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Richard A DiCioccio

Publications and source records attributed to Richard A DiCioccio.

11 recordsLinked to original sources
PubMed2006

Common variants in mismatch repair genes and risk of invasive ovarian cancer.

Mismatch repair (MMR) is important for repairing of nucleotide mismatches during DNA replication. Germline mutations in MMR genes are associated with hereditary non-polyposis colorectal cancer (HNPCC). Ovarian cancer occurs as part of the HNPCC phenotype, and so common variants in MMR genes are candidates for ovarian cancer susceptibility. We performed a large multicentre case-control study to investigate associations of common variations in MMR genes and ovarian cancer using a single nucleotide polymorphism (SNP) tagging approach. A total of 2570 controls and 1531 cases from three separate studies were genotyped for 44 tagging SNPs (stSNP) in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were marginally different between cases and controls for PMS2 rs7797466 (P(2df) = 0.046) with a 1.17-fold (95% CI 1.03-1.33) increase in risk for each 'a' allele carried (P-trend = 0.013). Haplotype analysis of PMS2 also showed significant differences in frequencies between cases and controls (P(7df) = 0.005), with one haplotype accounting for most of the effect. There was also marginal evidence for a recessive protective effect with common homozygote as the baseline comparator for two SNPs--MSH6 rs3136245 (OR 0.67; 95% CI 0.46-0.98) and MSH3 rs6151662 (OR 0.28; 95% CI 0.08-0.91)--but the comparisons of genotype frequencies for these variants were not significant (P = 0.10 and 0.054). In conclusion, it is unlikely that common variants in MLH1, MLH3, PMS1, MSH2, MSH3 and MSH6 contribute significantly to ovarian cancer susceptibility. The observed association of PMS2 rs7797466 with ovarian cancer warrants confirmation in an independent study.

Adenosine Triphosphatases↗
PubMed2006

Analysis of ovarian tumors for the presence of human papillomavirus DNA.

AIM: The role of human papillomavirus (HPV) infection in ovarian tumorigenesis is uncertain. The objective of this study was to screen a collection of ovarian tumors for the presence of high-risk oncogenic HPV types 16, 18 and 33. METHODS: Twenty benign and malignant ovarian tumors were obtained from women undergoing pelvic surgery at a regional comprehensive cancer institution in North America. DNA was isolated from the snap-frozen tumors, and commercial polymerase chain reaction (PCR) detection sets were used to analyze the tumor DNA samples for the presence of DNA from HPV types 16, 18 and 33. RESULTS: The DNA from HPV types 16, 18 and 33 was not detected in any of the ovarian tumors. CONCLUSIONS: Our findings do not support an association between infection with HPV types 16, 18 and 33 and ovarian neoplasia in this patient population.

Adult↗
PubMed2006

Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations.

BACKGROUND: First-degree relatives of patients with breast or ovarian cancer have increased risks for these cancers. Little is known about how their risks vary with the patient's cancer site, carrier status for predisposing genetic mutations, or age at cancer diagnosis. METHODS: We evaluated breast and ovarian cancer incidence in 2,935 female first-degree relatives of non-Hispanic White female patients with incident invasive cancers of the breast (n = 669) or ovary (n = 339) who were recruited from a population-based cancer registry in northern California. Breast cancer patients were tested for BRCA1 and BRCA2 mutations. Ovarian cancer patients were tested for BRCA1 mutations. We estimated standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) for breast and ovarian cancer among the relatives according to the patient's mutation status, cancer site, and age at cancer diagnosis. RESULTS: In families of patients who were negative or untested for BRCA1 or BRCA2 mutations, risks were elevated only for the patient's cancer site. The breast cancer SIR was 1.5 (95% CI, 1.2-1.8) for relatives of breast cancer patients, compared with 1.1 (95% CI, 0.8-1.6) for relatives of ovarian cancer patients (P = 0.12 for difference by patient's cancer site). The ovarian cancer SIR was 0.9 (95% CI, 0.5-1.4) for relatives of breast cancer patients, compared with 1.9 (95% CI, 1.0-4.0) for relatives of ovarian cancer patients (P = 0.04 for difference by site). In families of BRCA1-positive patients, relatives' risks also correlated with the patient's cancer site. The breast cancer SIR was 10.6 (95% CI, 5.2-21.6) for relatives of breast cancer patients, compared with 3.3 (95% CI, 1.4-7.3) for relatives of ovarian cancer patients (two-sided P = 0.02 for difference by site). The ovarian cancer SIR was 7.9 (95% CI, 1.2-53.0) for relatives of breast cancer patients, compared with 11.3 (3.6-35.9) for relatives of ovarian cancer patients (two-sided P = 0.37 for difference by site). Relatives' risks were independent of patients' ages at diagnosis, with one exception: In families ascertained through a breast cancer patient without BRCA mutations, breast cancer risks were higher if the patient had been diagnosed before age 40 years. CONCLUSION: In families of patients with and without BRCA1 mutations, breast and ovarian cancer risks correlate with the patient's cancer site. Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patient's age at diagnosis. These patterns support the presence of genes that modify risk specific to cancer site, in both carriers and noncarriers of BRCA1 and BRCA2 mutations.

