSD3B1, HSD3B2, HSD17B2, CYP17, SRD5A2, AKR1C3, UGT2B15, AR, SHBG, and KLK3 from the androgen pathway and CYP19, HSD17B1, CYP1A1, CYP1A2, CYP1B1, COMT, GSTP1, GSTT1, GSTM1, NQO1, ESR1, and ESR2 from the estrogen pathway. A case-control study design was used with two sets of cases: familial cases with a strong prostate cancer family history (n = 438 from 178 families) and sporadic cases with a negative prostate cancer family history (n = 499). The controls (n = 493) were derived from a population-based collection. Our results provide suggestive findings for an association with either familial or sporadic prostate cancer with polymorphisms in four genes: AKR1C3, HSD17B1, NQO1, and GSTT1. Additional suggestive findings for an association with clinical variables (disease stage, grade, and/or node status) were observed for single nucleotide polymorphisms in eight genes: HSD3B2, SRD5A2, SHBG, ESR1, CYP1A1, CYP1B1, GSTT1, and NQO1. However, none of the findings were statistically significant after appropriate corrections for multiple comparisons. Given that the point estimates for the odds ratio for each of these polymorphisms are <2.0, much larger sample sizes will be required for confirmation.     

ATM polymorphisms as risk factors for prostate cancer development

The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G>A (D1853N), 5558A>T (D1853V), ivs38-8t>c and ivs38-15g>c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17-3.87, P=0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C>G variant might be associated with prostate cancer risk.     

Prevalence of BER gene polymorphisms in sporadic breast cancer

Studies suggest that breast cancer is initiated by the induction of somatic mutations from errors in the base excision repair (BER) of endogenous estrogen-induced abasic sites. If so, the inheritance of certain polymorphic mutations in BER genes involved in the incorporation and management of such errors should increase the risk of breast cancer. To test this hypothesis, we examined breast tissues from 48 women (controls, histopathologically normal tissue from reduction mammoplasty) and 40 women with breast cancer (breast tumor-adjacent, histopathologically normal tissues) for the presence of reported polymorphic mutations in four BER genes. The breast tissues were obtained from the Cooperative Human Tissue Network-western division and from the University of Nebraska Medical Center. Using PCR-RFLP procedures, the XRCC1 gene was examined for Arg194Trp and Arg399Gln, APE1 for Asp148Glu, LIG3alpha for Arg780His and PARP1 for Pro377Ser mutations. The women in this study carried only the XRCC1 Arg399Gln polymorphism. This result was surprising because APE1 148Glu was reported to be frequently inherited (allele frequency, 0.47-0.495) by USA and European women. Thus, the USA women in our study are genetically different from those in the previous studies. Among the control women, 21 (43.75%) were Arg/Arg wild-types, 20 (41.67%) were Arg/Gln heterozygotes and 7 (14.6%) were Gln/Gln homozygotes. Among the breast cancer cases, 11 (27.5%) were Arg/Arg wild-types, 16 (40%) were Arg/Gln heterozygotes and 13 (32.5%) were Gln/Gln homozygotes. Thus, the Gln allele was significantly more frequent in breast cancer cases (allele frequency, 0.52) than in controls (allele frequency, 0.35), suggesting that XRCC1 399Gln may enhance the risk of breast cancer.     

Single nucleotide polymorphisms in the mitochondrial displacement loop and outcome of esophageal squamous cell carcinoma

Backgroud

Accumulation of single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) has been described for different types of cancers and might be associated with cancer risk and disease outcome. We used a population-based series of esophageal squamous cell carcinoma (ESCC) patients for investigating the prediction power of SNPs in mitochondrial D-loop.

Methods

The D-loop region of mtDNA was sequenced for 60 ESCC patients recorded in the Fourth Hospital of Hebei Medical University between 2003 and 2004. The 5 year survival curve were calculated with the Kaplan-Meier method and compared by the log-rank test at each SNP site, a multivariate survival analysis was also performed with the Cox proportional hazards method.

