PubMed Health⌕ Search

Biomedical subjects

Bowang Chen

Publications and source records attributed to Bowang Chen.

At least 19 recordsLinked to original sources

Familial risks and temporal incidence trends of multiple myeloma.

In several cancer registration areas, the trends in the incidence and mortality of multiple myeloma (MM) have been rising over the last few decades. Pedigrees studies on families with multiple affected members have supported the hypothesis of a contributing hereditary etiology of MM due to shared genetic factors. The aim of our study was twofold: 1) to assess incidence trends of MM over the period 1961-2003 using national cancer registry data and; 2) to quantify the familial risk of MM using the 2004 update of the Swedish Family-Cancer Database. For men, the age-standardized rates were 4.33 per 100,000 in 1961-65 and 4.79 in 2001-03. The corresponding rates for women were 2.76 and 3.43. In the elderly, MM rates have risen from 28.7 per 100,000 to 36.2 in men, and from 20.2 to 24.5 in women. MM clustered in families with MM (standardized incidence ratio, SIR=2.45), non-Hodgkin lymphoma (SIR=1.34) and chronic lymphocytic leukaemia (SIR=2.45). No association was found for Hodgkin lymphoma and other leukaemias. Significant associations were found for rectal, stomach, cervical, prostate, bladder, endocrine glands and connective tissue malignancies. Our study adds further evidence that the incidence of MM in Sweden has been constant for several decades. The apparent increase observed in the elderly is, at least in part, attributable to improved diagnostics and certification. MM aggregates in families with MM, chronic lymphocytic leukaemia and, to a lesser extent, with non-Hodgkin lymphoma. If environmental factors can be excluded, the pattern of familial risk of MM is consistent with an autosomal dominant mode of inheritance.

Adult↗

Parental lung cancer as predictor of cancer risks in offspring: clues about multiple routes of harmful influence?

The carcinogenic effects of active smoking have been demonstrated for many sites, but the effects of passive smoking and exposures during pregnancy and breastfeeding are less well documented. We examined whether 0-70-year-old offspring of parents with lung cancer are at a risk of cancer that cannot be explained by their smoking or familial risk. It was assumed that known target sites for tobacco carcinogenesis would be affected, if any. The nationwide Swedish Family-Cancer Database with cancers recorded from 1958 to 2002 was used to calculate age-specific standardized incidence ratios (SIRs). Among offspring of affected mothers, increased risks were observed for upper aerodigestive (SIR 1.45), nasal (2.93), lung (1.71) and bladder (1.52) cancers and for kidney cancer (6.41) in one age group. The risk of bladder cancer was found in younger age groups than that of lung cancer. Cancers at many of these sites, but not the kidney or the bladder, were in excess in offspring of affected fathers. Nasal cancer was even increased when either parent was diagnosed with lung cancer; the highest risk was for nasal adenoid cystic carcinoma (7.73). The data suggest that passive smoking during childhood is associated with an increase risk of nasal cancer. For bladder and kidney cancers, a contribution by tobacco carcinogens is implicated through breastfeeding and in utero exposure.

Adolescent↗

Lifestyle and cancer: effect of parental divorce.

According to previous studies, divorced individuals have increased risks of cancers related to alcohol and tobacco consumption and sexual habits, but the increases are balanced with decreased risks of many common cancers. In the present study, cancer risks were analyzed for 0-70-year-old offspring of divorced parents, on the basis the Swedish Family-Cancer Database with cancer data from the years 1958 to 2002. We calculated standardized incidence ratios for cancer among offspring of divorced parents (19,000 cancer patients) and compared them with offspring of stably married parents (121,000 cancer patients). Standardized incidence ratios were adjusted for many factors, including socio-economic status. Offspring of divorced parents were divided into groups depending on whether their mothers, fathers or both had had children with different partners. Offspring of divorced parents had an increased risk of upper aerodigestive tract, esophageal, anal, pancreatic, lung and cervical cancers. Decreased risks were noted for Hodgkin's disease and bone cancer. For Hodgkin's disease, the data suggest protective effects through early exposure to childhood pathogens but for bone cancer mechanisms remain to be established. The overall cancer risk for offspring of divorced parents was at or above unity. The results show that offspring of divorced parents have increased cancer risks at tobacco-related, alcohol-related and sex-related sites, in analogy to their parent, but they lack decreased risks at common sites, experienced by their parents. Divorce is becoming increasingly common in many countries and any deviant cancer patterns among offspring of divorced parents will have an impact on the population risk.

