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S E Bojesen,
K A Pooley,
S E Johnatty,
J Beesley,
K Michailidou,
J P Tyrer,
S L Edwards,
H A Pickett,
H C Shen,
C E Smart, [......],
P Hillemanns,
R Winqvist,
M Durst,
P Devilee,
I Runnebaum,
A Jakubowska,
J Lubinski,
A Mannermaa,
R Butzow,
others
[show abstract]
[hide abstract]
ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed approximately 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10(-14)) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
01/2013: pages 371-84;
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T Pal,
M R Akbari,
P Sun,
J-H Lee,
J Fulp,
Z Thompson,
D Coppola,
S Nicosia,
T A Sellers,
J McLaughlin, H A Risch,
B Rosen,
P Shaw,
J Schildkraut,
S A Narod
[show abstract]
[hide abstract]
ABSTRACT: Background:Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer.Methods:The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women.Results:Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers.Conclusions:Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.British Journal of Cancer advance online publication, 9 October 2012; doi:10.1038/bjc.2012.452 www.bjcancer.com.
British Journal of Cancer 10/2012; · 5.04 Impact Factor
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E J Duell,
E Lucenteforte,
S H Olson,
P M Bracci,
D Li, H A Risch,
D T Silverman,
B T Ji,
S Gallinger,
E A Holly, [......],
H B Bueno-de-Mesquita,
P Ghadirian,
R C Kurtz,
E Ludwig,
H Yu,
A B Lowenfels,
D Seminara,
G M Petersen,
C La Vecchia,
P Boffetta
[show abstract]
[hide abstract]
ABSTRACT: Background Pancreatitis is a known risk factor for pancreatic cancer; however, an unknown fraction of the disease is thought to be a consequence of tumor-related duct obstruction. Patients and methods A pooled analysis of a history of pancreatitis and risk of pancreatic cancer was carried out considering the time interval between diagnoses and potential modification by covariates. Adjusted pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from 10 case-control studies (5048 cases of ductal pancreatic adenocarcinoma and 10 947 controls) taking part in the International Pancreatic Cancer Case-Control Consortium (PanC4). Results The association between pancreatitis and pancreatic cancer was nearly three-fold at intervals of >2 years between diagnoses (OR: 2.71, 95% CI: 1.96-3.74) and much stronger at intervals of ≤2 years (OR: 13.56, 95% CI: 8.72-21.90) probably reflecting a combination of reverse causation and antecedent misdiagnosis of pancreas cancer as pancreatitis. The younger (<65 years) pancreatic cancer cases showed stronger associations with previous (>2 years) pancreatitis (OR: 3.91, 95% CI: 2.53-6.04) than the older (≥65 years) cases (OR: 1.68, 95% CI: 1.02-2.76; P value for interaction: 0.006). Conclusions Despite a moderately strong association between pancreatitis (diagnosed before >2 years) and pancreatic cancer, the population attributable fraction was estimated at 1.34% (95% CI: 0.612-2.07%), suggesting that a relatively small proportion of pancreatic cancer might be avoided if pancreatitis could be prevented.
Annals of Oncology 07/2012; 23(11):2964-70. · 6.43 Impact Factor
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C Bosetti,
E Lucenteforte,
D T Silverman,
G Petersen,
P M Bracci,
B T Ji,
E Negri,
D Li, H A Risch,
S H Olson, [......],
Y T Gao,
M Hassan,
H Yu,
R C Kurtz,
M Cotterchio,
J Su,
P Maisonneuve,
E J Duell,
P Boffetta,
C La Vecchia
[show abstract]
[hide abstract]
ABSTRACT: To evaluate the dose-response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables.
We analyzed data from 12 case-control studies within the International Pancreatic Cancer Case-Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models.
Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0-1.3) for former smokers and 2.2 (95% CI 1.7-2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR=3.4 for ≥35 cigarettes per day, P for trend<0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR=2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years.
This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ∼20 years after quitting.