Adult↗
PubMed2005

Aberrations of TACC1 and TACC3 are associated with ovarian cancer.

BACKGROUND: Dysregulation of the human Transforming Acidic Coiled Coil (TACC) genes is thought to be important in the development and progression of multiple myeloma, breast and gastric cancer. Recent, large-scale genomic analysis and Serial Analysis of Gene Expression data suggest that TACC1 and TACC3 may also be involved in the etiology of ovarian tumors from both familial and sporadic cases. Therefore, the aim of this study was to determine the occurrence of alterations of these TACCs in ovarian cancer. METHODS: Detection and scoring of TACC1 and TACC3 expression was performed by immunohistochemical analysis of the T-BO-1 tissue/tumor microarray slide from the Cooperative Human Tissue Network, Tissue Array Research Program (TARP) of the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Tumors were categorized as either positive (greater than 10% of cells staining) or negative. Statistical analysis was performed using Fisher's exact test and p < 0.05 (single comparisons), and p < 0.02 (multiple comparisons) were considered to be significant. Transgenomics WAVE high performance liquid chromatography (dHPLC) was used to pre-screen the TACC3 gene in constitutional DNA from ovarian cancer patients and their unaffected relatives from 76 families from the Gilda Radner Familial Ovarian Cancer Registry. All variant patterns were then sequenced. RESULTS: This study demonstrated absence of at least one or both TACC proteins in 78.5% (51/65) of ovarian tumors tested, with TACC3 loss observed in 67.7% of tumors. The distribution pattern of expression of the two TACC proteins was different, with TACC3 loss being more common in serous papillary carcinoma compared with clear cell carcinomas, while TACC1 staining was less frequent in endometroid than in serous papillary tumor cores. In addition, we identified two constitutional mutations in the TACC3 gene in patients with ovarian cancer from the Gilda Radner Familial Ovarian Cancer Registry. These patients had previously tested negative for mutations in known ovarian cancer predisposing genes. CONCLUSION: When combined, our data suggest that aberrations of TACC genes, and TACC3 in particular, underlie a significant proportion of ovarian cancers. Thus, TACC3 could be a hitherto unknown endogenous factor that contributes to ovarian tumorigenesis.

Journal Article↗
PubMed2005

BRAF polymorphisms and the risk of ovarian cancer of low malignant potential.

OBJECTIVE: The object of this study was to test the hypothesis that BRAF is a low-risk susceptibility gene for low malignant potential (LMP) ovarian cancer. A recent study of the relationship between BRAF polymorphisms and malignant melanoma identified strong linkage disequilibrium across the BRAF gene with one of the three most common haplotypes (haplotype C) having a population attributable risk of approximately 1.6%. We therefore hypothesized that the same BRAF haplotype may confer an increased risk of serous ovarian tumors of low malignant potential. METHODS: We genotyped 383 cases of LMP ovarian cancer, including 234 of serous histology, and 987 controls for seven SNPs, representative of the most common BRAF gene haplotypes, using MALDI-TOF mass spectrometry. RESULTS: Haplotype information was obtained for 369 LMP ovarian cancer cases and 983 healthy controls. None of the haplotypes were found to be associated with risk of LMP ovarian cancer (OR for haplotype C 0.81, 95% CI = 0.54-1.22), or with the risk of serous LMP ovarian cancer (OR for haplotype C 0.90, 95% CI = 0.56-1.45). CONCLUSION: We found no evidence to suggest that BRAF is a low-risk LMP ovarian cancer susceptibility gene.

Adult↗
PubMed2004

The effects of BRCA1 missense variants V1804D and M1628T on transcriptional activity.

