Jan Blaakær

A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ∼2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10−8). The most significant SNP (rs3814113; P = 2.5 × 10−17) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79–0.86, Ptrend = 5.1 × 10−19). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73–0.81, Ptrend = 4.1 × 10−21).

The association between endometriosis and ovarian cancer: A review of histological, genetic and molecular alterations

OBJECTIVE This article represents a review of histologic and genetic findings in endometriosis and describes the mechanisms whereby genetic and non-genetic factors potentially contribute to the neoplastic progression of endometriosis. METHODS Literature review of the English language literature based on searching in the MEDLINE (PubMed) database and additional collection of reports by systematically reviewing all references from retrieved papers. RESULTS Atypical endometriosis seems to represent a transition from benign endometriosis to carcinoma. Endometriosis is characterized by genetic instability: like neoplasms endometriosis seems to be monoclonal in origin, several studies have documented loss of heterozygosity (LOH) in endometriosis, data suggest that mutation of the tumor suppressor gene PTEN play a part in the malignant transformation of endometriosis, some studies have revealed TP53 mutations in endometriotic lesions, and mutation of ARID1A seems to be an important early event in the malignant transformation of endometriosis to endometrioid and clear cell carcinomas. Heme and iron induced oxidative stress, inflammation, and hyperestrogenism are possible links between endometriosis and cancer. CONCLUSIONS The histological and genetic alterations in endometriosis seem to explain why endometriosis can be a precursor of some ovarian cancers, especially clear cell and endometrioid carcinomas. However, the exact molecular mechanisms that may lead to this malignant transformation of endometriosis are not completely understood. More and larger studies are needed to clarify how exactly endometriotic tissue undergoes malignant transformation.

Consortium analysis of 7 candidate SNPs for ovarian cancer.

The Ovarian Cancer Association Consortium selected 7 candidate single nucleotide polymorphisms (SNPs), for which there is evidence from previous studies of an association with variation in ovarian cancer or breast cancer risks. The SNPs selected for analysis were F31I (rs2273535) in AURKA, N372H (rs144848) in BRCA2, rs2854344 in intron 17 of RB1, rs2811712 5′ flanking CDKN2A, rs523349 in the 3′ UTR of SRD5A2, D302H (rs1045485) in CASP8 and L10P (rs1982073) in TGFB1. Fourteen studies genotyped 4,624 invasive epithelial ovarian cancer cases and 8,113 controls of white non‐Hispanic origin. A marginally significant association was found for RB1 when all studies were included [ordinal odds ratio (OR) 0.88 (95% confidence interval (CI) 0.79–1.00) p = 0.041 and dominant OR 0.87 (95% CI 0.76–0.98) p = 0.025]; when the studies that originally suggested an association were excluded, the result was suggestive although no longer statistically significant (ordinal OR 0.92, 95% CI 0.79–1.06). This SNP has also been shown to have an association with decreased risk in breast cancer. There was a suggestion of an association for AURKA, when one study that caused significant study heterogeneity was excluded [ordinal OR 1.10 (95% CI 1.01–1.20) p = 0.027; dominant OR 1.12 (95% CI 1.01–1.24) p = 0.03]. The other 5 SNPs in BRCA2, CDKN2A, SRD5A2, CASP8 and TGFB1 showed no association with ovarian cancer risk; given the large sample size, these results can also be considered to be informative. These null results for SNPs identified from relatively large initial studies shows the importance of replicating associations by a consortium approach.

Different Risk Factor Profiles for Mucinous and Nonmucinous Ovarian Cancer: Results from the Danish MALOVA Study

Objectives: The aim of the study was to examine the overall risk factors for epithelial ovarian cancer and according to histologic subtypes. Materials and Methods: Ovarian cancer cases and controls were recruited from 1995 to 1999, and personal interviews were conducted. A total of 554 cases and 1,564 randomly selected controls were included. The analyses were done using multiple logistic regression models. Results: The overall risk of ovarian cancer decreased with ever being pregnant [odds ratios (OR), 0.40; 95% confidence intervals (CI), 0.30-0.55], with increasing pregnancies (OR, 0.63; 95% CI, 0.45-0.87 and OR, 0.51; 95% CI, 0.37-0.69 for two and three pregnancies as compared with one), and with older age at first and last pregnancy, respectively. Increasing years of ovulation was a very strong risk factor with a 7% to 8% increase in risk for each year of ovulation. Use of oral contraceptives (OR, 0.67, 95% CI, 0.53-0.85) and longer duration of use were associated with a decreased risk of ovarian cancer. Ever use of hormone replacement therapy increased the overall risk (OR, 1.30; 95% CI, 1.05-1.61). For all those variables, the effect was present for serous tumors, endometrioid tumors, and tumors of other histologies, but not for mucinous tumors. In contrast, current smoking was a risk factor only for mucinous tumors (OR, 1.78; 95% CI, 1.01-3.15) and increasing body mass index tended to increase the risk especially for mucinous and endometrioid tumors. Conclusions: We confirmed already known risk factors for ovarian cancer, and we observed significant differences in the risk profiles between mucinous and nonmucinous tumors indicating different etiologies. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1160–6)

High plasma YKL-40 level in patients with ovarian cancer stage III is related to shorter survival

YKL-40 (human cartilage glycoprotein-39) is a member of family 18 glycosyl hydrolases. YKL-40 is a growth factor and is secreted by cancer cells. High serum levels of YKL-40 in patients with colorectal cancer and recurrent metastatic breast cancer have been associated with a poor prognosis. We evaluated the prognostic value of plasma YKL-40 in patients with primary ovarian cancer (OC). YKL-40 was determined by ELISA in plasma obtained preoperatively from 47 women with stage III OC and in plasma from 79 healthy females. The results showed that plasma YKL-40 was elevated compared to healthy females in 57% of the OC patients and was highest in the patients who died during the follow-up compared to the patients still alive (186 vs. 78 micro g/l, p=0.002). Patients with high plasma YKL-40 (>130 micro g/l) had significantly (p=0.0003) shorter survival than patients with normal plasma YKL-40. Multivariate Cox regression analysis showed that plasma YKL-40 (RH=3.95; 95% CI, 1.52-10.27; p=0.005) and radicality after primary surgery (RH=4.03; 95% CI, 1.81-8.97; p=0.001) were independent prognostic factors of survival, whereas age, histological type of tumour and serum CA125 had no independent prognostic value. In conclusion, plasma levels of YKL-40 proved of prognostic value in stage III OC patients.