Annals of Oncology 11/2011; 23(7):1880-8. · 6.43 Impact Factor
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P Bertuccio,
C La Vecchia,
D T Silverman,
G M Petersen,
P M Bracci,
E Negri,
D Li, H A Risch,
S H Olson,
S Gallinger, [......],
E Lucenteforte,
M Hassan,
H Yu,
R C Kurtz,
M Cotterchio,
J Su,
P Maisonneuve,
E.J. Duell,
C Bosetti,
P Boffetta
Annals of Oncology 06/2011; · 6.43 Impact Factor
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P Bertuccio,
C La Vecchia,
D T Silverman,
G M Petersen,
P M Bracci,
E Negri,
D Li, H A Risch,
S H Olson,
S Gallinger, [......],
E Lucenteforte,
M Hassan,
H Yu,
R C Kurtz,
M Cotterchio,
J Su,
P Maisonneuve,
E J Duell,
C Bosetti,
P Boffetta
[show abstract]
[hide abstract]
ABSTRACT: Cigarette smoking is the best-characterized risk factor for pancreatic cancer. However, data are limited for other tobacco smoking products and smokeless tobacco.
We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk of pancreatic cancer using data from 11 case-control studies (6056 cases and 11,338 controls) within the International Pancreatic Cancer Case-Control Consortium (PanC4). Pooled odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models adjusted for study center and selected covariates.
Compared with never tobacco users, the OR for cigar-only smokers was 1.6 (95% CI: 1.2-2.3), i.e. comparable to that of cigarette-only smokers (OR 1.5; 95% CI 1.4-1.6). The OR was 1.1 (95% CI 0.69-1.6) for pipe-only smokers. There was some evidence of increasing risk with increasing amount of cigar smoked per day (OR 1.82 for ≥ 10 grams of tobacco), although not with duration. The OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI 0.75-1.3).
This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use.
Annals of Oncology 01/2011; 22(6):1420-6. · 6.43 Impact Factor
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A C Antoniou,
A P Cunningham,
J Peto,
D G Evans,
F Lalloo,
S A Narod, H A Risch,
J E Eyfjord,
J L Hopper,
M C Southey, [......],
J Lubinski,
J Gronwald,
B Gorski,
L Tryggvadottir,
K Syrjakoski,
O P Kallioniemi,
H Eerola,
H Nevanlinna,
P D P Pharoah,
D F Easton
British Journal of Cancer 07/2008; 98(12):2015. · 5.04 Impact Factor
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A C Antoniou,
A P Cunningham,
J Peto,
D G Evans,
F Lalloo,
S A Narod, H A Risch,
J E Eyfjord,
J L Hopper,
M C Southey, [......],
J Lubinski,
J Gronwald,
B Gorski,
L Tryggvadottir,
K Syrjakoski,
O-P Kallioniemi,
H Eerola,
H Nevanlinna,
P D P Pharoah,
D F Easton
[show abstract]
[hide abstract]
ABSTRACT: Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).
British Journal of Cancer 05/2008; 98(8):1457-66. · 5.04 Impact Factor
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C L Pearce,
A H Wu,
S A Gayther,
A E Bale,
P A Beck,
J Beesley,
S Chanock,
D W Cramer,
R DiCioccio,
R Edwards, [......],
K L Terry,
P M Webb,
D C Whiteman,
A S Whittemore,
W Zheng,
P D P Pharoah,
G Chenevix-Trench,
M C Pike,
J Schildkraut,
A Berchuck
[show abstract]
[hide abstract]
ABSTRACT: There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.
British Journal of Cancer 02/2008; 98(2):282-8. · 5.04 Impact Factor
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A C Antoniou,
P D P Pharoah,
S Narod, H A Risch,
J E Eyfjord,
J L Hopper,
H Olsson,
O Johannsson,
A Borg,
B Pasini, [......],
H Eerola,
H Nevanlinna,
K Syrjäkoski,
O-P Kallioniemi,
D Thompson,
C Evans,
J Peto,
F Lalloo,
D G Evans,
D F Easton
[show abstract]
[hide abstract]
ABSTRACT: A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.
