Staging Lymphadenectomy in Patients With Clear Cell Carcinoma of the Ovary.

OBJECTIVE: The purpose of this study was to assess the rate of lymph node (LN) metastasis in comprehensively staged ovarian clear cell carcinoma (OCCC) clinically confined to the ovary and determine factors associated with LN metastasis. METHODS: We identified all cases of OCCC treated at 4 institutions from January 1994 through December 2011. We included cases with disease grossly confined to the ovary that had surgical staging performed, including at least 10 LNs sampled. Clinical and pathologic data were abstracted from electronic medical records, and a deidentified data set was compiled and processed at a single institution. Factors potentially associated with LN metastasis were tested. Appropriate statistical tests were performed. RESULTS: We identified 145 eligible cases that met the criteria for this analysis. Median age was 52.9 years (range, 30-81 years), and median total LN count was 19 (range, 10-74). Seven (4.8%) of 145 comprehensively staged cases had LN metastasis; 6 of these cases (4.1%) were isolated metastasis. Cytologic washings, peritoneal, omental, and fallopian tube involvement were not associated with nodal metastasis. Cases with ovarian surface involvement and positive cytology had a 37.5% incidence of LN positivity, which was statistically meaningful when compared with all other cases (P = 0.003). CONCLUSIONS: Women who underwent comprehensive staging for clinical stage I OCCC had an LN metastasis rate of 4.8%. The subgroup of cases with both ovarian surface involvement and positive cytology had the highest incidence of LN metastasis. This may influence clinical decision making on whether to perform lymphadenectomy in patients with incidental OCCC found after salpingo-oophorectomy.

Gamma-ray-induced mutagen sensitivity and risk of sporadic breast cancer in young women: a case-control study.

Hypersensitivity to radiation exposure has been suggested to be a risk factor for the development of breast cancer. In this case-control study of 515 young women (≤ 55 years) with newly diagnosed sporadic breast cancer and 402 cancer-free controls, we examined the radiosensitivity as measured by the frequency of chromatid breaks induced by gamma-radiation exposure in the G2 phase of phytohemagglutinin-stimulated and short-term cultured fresh lymphocytes. We found that the average chromatid breaks per cell from 50 well-spread metaphases were statistically significantly higher in 403 non-Hispanic White breast cancer patients (0.52 ± 0.22) than that in 281 non-Hispanic White controls (0.44 ± 0.16) (P value < 0.001), and in 60 Mexican American breast cancer patients (0.52 ± 0.19) than that in 65 Mexican American controls (0.44 ± 0.16) (P value = 0.021), but the difference was not significant in African Americans (52 cases [0.45 ± 0.16] versus 56 controls [0.47 ± 0.16], P = 0.651). The frequency of chromatid breaks per cell above the median of control subjects was associated with two-fold increased risk for breast cancer in non-Hispanic Whites and Mexican Americans. A dose-response relationship was evident between radiosensitivity and risk for breast cancer (P (trend) < 0.001) in these two ethnic groups. We concluded that gamma-ray-induced mutagen sensitivity may play a role in susceptibility to breast cancer in young non-Hispanic White and Mexican American women.

The functional promoter polymorphism (-842G>C) in the PIN1 gene is associated with decreased risk of breast cancer in non-Hispanic white women 55 years and younger.