Adolescent↗

Familial risks for eye melanoma and retinoblastoma: results from the Swedish Family-Cancer Database.

No systematic population-based studies have been conducted on familial eye cancers. Reliable data on familial risks are important for clinical counselling and cancer genetics. The current analysis was based on the nation-wide Swedish Family-Cancer Database on 10.5 million individuals, containing families with parents and offspring. Cancer data were retrieved from the Swedish Cancer Registry from the years 1958 to 2002, including 3636 patients with any type of eye cancer. Familial risk for offspring was defined using the standardized incidence ratio (SIR), adjusted for many variables. Ocular melanoma was detected in two parent-offspring pairs, but the SIR of 3.90 was not significant. Parental upper aerodigestive tract (2.05), left-sided colon (1.83) and male non-medullary thyroid (6.98) cancers showed an association with ocular melanoma, albeit some with a borderline significance. The SIR for leukaemia was increased when parents were diagnosed with eye melanoma. There was no evidence for the association of ocular melanoma with cutaneous melanoma. The SIR for ocular melanoma was 1.76 when a sister was diagnosed with breast cancer, but there was no increase when a mother was diagnosed with breast cancer. When both a child and the parent presented with retinoblastoma, the SIR was 900. The parents of children with retinoblastoma had an excess of small intestinal and rectal cancers and Hodgkin's disease. The present findings were based on a limited number of cases, but they display a complex and heterogeneous pattern of familial associations in ocular melanoma, including an association with breast cancer through a putative recessive mechanism.

Adult↗

Differences in global gene expression in melanoma cell lines with and without homozygous deletion of the CDKN2A locus genes.

We studied differential global gene expression in four melanoma cell lines with three cell lines without homozygous deletion of the CDKN2A locus using HG-U133A microarrays with 22 277 transcripts. None of the cell lines carried mutations in the B-RAF and N-RAS genes. Data analysis using stringent criteria showed specific upregulation of 70 genes and downregulation of 86 genes in cell lines with homozygous deletion of the CDKN2A gene. A comparison with previous expression data showed overlapping of upregulation and downregulation of seven and 23 genes, respectively, in melanoma cell lines with homozygous deletion of the CDKN2A locus or mutations in the B-RAF and N-RAS genes. Microarray data for eight selected genes were validated with an extended number of cell lines using quantitative real-time polymerase chain reaction. The upregulated genes in cell lines with the deletion besides others included MAGE A2 [fold change 128, 95% confidence interval (CI) 82.8-172.2; t-test P=0.004], MAGE A6 (fold change 623, 95% CI 473.4-772.1; t-test P=0.001), MAGE A12 (fold change 90, 95% CI 65.1-115.5; t-test P=0.001) and dopachrome tautomerase (fold change 42, 95% CI 32.5-51.8; t-test P=0.001). Downregulated genes included interleukin 18 (fold change 489, 95% CI 146.4-831.2; t-test P=0.04), ID2 (fold change 3, 95% CI 2.2-4.9; t-test P=0.001), KLF4 (fold change 9, 95% CI 4.3-14.7; P=0.01) and CD24 antigen (fold change 1308, 95% CI 766.0-1850.8; t-test P=0.01). The upregulated genes common to cell lines with homozygous deletion of the CDKN2A gene and mutations in B-RAF and N-RAS gene included those that are involved in RAS/RAF/MEK/ERK pathways. Our results highlight effects of homozygous deletion of the CDKN2A locus on global gene expression.