Journal of Medical Genetics 08/2005; 42(7):602-3. · 6.36 Impact Factor
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A Antoniou,
P D P Pharoah,
S Narod, H A Risch,
J E Eyfjord,
J L Hopper,
N Loman,
H Olsson,
O Johannsson,
A Borg, [......],
H Eerola,
H Nevanlinna,
K Syrjäkoski,
O-P Kallioniemi,
D Thompson,
C Evans,
J Peto,
F Lalloo,
D G Evans,
D F Easton
[show abstract]
[hide abstract]
ABSTRACT: Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
The American Journal of Human Genetics 05/2003; 72(5):1117-30. · 10.60 Impact Factor
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S T Mayne, H A Risch,
R Dubrow,
W H Chow,
M D Gammon,
T L Vaughan,
D C Farrow,
J B Schoenberg,
J L Stanford,
H Ahsan,
A B West,
H Rotterdam,
W J Blot,
J F Fraumeni
[show abstract]
[hide abstract]
ABSTRACT: Incidence rates for adenocarcinoma of the esophagus and gastric cardia have been rising rapidly. We examined nutrient intake as a risk factor for esophageal and gastric cancers in a population-based case-control study in Connecticut, New Jersey, and western Washington state. Interviews were completed for cases with histologically confirmed esophageal adenocarcinoma (n = 282), adenocarcinoma of the gastric cardia (n = 255), esophageal squamous cell carcinoma (n = 206), and noncardia gastric adenocarcinoma (n = 352), along with population controls (n = 687). Associations between nutrient intake and risk of cancer were estimated by adjusted odds ratios (ORs), comparing the 75th versus the 25th percentile of intake. The following nutrients were significantly inversely associated with risk of all four tumor types: fiber, beta-carotene, folate, and vitamins C and B6. In contrast, dietary cholesterol, animal protein, and vitamin B12 were significantly positively associated with risk of all four tumor types. Dietary fat [OR, 2.18; 95% confidence interval (CI), 1.27-3.76] was significantly associated with risk of esophageal adenocarcinoma only. Dietary nitrite (OR, 1.65; 95% CI, 1.26-2.16) was associated with noncardia gastric cancer only. Vitamin C supplement use was associated with a significantly lower risk for noncardia gastric cancer (OR, 0.60; 95% CI, 0.41-0.88). Higher intake of nutrients found primarily in plant-based foods was associated with a reduced risk of adenocarcinomas of the esophagus and gastric cardia, whereas higher intake of nutrients found primarily in foods of animal origin was associated with an increased risk.
Cancer Epidemiology Biomarkers & Prevention 11/2001; 10(10):1055-62. · 4.12 Impact Factor
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P K Dhillon,
D C Farrow,
T L Vaughan,
W H Chow, H A Risch,
M D Gammon,
S T Mayne,
J L Stanford,
J B Schoenberg,
H Ahsan,
R Dubrow,
A B West,
H Rotterdam,
W J Blot,
J F Fraumeni
[show abstract]
[hide abstract]
ABSTRACT: The worldwide rates for histology- and subsite-specific types of esophageal and gastric cancer reveal strikingly divergent patterns. The contribution of environmental and genetic factors has been explored in several high-incidence areas, but data on genetic influences are scarce for Western countries. Using data from a multicenter, population-based, case-control study on 1,143 cases and 695 controls in the United States, we evaluated whether a family history of digestive or other cancers was associated with an increased risk of esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261) or non-cardia gastric adenocarcinoma (n = 368). After adjusting for other risk factors, individuals reporting a family history of digestive cancers experienced no increased risk of either type of esophageal cancer but they were prone to adenocarcinomas of the gastric cardia [odds ratio (OR) = 1.34, 95% confidence interval (CI) 0.91-1.97] and non-cardia segments (OR =1.46, 95% CI 1.03-2.08). This familial tendency, particularly for non-cardia gastric tumors, was largely explained by an association with family history of stomach cancer (OR = 2.52, 95% CI 1.50-4.23). In addition, family history of breast cancer was associated with increased risks of esophageal adenocarcinoma (OR = 1.74, 95% CI 1.07-2.83) and non-cardia gastric adenocarcinoma (OR = 1.76, 95% CI 1.09-2.82). Also seen were non-significant familial associations of esophageal squamous-cell cancer with prostate cancer as well as non-cardia gastric cancer with leukemia and brain tumors, though these relationships must be interpreted with caution. Our data point to the role of familial susceptibility to gastric cancer, but not to any form of esophageal cancer, in the United States.