The association between endometriosis and gynecological cancers and breast cancer: A review of epidemiological data

OBJECTIVE This article critically reviews the literature on the association between endometriosis and gynecological cancers and breast cancer, based on epidemiologic data. METHODS Literature review of the English language literature based on searching in the MEDLINE (PubMed) database and additional collection of reports by systematically reviewing all references from retrieved papers. RESULTS Data from large cohort and case-control studies indicate that endometriosis patients only have an increased risk of ovarian cancer among the gynecological malignancies and breast cancer, although most of the observed associations are modest. Data on the association between endometriosis and breast cancer are inconsistent. Endometriosis patients have a reduced risk of cervical cancer, and there is no association between endometriosis and endometrial cancer. Endometriosis-associated ovarian cancer seems to be a distinct clinical entity; patients are younger, diagnosed in earlier stages, have lower grade lesions and a better survival. Further, endometriosis-associated ovarian cancers are predominantly clear cell and endometrioid histologic subtypes. CONCLUSIONS Endometriosis seems to be a precursor of epithelial ovarian cancer, especially clear cell and endometrioid adenocarcinomas. However, current evidence is insufficient to draw any definitive conclusions whether this association represents causality or the sharing of similar risk factors and/or antecedent mechanisms.

BRCA1 and BRCA2 Mutation Prevalence and Clinical Characteristics of a Population-Based Series of Ovarian Cancer Cases from Denmark

Purpose: To evaluate the prevalence of BRCA1 and BRCA2 mutations and associations with clinical correlates of disease in a population-based series of ovarian cancer cases from Denmark. Methods: DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to analyze the BRCA1 and BRCA2 genes for coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer. We evaluated associations between mutation status and clinical characteristics, including cancer risks for first-degree relatives and clinicopathologic features of tumors. Results: Deleterious BRCA1 or BRCA2 mutations were identified in 26 cases; thus, mutations in these genes are responsible for at least 5.8% of ovarian cancer cases in this population. Five different mutations were identified in more than one individual, suggesting that they may be founder mutations in Denmark. We identified several differences between mutation carriers and noncarriers: mutation carriers were diagnosed at a significantly early age (median, 49 and 61 years, respectively; P = 0.0001); the frequency of BRCA1 mutation carriers was 23% for women diagnosed <40 years, 15% for 40 to 49 years, 4% for 50 to 59 years, and 2% for ≥60 years (P = 0.00002); ovarian cancer in carriers was diagnosed at a later stage (P = 0.002) and tumors were of poorer grade (P = 0.0001); and first-degree relatives of mutation carriers had greater relative risks of both ovarian cancer [10.6 (95% confidence interval, 4.2-26.6); P < 0.0001] and breast cancer <60 years [8.7 (95% confidence interval, 3.0-25.0); P < 0.0001]. Conclusion: These data may have a significant effect on risk assessment and clinical management of individuals from Denmark who are predisposed to ovarian cancer because they carry a BRCA1 or BRCA2 mutation.

Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r(2) = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07-1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region.

Smoking and Overweight: Negative Prognostic Factors in Stage III Epithelial Ovarian Cancer

Objective: Smoking and overweight are associated with poorer prognosis in several cancer types. The prognostic effect of smoking and body mass index (BMI) on ovarian cancer is unknown. Methods: Ovarian cancer cases were from the Danish MALOVA (MALignant OVArian cancer) study. Information on smoking status and BMI was obtained from a personal interview conducted closely after primary surgery. Cox regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for ovarian cancer–specific death in relation to smoking variables and BMI. Results: A total of 295 women with stage III epithelial ovarian cancer were identified and followed to death or for a median of 7.3 years (range, 5.4-9.5 years). Median survival time for normal-weight never smokers was 2.8 years (95% CI, 2.3-3.2) compared with 1.2 years (95% CI, 0.8-2.3) for overweight current smokers. Current smokers had a significantly increased risk of ovarian cancer death compared with never smokers in multivariate Cox analysis (HR, 1.65; 95% CI, 1.22-2.24). The negative effect of smoking diminished with increasing time since a former smoker had stopped smoking (HR, 0.89; 95% CI, 0.80-0.98 per 5 years since stop of smoking). Overweight women also had an increased risk of ovarian cancer death (HR, 1.83; 95% CI, 1.38-2.42) compared with normal-weight women. Conclusion: Smoking at the time of diagnosis and premorbid overweight were negative prognostic factors for ovarian cancer–specific survival. The negative effect of smoking decreased with increasing time since stop of smoking. (Cancer Epidemiol Biomarkers Prev 2006;15(4):798–803)

Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer

Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell‐mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty‐three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15–1.74) and the HomOR = 1.63 (1.10–1.42), p‐trend = 0.0002] and [HetOR = 0.97 (0.80–1.17), HomOR = 0.74 (0.58–0.93), p‐trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele‐specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele‐specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.