Biomarkers, Tumor↗

Familial risks in testicular cancer as aetiological clues.

We used the nationwide Swedish Family-Cancer Database to analyse the risk for testicular cancer in offspring through parental and sibling probands. Among 0 to 70-year-old offspring, 4,586 patients had testicular cancer. Standardized incidence ratios for familial risk were 3.8-fold when a father and 7.6-fold when a brother had testicular cancer. Testicular cancer was associated with leukaemia, distal colon and kidney cancer, melanoma, connective tissue tumours and lung cancer in families. Non-seminoma was associated with maternal lung cancer but the risk was highest for the late-onset cases, providing no support to the theory of the in utero effect of maternal smoking on the son's risk of testicular cancer. However, the theory cannot be excluded but should be taken up for study when further data are available on maternal smoking. The high familial risk may be the product of shared childhood environment and heritable causes.

Age Factors↗

Familial risks for cervical tumors in full and half siblings: etiologic apportioning.

Many studies have shown familial aggregation for cervical cancer, but they have been unable to distinguish between shared environmental and genetic effects. Full and half-siblings were identified from the nationwide Swedish Family-Cancer Database, including invasive and in situ cervical cancers in women up to age 70 years. Half-siblings were defined through a common father or mother. Standardized incidence ratios, adjusted for several variables, were calculated for proband-wise risks between full and half-siblings. The familial risk for full siblings was 1.84, compared with 1.40 for maternal and 1.27 for paternal half-siblings. These data were used to apportion familial risk for cervical tumors in full siblings into a heritable component, accounting for 64%, and an environmental component, accounting for 36% of the total risk. No evidence for gene-environment interactions was found. The intractable difficulty in separating cervical cancer causation will be an obstacle for a successful identification of susceptibility genes.

Adolescent↗

STR markers for kinship analysis.

The analysis of short tandem repeats is a widely used method to estimate relatedness between closely related populations or individuals. The AmpFlSTR PCR Amplification Kit has 15 highly variable autosomal markers of tetranucleotide repeats and is principally made to identify individuals and first- or second-degree relatives. However, in many studies one is searching for individuals who are related through more than one generation. We wanted to test whether the amplification kit can also be used to identify more distantly related individuals. Therefore we compared 16 different methods that calculate genetic distance with regard to each method's ability to cluster more distantly related individuals from two test families. Among all the tested methods Nei et al.'s (1983) DA distance performed well in clustering family members within a group of unrelated individuals for a broad range of scenarios. However, second-degree relatives were difficult to cluster with any of the examined methods when other family members were absent. With a simulation we further estimated how many markers would actually be needed to detect a certain degree of relatedness. According to this simulation, one would need at least 123 independent microsatellite markers to detect third-degree relatives with 90% probability. In conclusion, the 15 STR markers in the amplification kit are suitable for detecting only very closely related individuals or entire families.

Female↗

Association of genetic variants in the Rho guanine nucleotide exchange factor AKAP13 with familial breast cancer.

The A-kinase anchor protein 13 (AKAP13, alias BRX and lbc) tethers cAMP-dependent protein kinase to its subcellular environment and catalyses Rho GTPases activity as a guanine nucleotide exchange factor. The crucial role of members of the Rho family of GTPases in carcinogenesis is well established and targeting Rho proteins with antineoplastic compounds has become a major effort in the fight against cancer. Thus, genetic alterations within the candidate cancer susceptibility gene AKAP13 would be expected to provoke a constitutive Rho signalling, thereby facilitating the development of cancer. Here, we analysed the potential impact of four polymorphic non-conservative amino acid exchanges (Arg494Trp, Lys526Gln, Asn1086Asp and Gly2461Ser) in AKAP13 on familial breast cancer. We performed a case-control study using genomic DNA of BRCA1/2 mutation-negative German female index patients from 601 unrelated families, among a subset of 356 high-risk families, and 1053 German female unrelated controls. The newfound Lys526Gln polymorphism revealed a significant association with familial breast cancer (OR = 1.58, 95% CI = 1.07-2.35) and an even stronger association with high-risk familial breast cancer (OR = 1.85, 95% CI = 1.19-2.88). Haplotype analyses were in line with genotype results displaying a similar significance as analyses of individual polymorphisms. Due to the pivotal role of AKAP13 in the Rho GTPases signalling network, this variant might affect the susceptibility to other cancers as well.