Results

The SNP sites of nucleotides 16274G/A, 16278C/T and 16399A/G were identified for prediction of post-operational survival by the log-rank test. In an overall multivariate analysis, the 16278 and 16399 alleles were identified as independent predictors of ESCC outcome. The length of survival of patients with the minor allele 16278T genotype was significantly shorter than that of patients with 16278C at the 16278 site (relative risk, 3.001; 95% CI, 1.029 - 8.756; p = 0.044). The length of survival of patients with the minor allele 16399G genotype was significantly shorter than that of patients with the more frequent allele 16399A at the 16399 site in ESCC patients (relative risk, 3.483; 95% CI, 1.068 - 11.359; p = 0.039).

Conclusion

Genetic polymorphisms in the D-loop are independent prognostic markers for patients with ESCC. Accordingly, the analysis of genetic polymorphisms in the mitochondrial D-loop can help identify patient subgroups at high risk of a poor disease outcome.     

Polymorphism of the c-Ha-ras-1 proto-oncogene in sporadic and familial breast cancer

Two studies on breast cancer patients are described. Our aim was to examine whether the combined frequency of rare c-Ha-ras-1 alleles in cancer patients was raised. Firstly, the c-Ha-ras-1 locus in 56 breast cancer patients and 48 controls was examined for restriction fragment length polymorphism (RFLP) by Southern blot analysis of leukocyte DNA. Four predominant allelic fragments were found in both groups together with a variety of rare alleles. The 2 groups did not differ significantly in overall distribution of c-Ha-ras-1 alleles. Rare alleles combined were about as frequent in cases (7.1%) as in controls (6.3%). Secondly, 53 members of 3 families having a high incidence of breast cancer were c-Ha-ras-1 genotyped. None of 10 affected members was found to carry a rare c-Ha-ras-1 allele. The only c-Ha-ras-1 allele common to 11 affected members was a 6.8-kb allele which is found in 72% of the controls. Furthermore, this allele was found with equal frequency in affected and non-affected family members.     

Non-dietary factors as risk factors for breast cancer, and as effect modifiers of the association of fat intake and risk of breast cancer

To assess more precisely the relative risks associated with established risk factors for breast cancer, and whether the association between dietary fat and breast cancer risk varies according to levels of these risk factors, we pooled primary data from six prospective studies in North America and Western Europe in which individual estimates of dietary fat intake had been obtained by validated food-frequency questionnaires. Based on information from 322,647 women among whom 4,827 cases occurred during follow-up: the multivariate-adjusted risk of late menarche (age15 years or more compared with under 12) was 0.72 (95 percent confidence interval [CI]=0.62-0.82); of being postmenopausal was 0.82 (CI=0.69-0.97); of high parity (three or more births compared with none) was 0.72 (CI=0.61-0.86); of late age at first birth (over 30 years of age compared with 20 or under) was 1.46 (CI=1.22-1.75); of benign breast disease was 1.53 (CI=1.41-1.65); of maternal history of breast cancer was 1.38 (CI=1.14-1.67); and history of a sister with breast cancer was 1.47 (CI=1.27-1.70). Greater duration of schooling (more than high-school graduation compared with less than high-school graduation) was associated significantly with higher risk in age-adjusted analyses, but was attenuated after controlling for other risk factors. Total fat intake (adjusted for energy consumption) was not associated significantly with breast cancer risk in any strata of these non-dietary risk factors. We observed a marginally significant interaction between total fat intake and risk of breast cancer according to history of benign breast disease, with fat intake being associated nonsignificantly positively with risk among women with a previous history of benign breast disease; no other significant interactions were observed. Risks for reproductive factors were similar to those observed in case-control studies; relative risks for family history of breast cancer were lower. We found no clear evidence in any subgroups of a major relation between total energy-adjusted fat intake and breast cancer.     

