It has been suggested that increased numbers of ovulations might increase the risk of p53 gene (also known as TP53) mutation in the ovarian epithelium, thereby leading to the development of cancer. ...The data supporting this hypothesis have come from an observation that accumulation of p53 protein in epithelial ovarian cancer was strongly associated with increasing numbers of ovulatory cycles. We have further investigated the association between ovulatory history and p53 gene mutation by use of data from a large case-control study of ovarian cancer in Australia.
Tissue blocks were available for immunohistochemical analysis of p53 protein from 234 case subjects, aged 18-79 years, who had invasive epithelial ovarian cancer. Epidemiologic data were also available for these women and for 855 control subjects. Case-case comparisons were made by use of prevalence ratios and 95% confidence intervals (CIs), and case-control comparisons were made by use of odds ratios (ORs) and 95% CIs. All statistical tests were two-sided.
There was no association between p53 accumulation and years of ovulation. Women with p53-positive cancers had undergone an average of 29.3 years of ovulation compared with 29.0 years of ovulation for women with p53-negative cancers (P=.8). Although the overall risk of ovarian cancer development was significantly increased in women who had undergone more years of ovulation (OR=2.17; 95% CI =1.54-3.05-for > or =35 years versus <23 years of ovulation), there was no difference in the risk associated with p53-positive and p53-negative cancers.
These results confirm the association between increased ovulation and ovarian cancer risk but do not support the hypothesis that this association is due to an increased risk of p53 mutation with a greater number of ovulatory cycles.
Carcinoma of the breast is thought to evolve through a sequential progression from normal to proliferative epithelium and eventually into carcinoma. Here lumpectomy specimens from five patients were ...studied, selected for the presence of ductal hyperplasia without atypia, atypical ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Laser microdissection of tissue allowed precise sampling and direct correlation of phenotypic and genotypic changes. Analyses of the samples revealed an increasing mean number of chromosomal changes occurring with increasing histologic severity, and for the first time chromosomal abnormalities were demonstrated in ductal hyperplasia without atypia. Chromosomal changes found in each of the four histologic entities included gains on 10q, 12q, 16p, and 20q and loss on 13q. In ductal hyperplasia without atypia, gain on 20q as well as loss on 13q was detected with high frequency (four of five samples). Alterations identified in more than 50% of atypical ductal hyperplasia samples included gains on 3p, 8q, 15q, and 22q and loss on 16q. In ductal carcinoma in situ, gain of DNA on 1q and 17q and loss on 4q were additionally found, and in invasive ductal carcinoma, further gains on 6p, 10q, 11q13, and 17p were identified. The chromosomal alterations occurring in the different histopathologic lesions strongly suggest that these regions harbor tumor suppressor genes or oncogenes significant for the development of ductal carcinoma of the breast.
Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The ...purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients.
Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model.
The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05-1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91-1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17-2.45).
ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families ...suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10–6T→G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case–control series of breast cancer families and multiple-case breast cancer families. Methods: Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10–6T→G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. Results: In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10–6T→G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval CI = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. Conclusion: At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.
Mono-allelic germline pathogenic variants in the
(
) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, ...we sought to define the repertoire of somatic genetic alterations in
-associated breast cancers (BCs), and whether
-associated BCs display bi-allelic inactivation of
and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic
germline mutations were analyzed by whole-exome sequencing (WES,
= 16) or targeted capture massively parallel sequencing (410 cancer genes,
= 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the
wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined.
-associated BCs were found to be heterogeneous at the genetic level, with
(29%),
(21%),
(21%), and
(17%) being the genes most frequently affected by somatic mutations. Bi-allelic
inactivation was found in 16 of the 24 cases (67%), either through LOH (
= 11) or second somatic mutations (
= 5) of the wild-type allele. High LST scores were found in all 12
-associated BCs with bi-allelic
inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of
was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic
inactivation in
-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of
-associated BCs without
bi-allelic inactivation lack genomic features of HRD.
Classification of rare missense variants as neutral or disease causing is a challenge and has important implications for genetic counseling. A multifactorial likelihood model for classification of ...unclassified variants in BRCA1 and BRCA2 has previously been developed, which uses data on co-occurrence of the unclassified variant with pathogenic mutations in the same gene, cosegregation of the unclassified variant with affected status, and Grantham analysis of the fit between the missense substitution and the evolutionary range of variation observed at its position in the protein. We have further developed this model to take into account relevant features of BRCA1- and BRCA2-associated tumors, such as the characteristic histopathology and immunochemical profiles associated with pathogenic mutations in BRCA1, and the fact that approximately 80% of tumors from BRCA1 and BRCA2 carriers undergo inactivation of the wild-type allele by loss of heterozygosity. We examined 10 BRCA1 and 15 BRCA2 unclassified variants identified in Australian, multiple-case breast cancer families. By a combination of genetic, in silico, and histopathologic analyses, we were able to classify one BRCA1 variant as pathogenic and six BRCA1 and seven BRCA2 variants as neutral. Five of these neutral variants were also found in at least 1 of 180 healthy controls, suggesting that screening a large number of appropriate controls might be a useful adjunct to other methods for evaluation of unclassified variants.
Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the
gene is essential to determine the ...most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of
variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies.
We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146
-positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals.
Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with
pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years.
The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for
pathogenic variant carriers and improve
variant classification.
Objective
To evaluate the use of the ThinPrep method to reduce rates of unsatisfactory Papanicolaou (Pap) smears in women in remote communities.
Design
Prospectively collected samples were split and ...screened conventionally and by ThinPrep at the Queensland Cytology Service.
Patients
Three hundred women having cervical smears taken by a Mobile Women's Health Service nurse or at the antenatal and sexual health clinics of a remote north Queensland community.
Main outcome measure
Number of Pap smears reported as unsatisfactory for evaluation and requiring a repeat smear request.
Results
17.3% of conventionally prepared smears were technically unsatisfactory, compared with 6.3% prepared with ThinPrep. The overall rate of unsatisfactory smears was only 4.3% when both ThinPrep and conventional smears were assessed for a combined report.
Conclusion
A significant reduction in the proportion of unsatisfactory Pap smears is possible with the ThinPrep method. Targeted use of ThinPrep in communities with high rates of unsatisfactory smears may prove cost‐effective.
Liver samples from red-tailed hawks (
Buteo
jamaicensis
) and great horned owls (
Bubo virginianus
) were analyzed for anticoagulant rodenticides. Residues of one or more second generation ...anticoagulant rodenticides (SGARs) were detected in 81 % of red-tailed hawks and 82 % of great horned owls. The most frequently detected SGAR was brodifacoum, which was detected in 76 % of red-tailed hawks and 73 % of great horned owls. Bromadiolone was detected in 20 % of red-tailed hawks and 27 % of great horned owls. Difenacoum was detected in one great horned owl. No other ARs were detected. There were no significant differences between species in the frequency of detection or concentration of brodifacoum or bromadiolone. There was a marginally significant difference (
p
= 0.0497) between total SGAR residues in red-tailed hawks (0.117 mg/kg) and great horned owls (0.070 mg/kg). There were no seasonal differences in the frequency of detection or concentration of brodifacoum in red-tailed hawks. The data suggest that SGARs pose a significant risk of poisoning to predatory birds in New Jersey.
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