A Kinase Anchor Proteins↗

Familial association of prostate cancer with other cancers in the Swedish Family-Cancer Database.

BACKGROUND: Familial associations between cancer sites may implicate true familial clustering which is relevant for the identification of new cancer syndromes and for clinical counseling. METHODS: We used the nation-wide Swedish Family-Cancer Database, containing 10,553 sons and 107,518 fathers with prostate cancer among a total of 170,000 cancer patients in the 0- to 70-year-old offspring generation and over 800,000 cancer patients in the parental generation. We calculated familial standardized incidence ratios (SIRs) and confidence intervals (CIs) for prostate cancers and other cancers in family members. RESULTS: SIRs for prostate cancer were increased in sons when mothers were diagnosed with breast and ovarian cancers, and when siblings were diagnosed with Hodgkins disease (1.78, N = 18, 95% CI 1.05-2.82) and leukemia (1.39, 43, 1.01-1.88). Liver cancer and melanoma were also in excess in the high-risk families. CONCLUSIONS: The present analysis, the largest yet carried out, found many novel associations implying familial links between prostate cancer and other sites.

Adolescent↗

Familial risks for nonmedullary thyroid cancer.

CONTEXT: Reliable data on familial risks are important for clinical counseling and cancer genetics. OBJECTIVE: We wanted to define familial risks for histopathology-specific nonmedullary thyroid cancers through parental and sibling probands. SETTING: The study examines the nationwide Swedish Family-Cancer Database on 10.5 million individuals, containing families with parents and offspring. PATIENTS: Cancer data were retrieved from the Swedish Cancer Registry from years 1958 to 2002, including 3292 patients with thyroid adenocarcinoma. The Systematized Nomenclature of Medicine histology was available from 1993 onward, with 1449 papillary, 288 follicular, 148 anaplastic, and 68 Hurthle cell tumors. MAIN OUTCOME MEASURES: Familial risk for offspring was defined through standardized incidence ratio, adjusted for many variables. RESULTS: The familial risk for papillary carcinoma was 3.21 and 6.24 when a parent and a sibling, respectively, were diagnosed with thyroid cancers. There was an apparent gender preference, particularly among sisters, whose risk was 11.19. The risks were highest for early onset cancers. Thyroid adenocarcinoma was shown to be associated with melanoma and connective tissue tumors, and probably also with neurinomas (schwannomas). Associations found in single comparisons with papillary thyroid cancer and other sites included right-sided colon, breast, ovarian, and kidney cancers. Hurthle cell tumors were associated with Hodgkin's and non-Hodgkin's lymphoma, but the numbers of cases were small. CONCLUSIONS: The present findings were based on a limited number of cases, but they display a complex and heterogeneous pattern of familial nonmedullary thyroid cancer. The high risk for papillary carcinoma among women requires clinical attention, although the absolute risks for this rare cancer are still low.

Adenocarcinoma↗

Familial risks for colorectal cancer show evidence on recessive inheritance.