Infrequent occurrence of microsatellite instability in sporadic and familial breast cancer

Microsatellite instability was analysed in 93 primary breast tumours at 13 chromosomal loci frequently altered in breast cancer. RER (replication errors) were observed at a low (5%) frequency in sporadic, familial and hereditary breast tumours, as well as in breast tumours from patients with multiple primary cancers. Our study suggests that the RER+ phenotype is rare in breast tumours, and that breast cancer is not included in the hereditary non-polyposis colon cancer (HNPCC) syndrome. Moreover, the RER+ tumours revealed an atypical pattern of microsatellite alteration as compared with those usually seen in HNPCC tumours. In agreement with the findings in HNPCC tumours, all RER+ breast tumours were diploid, although having a similar frequency of allelic imbalance as RER— tumours. Thus, mismatch repair deficiency is rare in breast cancer, is most likely caused by somatic mutations, and possibly in a set of DNA repair genes different from that involved in the HNPCC syndrome.     

Association of mitochondrial DNA displacement loop (CA)n dinucleotide repeat polymorphism with breast cancer risk and survival among Chinese women

Mitochondrial genome alternations may be involved in carcinogenesis. The noncoding region of the mitochondrial DNA (mtDNA) displacement loop (D-loop) has emerged as a mutational hotspot. Using data from a population-based case-control study conducted among Chinese women in Shanghai, we evaluated associations of breast cancer risk and survival with the mtDNA D-loop (CA)(n) dinucleotide repeat polymorphism. Included in the study were 1,058 cases and 1,129 age frequency-matched community controls that participated in the Shanghai Breast Cancer Study between 1996 and 1998. Breast cancer patients were followed to determine intervals of overall survival and disease-free survival. Overall, there was no association between the mtDNA D-loop (CA)(n) repeat polymorphism and breast cancer risk. Patients with multiple alleles of the mtDNA D-loop (CA)(n) polymorphism (heteroplasmy) had significantly poorer disease-free survival than those with one allele of the mtDNA D-loop (CA)(n) polymorphism (hazard ratio 1.62; 95% confidence interval, 1.16-2.26). These results suggest that the mtDNA D-loop (CA)(n) repeat polymorphism may be associated with breast cancer survival. Additional studies with a larger sample size are warranted.     

Mammographic signs as risk factors for breast cancer.

We have carried out a case-control study to examine the relationship between mammographic signs and breast cancer. The mammographic signs assessed were prominent ducts and dysplasia. The cases were a group of 183 women with histologically verified unilateral breast cancer. The controls were a group of women attending a screening centre. Cases and controls were individually age-matched. Mammograms from the non-cancerous breast of the cases were randomly assembled with those of the controls and classified by 3 radiologists without knowledge of which films were from cases and which from controls. Mammographic dysplasia was found to be strongly associated with breast cancer, particularly in women aged less than 50. Prominent ducts were only weakly associated with breast cancer. Multivariate analysis showed that the association between dysplasia and breast cancer could not be explained on the basis of other risk factors for breast cancer, and that classification of dysplasia discriminated more strongly between cases and controls than did classification of Wolfe''s mammographic patterns. These results show that mammograms contain information about risk of breast cancer. Mammographic dysplasia is strongly associated with breast cancer, is present in a substantial proportion of patients with the disease, and may offer opportunities for prevention.     