International Journal of Cancer 08/2001; 93(1):148-52. · 5.44 Impact Factor
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H A Risch,
J R McLaughlin,
D E Cole,
B Rosen,
L Bradley,
E Kwan,
E Jack,
D J Vesprini,
G Kuperstein,
J L Abrahamson,
I Fan,
B Wong,
S A Narod
[show abstract]
[hide abstract]
ABSTRACT: A population-based series of 649 unselected incident cases of ovarian cancer diagnosed in Ontario, Canada, during 1995-96 was screened for germline mutations in BRCA1 and BRCA2. We specifically tested for 11 of the most commonly reported mutations in the two genes. Then, cases were assessed with the protein-truncation test (PTT) for exon 11 of BRCA1, with denaturing gradient gel electrophoresis for the remainder of BRCA1, and with PTT for exons 10 and 11 of BRCA2. No mutations were found in all 134 women with tumors of borderline histology. Among the 515 women with invasive cancers, we identified 60 mutations, 39 in BRCA1 and 21 in BRCA2. The total mutation frequency among women with invasive cancers, 11.7% (95% confidence interval [95%CI] 9.2%-14.8%), is higher than previous estimates. Hereditary ovarian cancers diagnosed at age <50 years were mostly (83%) due to BRCA1, whereas the majority (60%) of those diagnosed at age >60 years were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives. Risks of ovarian, breast, and stomach cancers and leukemias/lymphomas were increased nine-, five-, six- and threefold, respectively, among first-degree relatives of cases carrying BRCA1 mutations, compared with relatives of noncarriers, and risk of colorectal cancer was increased threefold for relatives of cases carrying BRCA2 mutations. For carriers of BRCA1 mutations, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast-cancer risk for first-degree relatives, there was a strong trend according to mutation location along the coding sequence of BRCA1, with little evidence of increased risk for mutations in the 5' fifth, but 8.8-fold increased risk for mutations in the 3' fifth (95%CI 3.6-22.0), corresponding to a carrier penetrance of essentially 100%. Ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer-cluster region (OCCR) of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. Past studies may have underestimated the contribution of BRCA2 to ovarian cancer, because mutations in this gene cause predominantly late-onset cancer, and previous work has focused more on early-onset disease. If confirmed in future studies, the trend in breast-cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have significant impact on treatment decisions for carriers of BRCA1-mutations. As well, BRCA2 mutations may prove to be a greater cause of cancer in male carriers than previously has been thought.
The American Journal of Human Genetics 04/2001; 68(3):700-10. · 10.60 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Prevailing hypotheses about the causes of ovarian carcinogenesis predict that women with a history of multiple births (twins, triplets, etc.) should be at increased risk of epithelial ovarian cancer. However, the scant available evidence suggests that they may actually be at lower risk. To resolve this issue, we pooled data from eight studies involving 2859 parous women with epithelial ovarian cancer (case patients) and 7434 parous women without ovarian cancer (control women). In addition to assessing their history of multiple births (and the sex of the children, where available), we obtained information on age, parity, oral contraceptive use, and other reproductive factors for each woman. Details of tumor histology were available for all case patients. We estimated the relative risks of various histologic types of ovarian cancers associated with multiple births by using multivariable logistic regression analysis, adjusting for matching and confounding variables.
Among these parous women, 73 case patients (2. 6%) and 257 control women (3.5%) had a history of multiple births. The adjusted summary odds ratio (OR) for developing all types of epithelial ovarian cancer that are associated with multiple births was 0.81 (95% confidence interval [CI] = 0.61-1.08). We found no evidence that risks associated with multiple births differed among women with borderline or invasive tumors and among women with same-sex and opposite-sex offspring from multiple births. The risk reductions appeared specific for nonmucinous tumors (n = 2453; summary adjusted OR = 0.71 [95% CI = 0.52-0.98]); in contrast, associations with mucinous tumors (n = 406) were heterogeneous across studies.
Parous women with nonmucinous ovarian cancer are no more likely to have a history of multiple births than other parous women, counter to the predictions of current hypotheses for causes of ovarian cancer.
JNCI Journal of the National Cancer Institute 08/2000; 92(14):1172-7. · 13.76 Impact Factor
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D C Farrow,
T L Vaughan,
C Sweeney,
M D Gammon,
W H Chow, H A Risch,
J L Stanford,
P D Hansten,
S T Mayne,
J B Schoenberg,
H Rotterdam,
H Ahsan,
A B West,
R Dubrow,
J F Fraumeni,
W J Blot
[show abstract]
[hide abstract]
ABSTRACT: The incidence of esophageal adenocarcinoma has risen rapidly in the past two decades, for unknown reasons. The goal of this analysis was to determine whether gastroesophageal reflux disease (GERD) or the medications used to treat it are associated with an increased risk of esophageal or gastric cancer, using data from a large population-based case-control study.