Recent molecular genetic data have become available on a recessive inheritance in colorectal cancer (CRC). We wanted to search for evidence for recessive inheritance from a population-based family data set, which is not sensitive to reporting or ascertainment bias. The nationwide Swedish Family-Cancer Database covered 10.3 million individuals whose invasive CRCs of adenocarcinoma histology were followed from 1991 to 2000. Age of the offspring and parental populations was limited to less than 69 years. Standardized incidence ratios (SIRs) were calculated for site-specific CRC in offspring whose parents or siblings were diagnosed with CRC. A total of 6,774 offspring were recorded with CRC, whose risk was 2.13 when a parent was diagnosed with CRC and it was 2.75 when a sibling was affected. The SIRs for right-sided colon cancer were 7.53 among siblings and 3.66 among offspring of affected parents, giving a 1.8-fold excess familial risk among siblings. Colon cancer among the 0- to 68-year-old population accounted for about 25% of all colon cancers. Examination of all cancers in family members of the affected siblings did not reveal large contribution by known syndromes, such as hereditary nonpolyposis colorectal cancer. The most likely explanation to the high risk of right-sided colon cancer among siblings is a recessive inheritance, which would account for 0.75% of all CRCs. Its high prevalence and predilection to right-sided colon suggest that only a small proportion of this familial aggregation could be due to MYH mutations.

Adolescent↗

SNP microarray analysis for genome-wide detection of crossover regions.

There is a great deal of interest in understanding the non-random distribution of recombination events over the human genome, because it has important implications for using linkage disequilibrium (LD) to identify human disease genes. So far, only a few recombination hotspots in the human genome have been characterised and the identification of new crossover hotspots will contribute to a better understanding of the mechanisms that govern their formation and distribution. This study shows that high-density single nucleotide polymorphism (SNP) arrays, together with the presented analysis method, are an appropriate tool for generating a whole-genome recombination pattern and for detecting new crossover regions with enhanced recombination frequency. Based on the genotype data of 16 members of a Caucasian three-generation family, we identified 825 crossover regions. The average recombination frequency of females and males was 0.77 and 0.56 cM/Mb, respectively. We detected 24 crossover regions showing elevated recombination activity, which comprised known hotspots, like the MHC II region, confirming the non-random distribution of recombination events along the genome. Interestingly, 29.2% of the identified crossover hotspot regions overlapped with regions flanked by segmental duplications published by Bailey et al. (Science 297:1003-1007, 2002) suggesting that segmental duplications and crossover hotspot regions are mechanistically linked. By extrapolating the results of the present study, we conclude that it might be feasible, at least in part, to estimate to what extent the block-like pattern of LD exactly relies on the genome-wide crossover pattern using the next generation high-density SNP microarrays.

Crossing Over, Genetic↗

Vascular endothelial growth factor polymorphisms in relation to breast cancer development and prognosis.

PURPOSE: Angiogenesis is a necessary step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a major mediator of breast cancer angiogenesis. Therefore, we investigated the association of polymorphisms in the VEGF gene with breast cancer risk and prognostic characteristics of the tumors in a large case-control study. EXPERIMENTAL DESIGN: We examined three polymorphisms in the VEGF gene (-2578C/A, -1154G/A, and +936C/T) in 571 familial breast cancer cases from Poland and Germany and -2578C/A, -634G/C, and +936C/T polymorphisms in 974 unselected breast cancer cases from Sweden together with ethnically and geographically selected controls. RESULTS: None of the polymorphisms or any haplotype was significantly associated with either familial or unselected breast cancers. Our study suggests that the +936C/T polymorphism is unlikely to be associated with breast cancer. We also analyzed the unselected cases for genotypes or haplotypes that associated with tumor characteristics. The -634CC genotype and the -2578/-634 CC haplotype were significantly associated with high tumor aggressiveness (large tumor size and high histologic grade, P < 0.01) and the -2578AA genotype and the -2578/-634 AG haplotype with low histologic grade tumors (P = 0.04). The genotypes and haplotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status. CONCLUSIONS: Although none of the polymorphisms studied in the VEGF gene was found to influence susceptibility to breast cancer significantly, some of the VEGF genotypes and haplotypes may influence tumor growth through an altered expression of VEGF and tumor angiogenesis.

Adult↗

Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines.