Management of familial breast cancer risk

Women who are members of breast cancer families are at increased risk for breast cancer. The cloning of BRCA1 and BRCA2 has made it possible to identify mutation carriers within some of these families. Management of breast cancer risk in these families, which presents enormous challenges to patients and clinicians, is addressed. Management should begin with a full evaluation of the patient, including construction of a three-generation pedigree, ascertainment of non-genetic factors that may impact on risk, information on previous and current breast health, practice of and attitudes toward screening, and the psychosocial impact of family history on the individual. Patient priorities in risk management should be explicitly reviewed; these may include survival, cancer prevention, breast preservation, optimization of quality of life or minimization of disruption of day-to-day activities. Approaches to risk management involve screening (usually considered the mainstay), anti-estrogens, prophylactic surgery and/or lifestyle modifications. Specific gene therapy may become available in the future. Management decisions should be individualized to reflect risk levels and patient priorities and goals, within bounds that are medically and scientifically reasonable. An explicit examination of different time-frames (1, 5, 10 years) is recommended given the rapid evolution of knowledge in this area.     

B7-H4基因多态性与黑龙江省乳腺癌易感性的研究

 目的　探讨B7-H4基因 rs10754339、rs10801935和rs3738414等SNP位点多态性与黑龙江省妇女乳腺癌发病风险的相关性。方法　利用聚合酶链反应限制性片段长度多态性（PCR-RFLP）技术,对287例黑龙江省汉族女性乳腺癌患者和305名健康对照者进行B7-H4基因位点多态性检测,并确定常见单体型（频率≥1 %）,分析患者与健康对照差异,进而确定该基因与黑龙江省汉族妇女乳腺癌的相关性。结果　B7-H4基因3'-UTR区rs10754339位点的G等位基因、AA、AG基因型发生频率在乳腺癌组和健康对照组间差异有统计学意义（P＝0.030,OR 1.359,95 % CI 1.030～1.794;P＝0.018,OR 0.671,95 % CI 0.482～0.935;P＝0.029,OR 1.455,95 % CI 1.038～2.038）。5'-UTR区rs3738414位点的A等位基因、GG基因型和AG基因型发生频率在乳腺癌患者和健康对照组之间差异有统计学意义（P＝0.0008,OR 0.604,95 % CI 0.455～0.803;P＝0.001,OR 1.804,95 % CI 1.289～2.253;P＝0.005,OR 0.612,95 % CI 0.435～0.862）。AAA单体型和GAG单体型发生频率在乳腺癌患者和健康对照组之间差异有统计学意义（P＝0.0015,OR 0.614,95 % CI 0.456～0.828;P＝0.0003,OR 1.954,95 % CI 1.363～2.803）。结论　B7-H4基因多态性与黑龙江省汉族妇女乳腺癌发病存在一定相关性。     

Oral contraceptives and risk of familial breast cancer

The risk of breast cancer of oral contraceptive (OC) use in 1423 women from families with hereditary/familial breast cancer recruited through a cancer family clinic was analyzed in a matched case-control study. Ninety-eight women tested positive for a BRCA1 mutation. Hazard ratio for ever use of OCs adjusted for other risk factors was 0.90 (95% confidence interval (CI) 0.68-1.18) in the total data set and 2.00 (0.36-10.9) in BRCA1 mutation carriers. We did not find evidence for interaction between BRCA1 mutation status and OC use on breast cancer risk. Recent users had a statistically significant increase in risk with hazard ratios of 1.99, 2.05, and 1.69 for up to 5, 10, and 15 years since last OC use, while users with more than 15 years since last use had a reduction of risk to 0.69 compared to never users. We conclude that the effects of OC use on breast cancer risk in familial breast cancer may be similar to the effects in the general population. For BRCA1 mutation carriers, the point estimate is a doubling of risk, but CI is wide and no conclusion may be drawn from this study alone.     