Many families with multiple cases of ovarian cancer, breast cancer, or both segregate inherited mutations in one allele of the tumor suppressor gene BRCA1. Genetic testing is used to assess cancer risk; however, testing can detect missense DNA alterations, called unclassified variants, of unknown functional and biological significance with uncertain risk implications. Some missense variants at the transcriptional activation domain of BRCA1 of cancer patients inactivate transcriptional activity of BRCA1, providing evidence that they are deleterious. We identified the variants V1804D and M1628T at the transcriptional activation domain of BRCA1 of two ovarian cancer patients without a family history of ovarian or breast cancer. To test if these residues are critical for transcriptional activation, we created V1804D and M1628T independently in BRCA1 cDNA via site-directed mutagenesis in a mammalian expression vector, pcDNA3.1. Wild-type, mutant, and empty vector constructs were tested in human kidney 293 cells using a p53-responsive luciferase reporter. M1628T had the same transcriptional activity as wild-type BRCA1 but V1804D and the empty vector control showed a 60% reduction. This indicates that V1804D is deleterious but M1628T is not.

Amino Acid Substitution↗
PubMed2004

Histopathology, FIGO stage, and BRCA mutation status of ovarian cancers from the Gilda Radner Familial Ovarian Cancer Registry.

Studies of the histopathology of ovarian cancer arising in patients with germline mutations in BRCA1 or BRCA2 have shown inconsistent findings. We analyzed the large number of tumors from women enrolled in the Gilda Radner Familial Ovarian Cancer Registry for correlations between histopathology and BRCA mutation status. Histopathology slides and reports were reviewed for histology, grade, and stage for cancers of the ovary or peritoneum in 220 women from 126 Gilda Radner Familial Ovarian Cancer Registry families. At least one affected member of each family was analyzed for mutations in the BRCA1 and BRCA2 genes, and tumors from mutation-positive families were compared with those from mutation-negative families. Of 70 patients from 38 BRCA1-positive families, 69 had epithelial ovarian carcinoma and one had a dysgerminoma. Fifteen of 16 patients from nine BRCA2-positive families had epithelial ovarian cancer, and one had a primary peritoneal cancer. Of 134 patients from 79 BRCA-negative families, 118 had epithelial ovarian carcinoma, 11 had ovarian borderline tumors, three had nonepithelial tumors, and two had primary peritoneal carcinoma. There were fewer grade 1 (p < 0.001) and stage I (p = 0.005) cancers in patients from BRCA-positive families than in patients from BRCA-negative families. Neither mucinous nor borderline tumors were found in the BRCA-positive families. In conclusion, ovarian cancers arising in women from BRCA-positive families are more likely to be high-grade and have extraovarian spread than tumors arising in women from BRCA-negative families. Borderline and mucinous tumors do not appear to be part of the phenotype of families with germline mutations in the BRCA genes.

Female↗
PubMed2003

BRCA1/2 mutation status influences somatic genetic progression in inherited and sporadic epithelial ovarian cancer cases.

Metaphase comparative genomic hybridization was used to analyze the spectrum of genetic alterations in 141 epithelial ovarian cancers from BRCA1 and BRCA2 mutation carriers, individuals with familial non-BRCA1/2 epithelial ovarian cancer, and women with nonfamilial epithelial ovarian cancer. Multiple genetic alterations were identified in almost all tumors. The high frequency with which some alterations were identified suggests the location of genes that are commonly altered during ovarian tumor development. In multiple chromosome regions, there were significant differences in alteration frequency between the four tumor types suggesting that BRCA1/2 mutation status and a family history of ovarian cancer influences the somatic genetic pathway of ovarian cancer progression. These findings were supported by hierarchical cluster analysis, which identified genetic events that tend to occur together during tumorigenesis and several alterations that were specific to tumors of a particular type. In addition, some genetic alterations were strongly associated with differences in tumor differentiation and disease stage. Taken together, these data provide molecular genetic evidence to support previous findings from histopathological studies, which suggest that clinical features of ovarian and breast tumors differ with respect to BRCA1/2 mutation status and/or cancer family history.

Chromosome Aberrations↗
PubMed2003

BRCA1 mutations.

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Female↗
PubMed2002

Comparison of techniques for the successful detection of BRCA1 mutations in fixed paraffin-embedded tissue.

Genomic DNA isolated from archived paraffin-embedded tissues (PETs) has important applicability in genetic epidemiological studies. To determine the accuracy of the sequence data, using DNA derived from PET among patients with known mutations characterized from blood, we conducted a blinded factorial experiment to simultaneously examine the influence of mutation type, age of the PET, PCR product type, and Taq DNA polymerase on BRCA1 gene mutation detection. The probability of detecting sequencing artifacts was also investigated. We found that: (a) gene detection was most accurate for newer PET; (b) high fidelity Taq with shorter PCR amplicon length yielded the highest mutation detection success rate and lowest artifact rate; and (c) base substitutions were more often correctly identified than frameshift mutations or wild-type sequences. We concluded that DNA derived from PET that archived for less than 18 years can be used successfully for detecting BRCA1 gene mutations if quality control is strictly maintained.

DNA Mutational Analysis↗