Ovarian cancer is the second most lethal gynecological malignancy. The tumour biomarker CA125 has been used as the primary ovarian cancer marker for the past four decades. The focus on diagnosing ...ovarian cancer in stages I and II using CA125 as a diagnostic biomarker has not improved patients' survival. Therefore, screening average-risk asymptomatic women with CA125 is not recommended by any professional society. The dualistic model of ovarian cancer carcinogenesis suggests that type II tumours are responsible for the majority of ovarian cancer mortality. However, type II tumours are rarely diagnosed in stages I and II. The recent shift of focus to the diagnosis of low volume type II ovarian cancer in its early stages of evolution provides a new and valuable target for screening. Type II ovarian cancers are usually diagnosed in advanced stages and have significantly higher CA125 levels than type I tumours. The detection of low volume type II carcinomas in stage IIIa/b is associated with a higher likelihood for optimal cytoreduction, the most robust prognostic indicator for ovarian cancer patients. The diagnosis of type II ovarian cancer in the early substages of stage III with CA125 may be possible using a higher cutoff point rather than the traditionally used 35 U/mL through the use of point-of-care CA125 assays in primary care facilities. Rapid point-of-care testing also has the potential for effective longitudinal screening and quick monitoring of ovarian cancer patients during and after treatment. This review covers the role of CA125 in the diagnosis and management of ovarian cancer and explores novel and more effective screening strategies with CA125.
Breast cancer exhibits various epigenetic abnormalities that regulate gene expression and contribute to tumor characteristics. Epigenetic alterations play a significant role in cancer development and ...progression, and epigenetic-targeting drugs such as DNA methyltransferase inhibitors, histone-modifying enzymes, and mRNA regulators (such as miRNA mimics and antagomiRs) can reverse these alterations. Therefore, these epigenetic-targeting drugs are promising candidates for cancer treatment. However, there is currently no effective epi-drug monotherapy for breast cancer. Combining epigenetic drugs with conventional therapies has yielded positive outcomes and may be a promising strategy for breast cancer therapy. DNA methyltransferase inhibitors, such as azacitidine, and histone deacetylase inhibitors, such as vorinostat, have been used in combination with chemotherapy to treat breast cancer. miRNA regulators, such as miRNA mimics and antagomiRs, can alter the expression of specific genes involved in cancer development. miRNA mimics, such as miR-34, have been used to inhibit tumor growth, while antagomiRs, such as anti-miR-10b, have been used to inhibit metastasis. The development of epi-drugs that target specific epigenetic changes may lead to more effective monotherapy options in the future.
BRCA1/2‐associated breast cancers are sensitive to poly(ADPribose) polymerase (PARP) inhibitors and platinum compounds mainly due to their deficiency in DNA repair via homologous recombination (HR). ...However, approximately only 15% of triple‐negative breast cancers (TNBCs) are BRCA1/2‐associated. TNBCs that exhibit BRCAness (a phenotype reflecting impaired HR in BRCA1/2‐negative tumors) are also regarded sensitive to PARP inhibitors and platinum compounds. Thus, we hypothesized that hereditary BRCA1/2‐negative TNBCs may exhibit BRCAness. To find a subset of hereditary BRCA1/2‐negative TNBCs among 360 TNBCs, we first identified a group of 41 hereditary TNBCs by analyzing the family histories of the patients. Next, we tested this group for the presence of germline BRCA1/2 mutations, and finally, we compared the expression levels of 120 genes involved in HR and five other major mechanisms of DNA damage repair between BRCA1/2‐associated and BRCA1/2‐negative subgroups of hereditary TNBCs using real‐time PCR arrays. Approximately 73% of the hereditary TNBCs were BRCA1/2‐associated and 27% were BRCA1/2‐negative. The expression levels of the analyzed genes showed no significant differences between these two subgroups indicating the BRCAness of the BRCA1/2‐negative hereditary TNBCs and thereby distinguishing a novel subset of TNBCs as a potential target for PARP inhibitors or platinum‐based therapy. The results show the significance of family history in selecting patients with TNBC for therapies directed at incompetent DNA repair (e.g., PARP inhibitors and/or platinum‐based therapies) and indicate that a relatively simple strategy for broadening the target group for these modes of treatment is to identify patients with hereditary TNBCs.
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Triple‐negative breast cancers (TNBCs) that are positive for BRCA1/2 mutations display impairments in DNA repair via homologous recombination (HR), rendering the tumors sensitive to poly(ADPribose) polymerase (PARP) inhibitors and DNA cross‐linking drugs. Only a minority of TNBC patients, however, carry germline BRCA1/2 aberrations. In the present study, 27% of hereditary TNBCs examined were found to be BRCA1/2‐negative, yet showed no significant differences in the expression of HR‐related genes or other DNA damage repair genes when compared with BRCA1/2‐associated tumors. The BRCAness phenomenon distinguishes a subset of BRCA1/2‐negative hereditary TNBCs, which may be susceptible to PARP inhibitors and platinum‐based therapies.
To estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on her family history of breast cancer.
Seven thousand four hundred ninety-four BRCA1 mutation-negative patients ...with breast cancer and 4,346 control women were genotyped for four founder mutations in CHEK2 (del5395, IVS2+1G>A, 1100delC, and I157T).
A truncating mutation (IVS2+1G>A, 1100delC, or del5395) was present in 227 patients (3.0%) and in 37 female controls (0.8%; odds ratio OR, 3.6; 95% CI, 2.6 to 5.1). The OR was higher for women with a first- or second-degree relative with breast cancer (OR, 5.0; 95% CI, 3.3 to 7.6) than for women with no family history (OR, 3.3; 95% CI, 2.3 to 4.7). If both a first- and second-degree relative were affected with breast cancer, the OR was 7.3 (95% CI, 3.2 to 16.8). Assuming a baseline risk of 6%, we estimate the lifetime risks for carriers of CHEK2 truncating mutations to be 20% for a woman with no affected relative, 28% for a woman with one second-degree relative affected, 34% for a woman with one first-degree relative affected, and 44% for a woman with both a first- and second-degree relative affected.
CHEK2 mutation screening detects a clinically meaningful risk of breast cancer and should be considered in all women with a family history of breast cancer. Women with a truncating mutation in CHEK2 and a positive family history of breast cancer have a lifetime risk of breast cancer of greater than 25% and are candidates for magnetic resonance imaging screening and for tamoxifen chemoprevention.
Summary Background Mutations in PALB2 predispose to breast cancer, but the effect on prognosis of carrying a PALB2 mutation has not been ascertained. We aimed to estimate the odds ratio for breast ...cancer in women with an inherited mutation in PALB2 and 10-year survival after breast cancer in patients who carry a PALB2 mutation. Methods Between 1996 and 2012, patients with invasive breast cancer were recruited prospectively from 18 hospitals in Poland and genotyped for two deleterious mutations in PALB2 (509_510delGA and 172_175delTTGT). A control group of 4702 women without cancer was recruited for comparison. The primary endpoint was death from any cause, as determined by medical records from the Polish Ministry of the Interior and Administration. In patients with breast cancer, 10-year survival of carriers of a PALB2 mutation was calculated and compared with that of non-carriers. Findings 17 900 women with breast cancer were invited to participate, of whom 12 529 were genotyped successfully. A PALB2 mutation was present in 116 (0·93%, 95% CI 0·76–1·09) of 12 529 patients and in ten (0·21%, 0·08–0·34) of 4702 controls (odds ratio 4·39, 95% CI 2·30–8·37; p<0·0001). 10-year survival for women with breast cancer and a PALB2 mutation was 48·0% (95% CI 36·5–63·2), compared with 74·7% (73·5–75·8) for patients with breast cancer without a mutation (adjusted hazard ratio for death 2·27, 95% CI 1·64–3·15; p<0·0001). Interpretation Women with a PALB2 mutation face an increased risk of breast cancer and might be at a higher risk of death from breast cancer compared with non-carriers. Increased surveillance should be offered to unaffected women who carry a PALB2 mutation. Funding Polish National Science Centre.
To estimate 10-year overall survival (OS) rates for patients with early-onset breast cancer, with and without a BRCA1 mutation, and to identify prognostic factors among those with BRCA1-positive ...breast cancer.
A total of 3,345 women with stage I to III breast cancer, age ≤ 50 years, were tested for three founder mutations in BRCA1. Information on tumor characteristics and treatments received was retrieved from medical records. Dates of death were obtained from the vital statistics registry. Survival curves for the mutation-positive and -negative subcohorts were compared. Predictors of OS were determined using the Cox proportional hazards model.
Of the 3,345 patients enrolled onto the study, 233 (7.0%) carried a BRCA1 mutation. The 10-year survival rate for mutation carriers was 80.9% (95% CI, 75.4% to 86.4%); for noncarriers, it was 82.2% (95% CI, 80.5% to 83.7%). The adjusted hazard ratio (HR) associated with carrying a BRCA1 mutation was 1.81 (95% CI, 1.26 to 2.61). Among BRCA1 carriers with a small (< 2 cm) node-negative tumor, the 10-year survival rate was 89.9%. Among BRCA1 mutation carriers, positive lymph node status was a strong predictor of mortality (adjusted HR, 4.1; 95% CI, 1.8 to 8.9). Oophorectomy was associated with improved survival in BRCA1 carriers (adjusted HR, 0.30; 95% CI, 0.12 to 0.75).
The 10-year survival rate among women with breast cancer and a BRCA1 mutation is similar to that of patients without a BRCA1 mutation. Among women with a BRCA1 mutation, survival was much improved after oophorectomy.