Heightened perception of breast cancer risk in young women at risk of familial breast cancer

The objective of this study was to explore the factors that influence perceived personal risk of developing breast cancer (BC) in younger women (<35) who are considering or have undergone bilateral prophylactic mastectomy (BPM). Qualitative interviews guided by interpretative phenomenological analysis were conducted with 46 women who had a strong family history of BC and had either undergone (n?=?26) or were considering (n?=?20) BPM. Participants were recruited from Australia and New Zealand via hospitals, a genetics clinic, a research cohort, a registry and online. Three main themes were identified: information that increases fear of BC and death, underlying anxiety and fear and screening anxiety. A further two themes: relief following surgery and confusion about residual risk following surgery were identified. Younger women (<35) appeared to have heightened and sometimes inaccurate perceptions of their BC risk. They appeared less relieved of anxiety and fear of developing BC by BPM surgery, in comparison to previous research with older women (>40). Those who had undergone BPM seemed more anxious about their risk of developing BC than those who were still considering surgery. This research has important implications for practice, particularly improving communication of accurate risk statistics. Future research should examine why some women interpret information differently and explore the benefits of psychological consultation for very anxious women.     

家族性乳腺癌与散发性乳腺癌的临床生物学特性分析

目的比较家族性乳腺癌与散发性乳腺癌的临床和分子生物学特性，探讨家族性乳腺癌的临床特点和预后。方法回顾性分析河北医科大学第四医院外科2005年6月至2006年5月收治的681例乳腺癌患者的临床资料，其中家族性乳腺癌18例，散发性乳腺癌663例，比较两组间临床生物学行为特点。结果家族性乳腺癌的组织学分级Ⅲ级比例（44．4％）明显高于散发性乳腺癌（17．2％），两组间差异有统计学意义（Х^2=9．943，P=0．007）；家族性乳腺癌的ER阴性率（50．0％）高于散发性乳腺癌（27．0％），两组间差异有统计学意义（Х^2=6．203，P=0．045）；家族性乳腺癌的VEGF表达阳性率（44．4％）高于散发性乳腺癌（21．9％），两组间差异有统计学意义（Х^2=6．783，P=0．034）。但家族性乳腺癌和散发性乳腺癌患者在年龄分布（Х^2=0．505，P=0．918），绝经状况（Х^2=0．915，P=0．633），肿瘤大小（Х^2=1．595，P=0．660），临床分期（Х^2=1．882，P：0．597），病理类型（Х^2=2．430，P=0．876），腋淋巴结转移率（Х^2=0．999，P=0．607），PR（Х^2=3．088，P=0．214）及C—erbB-2表达（Х^2=3．094，P=0．213）等方面的差异均无统计学意义。结论家族性乳腺癌的组织学分级、ER阴性率、VEGF表达阳性率均明显高于散发性乳腺癌，提示预后较差。     

Impact of chemotherapy on telomere length in sporadic and familial breast cancer patients

Breast Cancer Research and Treatment - Recently, we observed that telomeres of BRCA1/2 mutation carriers were shorter than those of controls or sporadic breast cancer patients, suggesting that...     

Identification of novel deletion polymorphisms in breast cancer

Breast cancer is the most frequent cancer in females worldwide and it has long been known that multiple genetic rearrangements correlate with complex biology and clinical behavior. In addition, copy number variations (CNVs) of DNA sequences account for a significant proportion of normal phenotypic variation and may have an important role in human pathological variation. In this study, we carried out a high-density oligonucleotide array comparative genomic hybridization (CGH) analyses in a series of breast cancer cell lines to identify novel homozygous deletion loci. The results were confirmed by quantitative PCR (Q-PCR) and 4 genes, the REV1L, ZNF14, NPAS1 and APOBEC3B genes, were selected. Analyses of 30 microdissected human breast tumors and paired normal mammary tissue samples indicated that these homozygous deletions are small-scale deletion polymorphisms. The variation in copy number at the loci of the 4 genes in blood-derived DNA demonstrated the frequency of deletions including homozygous deletions and single copy variants to be higher in breast cancer patients than healthy females. Notably, the homozygous deletion of APOBEC3B involved part of exon 5 and seemed to be cancer-specific in some patients, indicating that this is a functionally important structural variant. These copy number changes may play an important role in breast cancer and array-CGH analyses can thus be expected to provide new insight into the genetic background of breast cancer.