Cases were aged 30-79 years, newly diagnosed with esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261), or non-cardia gastric adenocarcinoma (n = 368) in three areas with population-based tumor registries. Controls (n = 695) were chosen by random digit dialing and from Health Care Financing Administration rosters. Data were collected using an in-person structured interview.
History of gastric ulcer was associated with an increased risk of non-cardia gastric adenocarcinoma (OR 2.1, 95% CI 1.4-3.2). Risk of esophageal adenocarcinoma increased with frequency of GERD symptoms; the odds ratio in those reporting daily symptoms was 5.5 (95% CI 3.2-9.3). Ever having used H2 blockers was unassociated with esophageal adenocarcinoma risk (OR 0.9, 95% CI 0.5-1.5). The odds ratio was 1.3 (95% CI 0.6-2.8) in long-term (4 or more years) users, but increased to 2.1 (95% CI 0.8-5.6) when use in the 5 years prior to the interview was disregarded. Risk was also modestly increased among users of antacids. Neither GERD symptoms nor use of H2 blockers or antacids was associated with risk of the other three tumor types.
Individuals with long-standing GERD are at increased risk of esophageal adenocarcinoma, whether or not the symptoms are treated with H2 blockers or antacids.
Cancer Causes and Control 04/2000; 11(3):231-8. · 2.88 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: We examined the effect of abortion type, number, and gestational age on the risk of preeclampsia and transient hypertension among women who received prenatal care from 13 obstetric practices in southern Connecticut between April 1988 and December 1991 (N = 2,739). Subjects were interviewed before 16 weeks' gestation regarding reproductive history and pregnancy-related risk factors. We estimated the risk of preeclampsia (N = 44) and transient hypertension (N = 172) among nulliparous women who had had one or more abortions, with nulliparous women with no abortion as the referent group. Similar effects were seen for one spontaneous or induced abortion, when analyzed separately. A single prior abortion was associated with a decreased risk of preeclampsia [odds ratio (OR) = 0.35; 95% exact confidence interval (CI) = 0.09-1.01]. One abortion had only a small association with risk of transient hypertension (OR = 1.09, 95% exact CI = 0.68-1.72); however, a history of two or more abortions was associated with a decreased risk (OR = 0.42, 95% exact CI = 0.16-0.94). Among nulliparous women with a history of one abortion, a decreased risk of both hypertensive disorders was observed among women whose aborted pregnancy ended at > or =3 months gestation. These findings suggest that a history of abortion in nulliparous women is a protective factor against the risk of preeclampsia in the subsequent pregnancy.
Epidemiology 01/2000; 11(1):36-43. · 5.57 Impact Factor
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H A Risch
[show abstract]
[hide abstract]
ABSTRACT: In the United States, ovarian cancer is the fourth most frequent cause of cancer death among women, following lung, breast, and colorectal cancers. Each year, approximately 26,000 women are diagnosed with ovarian cancer and 14,000 die of it. Germline mutations in BRCA1, BRCA2, or other genes have been implicated in a small fraction of cases. However, it has been suggested that, for the great majority of patients, the risk of epithelial ovarian cancer could be related to "incessant ovulation" (i.e., to the chronically repeated formation of stromal epithelial clefts and inclusion cysts following ovulation) or to some type of hormonal stimulation of ovarian epithelial cells, either on the surface of the ovary or within ovarian inclusion cysts, possibly mediated through excessive gonadotropin secretion. From the evidence to date, the relative importance of these two hypotheses--incessant ovulation and gonadotropin stimulation--cannot be distinguished. While either or both may play a role in the development of ovarian cancer, it appears that an additional major factor must also be involved. The purpose of this review is to evaluate evidence for and against the incessant ovulation and gonadotropin hypotheses, as well as to consider the possibility that risk of ovarian cancer may be increased by factors associated with excess androgenic stimulation of ovarian epithelial cells and may be decreased by factors related to greater progesterone stimulation. Many features of the evidence bearing on the pathophysiology of ovarian cancer appear to support a connection with androgens and progesterone.