PIN1, an isomerase that causes conformational changes in proteins, plays an important role in mammary epithelial cell growth both physiologically and pathologically. Thus, genetic variants in the PIN1 gene may alter protein function and cancer risk. We have previously demonstrated an association between a PIN1 promoter variant (-842G>C; rs2233678) and risk of squamous cell carcinoma of the head and neck, a finding supported by additional functional data. In the present study, we genotyped two promoter single nucleotide polymorphisms (SNPs) (-842G>C, rs2233678 and -667T>C, rs2233679) and one synonymous SNP (Gln33Gln; G>A, rs2233682) in exon 2 to evaluate their associations with risk of sporadic breast cancer in non-Hispanic white women 55 years and younger. We found that the carriers of -842C variant alleles had decreased risk of breast cancer with an adjusted odd ratio (OR) of 0.67 and 95% confidence interval (CI) of 0.50-0.90. This reduced risk was more evident in women after reproductive age of 45 (OR = 0.63, 95% CI = 0.42-0.93), ever-smokers (OR = 0.56, 95% CI = 0.36-0.88), and ever-drinkers (OR = 0.67, 95% CI = 0.45-0.99). No such associations were observed for PIN1 -667T>C and PIN1 Gln33Gln. However, the haplotypes of these three SNPs were also associated with reduced risk of breast cancer. In conclusion, the PIN1 polymorphisms may contribute to the etiology of sporadic breast cancer in non-Hispanic white women 55 years and younger. Further validation in large population-based studies is needed.

Polymorphisms in the SULF1 gene are associated with early age of onset and survival of ovarian cancer.

BACKGROUND: SULF1 (sulfatase 1) selectively removes the 6-O-sulphate group from heparan sulfate, changing the binding sites for extracellular growth factors. SULF1 expression has been reported to be decreased in various cancers, including ovarian cancer. We hypothesized that single nucleotide polymorphisms (SNPs) of SULF1 would impact clinicopathologic characteristics. METHODS: We genotyped five common (minor allele frequency>0.05) regulatory SNPs with predicted functionalities (rs2623047 G>A, rs13264163 A>G, rs6990375 G>A, rs3802278 G>A, and rs3087714 C>T) in 168 patients with primary epithelial ovarian cancer, using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: We found that rs2623047 G>A was significantly associated with an early age of onset of ovarian cancer in the G allele dose-response manner (P = 0.027; Ptrend = 0.007) and that rs2623047 GG/GA genotypes were associated with longer progression-free survival; rs6990375 G>A was also associated with the early age of onset in the A allele dose-response manner (P = 0.013; Ptrend= 0.009). The significant differences in age of disease onset persisted among carriers of haplotypes of rs2623047 and rs6990375 (P = 0.014; Ptrend = 0.004). In luciferase reporter gene assays, rs2623047 G allele showed a slightly higher promoter activity than the A allele in the SKOV3 tumorigenic cell line. CONCLUSIONS: These findings suggest that genetic variations in SULF1 may play a role in ovarian cancer onset and prognosis. Further studies with large sample sizes and of the mechanistic relevance of SULF1 SNPs are warranted.

Polymorphisms in the survivin promoter are associated with age of onset of ovarian cancer.

Survivin has been identified as an apoptosis inhibitor and a key regulator of mitosis. A common polymorphism (-31G>C) at the survivin promoter has been extensively studied in various cancers and reported to influence survivin expression. We hypothesize that polymorphisms in the survivin promoter are associated with clinical outcomes of patients with ovarian cancer. In this study, we genotyped all of five common and independent (r(2) < 0.25 for all LD) survivin promoter polymorphisms (-1547A/G [rs3764383], -644C/T [rs8073903], -625C/G [rs8073069], -241C/T [rs17878467], and -31G/C [rs9904341]) in 168 patients with primary epithelial ovarian cancer, using the polymerase chain reaction-restriction fragment length polymorphism method. We found that -1547A/G and -31G/C were significantly associated with age of disease onset. Compared with patients with the -1547GG genotype, the -1547AA genotype showed a significantly younger age of disease onset (58.8 years vs. 70.1 years; P = 0.001); the -31CC genotype had a decrease, though not significant, in the age of disease onset, compared with patients with the -31GG genotype (57.1 years vs. 62.8 years; P = 0.058). The numbers of -1547A and -31C alleles were associated with a decrease in age of onset in an allele-dose response manner (P(trend) = 0.001 and 0.026, respectively). However, no association was found between survivin polymorphisms and patients' prognosis, except for -625C/G SNP in 37 patients with a persistent disease. The findings suggest that the promoter variants of survivin may have an effect on age of onset of ovarian cancer. Validation studies with larger sample sizes are warranted.