Purpose The purpose of this study was to compare the clinical characteristics and the survival of CHEK2 mutation positive and CHEK2 mutation negative patients diagnosed with bladder or kidney cancer. ...Materials and methods 1016 patients with bladder and 402 cases with kidney cancer and 8302 controls were genotyped for four CHEK2 variants: 1100delC, del5395, IVS2+1G>A and I157T. Predictors of survival were determined among CHEK2 pathogenic variant carriers using the Cox proportional hazards model. The median follow-up was 17.5 years. Covariates included age (less than or equal to60; >61 years), sex (female; male), clinical characteristics (stage: TNM, grade, histopathological type), smoking status (non-smoking; smoking) and cancer family history (negative; positive). Results We found no impact of CHEK2 mutations on bladder or kidney cancer survival. However, we observed a possible increased survival in the subgroup of patients with stage T1 bladder cancer with CHEK2 mutations but this did not meet statistical significance (HR = 0.14; 95% CI 0.02-1.04; p = 0.055). Moreover, we observed that the missense mutations were more frequent in the low grade invasive bladder cancer patient group (OR = 7.9; 95% CI 1.50-42.1; p = 0.04) and in patients with bladder cancer with stage Ta (OR = 2.4; 95% CI 1.30-4.55; p = 0.006). The different results where missense mutations occurs less often we observed among patients with high grade invasive bladder cancer (OR = 0.12; 95% CI 0.02-0.66; p = 0.04) and those with stage T1 disease (OR = 0.2; 95% CI 0.07-0.76; p = 0.01). Our investigations revealed that any mutation in CHEK2 occurs more often among patients with stage Ta bladder cancer (OR = 2.0; 95% CI 1.19-3.47; p = 0.01) and less often in patients with stage T1 disease (OR = 0.31; 95% CI 0.12-0.78; p = 0.01). In the kidney cancer patients, truncating mutations were present more often in the group with clear cell carcinoma GII (OR = 8.0; 95% CI 0.95-67.7; p = 0.05). The 10-year survival for all CHEK2 mutation carriers with bladder cancer was 33% and for non-carriers 11% (p = 0.15). The 10-year survival for CHEK2 mutation carriers with kidney cancer 34% and for non-carriers 20% (p = 0.5). Conclusion CHEK2 mutations were not associated with any change in bladder or kidney cancer survival regardless of their age, sex, smoking status and family history. We observed a potentially protective effect of CHEK2 mutations on survival for patients with stage T1 bladder cancer. CHEK2 missense mutations were more common among patients with low grade invasive bladder cancer and in patients with stage Ta diease. The frequencies of the I157T CHEK2 pathogenic variant were less in patients with high grade invasive bladder cancer and those with stage T1 disease. Among patients with bladder cancer with stage Ta disease, the OR for any mutation in CHEK2 was 2.0 but for those with stage T1 disease, the OR was 0.3. We observed truncating CHEK2 mutations were associated with kidney cancer patients with GII clear cell carcinoma.
Cadmium (Cd) is a known carcinogen, but its impact on cancer risk at lower concentrations is poorly understood. Previous studies on Cd and cancer risk in men show inconsistent results, prompting ...further investigation. A prospective cohort study involving 2956 men was conducted. Blood Cd levels were measured, and participants were followed for 78 months to assess cancer incidence. Men with high blood Cd levels (>0.71 µg/L) had a significantly increased risk of cancer compared to those with low levels (<0.19 µg/L) (HR 3.42,
< 0.001), particularly among non-smokers (HR 3.74,
= 0.003), individuals aged < 60 years (HR 2.79,
= 0.017), and ≥60 (HR 4.63,
= 0.004). The influence of smoking on cancer risk based on Cd levels was not significant in this study. Blood Cd levels may influence cancer risk in men, emphasizing the importance of minimizing Cd exposure to reduce risk. Confirmation of these results in other populations is essential for effective preventive measures against Cd-related cancers.
Prostate cancer is one of the most commonly diagnosed malignancies among men in Western populations. Evidence reported in the literature suggests that zinc may be related to prostate cancer. In this ...study we evaluated the association of serum zinc levels and polymorphisms in genes encoding zinc-dependent proteins with prostate cancer in Poland.
The study group consisted of 197 men affected with prostate cancer and 197 healthy men. Serum zinc levels were measured and 5 single nucleotide polymorphisms in MMP-1, MMP-2, MMP-7, MMP-13, MT2A genes were genotyped.
The mean serum zinc level was higher in prostate cancer patients than in healthy controls (898.9±12.01 μg/l vs. 856.6±13.05 μg/l, p<0.01). When compared in quartiles a significant association of higher zinc concentration with the incidence of prostate cancer was observed. The highest OR (OR = 4.41, 95%CI 2.07-9.37, p<0.01) was observed in 3rd quartile (>853.0-973.9 μg/l). Among five analyzed genetic variants, rs11568818 in MMP-7 appeared to be correlated with 2-fold increased prostate cancer risk (OR = 2.39, 95% CI = 1.19-4.82, p = 0.015).
Our results suggest a significant correlation of higher serum zinc levels with the diagnosis of prostate cancer. The polymorphism rs11568818 in MMP-7 gene was also associated with an increased prostate cancer risk in Poland.
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