JNCI Journal of the National Cancer Institute 01/1999; 90(23):1774-86. · 13.76 Impact Factor
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T L Vaughan,
D C Farrow,
P D Hansten,
W H Chow,
M D Gammon, H A Risch,
J L Stanford,
J B Schoenberg,
S T Mayne,
H Rotterdam,
R Dubrow,
H Ahsan,
A B West,
W J Blot,
J F Fraumeni
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ABSTRACT: Incidence of adenocarcinomas of the esophagus and gastric cardia has risen dramatically over the past 2 decades in the U. S., for reasons that are not yet clear. A number of common medications (e.g., calcium channel blockers, tricyclic antidepressants, and certain asthma medications) promote gastroesophageal reflux by relaxing the lower esophageal sphincter (LES). Reflux is thought to increase cancer risk by promoting cellular proliferation, and by exposing the esophageal epithelium to potentially genotoxic gastric and intestinal contents. Recent studies have suggested that calcium channel blockers may also increase cancer risk by inhibiting apoptosis. Using personal interview data from a multicenter, population-based case-control study conducted between 1993 and 1995 in three areas of the U. S., we evaluated whether the use of LES-relaxing drugs was associated with increased risk of adenocarcinomas of the esophagus and gastric cardia. Cases of esophageal adenocarcinoma (n = 293) and gastric cardia adenocarcinoma (n = 261) were compared with general population controls (n = 695). Information on additional case groups of esophageal squamous cell carcinoma (n = 221) and noncardia gastric cancer (n = 368) were also available for comparison. Overall, 27.4% of controls had used one or more of these drugs for at least 6 months, compared with 30.2% of esophageal adenocarcinoma and 23.8% of gastric cardia adenocarcinoma cases. The adjusted odds ratios (ORs) for ever use were 1.0 [95% confidence interval (CI) = 0.7-1.5] and 0.8 (95% CI = 0.5-1.1), respectively. There was little evidence of increasing risk with increasing duration of use of all LES-relaxing drugs together. We found an increased risk of esophageal adenocarcinoma among persons reporting use of asthma drugs containing theophylline (OR = 2.5; 95% CI = 1.1-5.6) or beta agonists (OR = 1.7; 95% CI = 0.8-3.8). Risks were higher among long-term users (>5 years) of these drugs (OR = 3.1; 95% CI = 0.9-10.3 and OR = 2.3; 95% CI = 0.8-7.0, respectively). In contrast, there was no evidence that the use of calcium channel blockers or other specific groups of drugs increased the risk of any of the cancers studied. These results provide reassuring evidence that the increases in incidence of adenocarcinomas of the esophagus and gastric cardia are not likely to be related to the use of LES-relaxing drugs as a group, or calcium channel blockers in particular, but they do suggest that persons treated for long-standing asthma may be at increased risk of esophageal adenocarcinoma.
Cancer Epidemiology Biomarkers & Prevention 10/1998; 7(9):749-56. · 4.12 Impact Factor
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D C Farrow,
T L Vaughan,
P D Hansten,
J L Stanford, H A Risch,
M D Gammon,
W H Chow,
R Dubrow,
H Ahsan,
S T Mayne,
J B Schoenberg,
A B West,
H Rotterdam,
J F Fraumeni,
W J Blot
[show abstract]
[hide abstract]
ABSTRACT: Regular users of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are at reduced risk of colon cancer, but the evidence for protective effects of NSAIDs elsewhere in the digestive tract is scant. We investigated the association between the use of NSAIDs and risk of esophageal and gastric cancer, using data from a large population-based, case-control study. Cases were individuals, ages 30-79 years, diagnosed with esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261), or noncardia gastric adenocarcinoma (n = 368) in three areas with population-based tumor registries. Controls (n = 695) were selected by random digit dialing and through the rosters of the Health Care Financing Administration. After controlling for the major risk factors, we found that current users of aspirin were at decreased risk of esophageal adenocarcinoma [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.24-0.58], esophageal squamous cell carcinoma (OR, 0.49; 95% CI, 0.28-0.87), and noncardia gastric adenocarcinoma (OR, 0.46; 95% CI, 0.31-0.68), but not of gastric cardia adenocarcinoma (OR, 0.80; 95% CI, 0.54-1.19), when compared to never users. Risk was similarly reduced among current users of nonaspirin NSAIDs. The associations with current NSAID use persisted when we excluded use within 2 or 5 years of reference date, which might have been affected by preclinical disease in cases, and when we restricted analyses to subjects reporting no history of chronic gastrointestinal symptoms. Our findings add to the growing evidence that the risk of cancers of the esophagus and stomach is reduced in users of NSAIDs, although whether the association is causal in nature is not clear.
Cancer Epidemiology Biomarkers & Prevention 03/1998; 7(2):97-102. · 4.12 Impact Factor