We studied global gene expression in three melanoma cell lines with the most common and potent V600E mutation in the B-RAF gene-four cell lines with a common Q61R mutation in the N-RAS gene and three cell lines with no mutations using human HG-U133A 2.0 micro-arrays with 22 277 transcripts. Data analysis using stringent criteria revealed several upregulated and downregulated genes in cell lines with B-RAF and N-RAS mutations compared with cell lines without mutations. We found 29 genes specifically upregulated and 32 genes downregulated in cell lines with B-RAF mutations, whereas 70 genes were upregulated and 39 downregulated in cell lines with N-RAS mutations; 11 genes showed overlapping upregulation and 45 downregulation. The micro-array data for nine selected genes were validated by the real-time PCR technique. Expression of a large number of genes, that encode members or regulators of the RAS/RAF/MEK/ERK pathways or are involved in metastasis or invasion, was affected in cell lines with mutations in B-RAF and N-RAS. Upregulated genes in cell lines with mutations included dual-specificity phosphatase 6 (DUSP6), sprouty 2 (SPRY2), v-akt murine thymoma viral oncogene homolog 3 (AKT3) and matrix metalloproteinase 14 (MMP14); downregulated genes included interleukin 18 (IL18), Krüppel-like factor 5 (KLF5) and inhibitor of DNA binding 2 (ID2). Our results, though carried on cell lines, provide a novel insight into the effect of mutations in the B-RAF and N-RAS genes on global gene expression in melanoma and highlight the complexity of mechanisms involved in tumour initiation and maintenance.

DNA Mutational Analysis↗

Are twins at risk of cancer: results from the Swedish family-cancer database.

A few twin studies on cancer have addressed questions on the possible carcinogenic or protective effects of twining by comparing the occurrence of cancer in twins and singletons. The nationwide Swedish Family-Cancer Database of 10.2 million individuals and 69,654 0- to 70-year-old twin pairs were used to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for all main cancers compared to singletons. The overall risk of cancer in same- or different-sex twins was at the same level as the risk for singletons. Testicular cancer, particularly seminoma, was increased among same-sex twins (1.54) and all twins to an SIR of 1.38. Among other tumors, neurinomas and non-thyroid endocrine gland tumors were increased. Colorectal cancers and leukemia were decreased among all twins. Melanoma and squamous cell skin cancer were decreased in male same-sex twins. The data on this unselected population of twins suggest that twinning per se is not a risk factor of cancer. In utero hormonal exposures or postnatal growth stimulation may be related to the risk of testicular cancer and pituitary tumors. Protective effects against colorectal cancer may be related to a beneficial diet, and in melanoma and skin cancer, to socioeconomic factors. The study involved multiple comparisons, and internal consistency between the results was one of the main factors considered for their plausibility. The results should encourage others working on twin and singleton populations to examine the specific associations and emerging hypotheses.

Adolescent↗

Genetic epidemiology of cancer: from families to heritable genes.

A reliable determination of familial risks for cancer is important for clinical counseling, prevention and understanding cancer etiology. Family-based gene identification efforts may be targeted if the risks are well characterized and the mode of inheritance is identified. Medically verified data on familial risks have not been available for all types of cancer but they have become available through the use of the nationwide Swedish Family-Cancer Database, which includes all Swedes born in 1932 and later with their parents, totaling over 10 million individuals. Over 150 publications have emanated from this source. The familial risks of cancer have been characterized for all main cancers and the contribution of environmental and heritable effects to the familial aggregation has been assessed. Furthermore, the mode of inheritance has been deduced by comparing risks from parental and sibling probands. Examples are shown on familial clustering of cancers, for which heritable susceptibility genes are yet unknown, such as squamous cell carcinoma of the skin, intestinal carcinoids, thyroid papillary tumors, brain astrocytomas and pituitary adenomas. Some common cancers, such as lung and kidney cancers, appear to show an early-onset recessive component because familial risks among siblings are much higher than those in families where parents are probands. Many of the cancer sites showing high familial risks lack guidelines for clinical counseling or action level. In conclusion, we recommend that any future gene identification efforts, either using linkage or association designs, devise their strategies based on data from family studies. Clinical genetic counseling would benefit from reviewing established familial risks on all main types of cancer.

Cluster Analysis↗