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The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only approximately 30% of breast tumors, indicating that either very few molecular alterations are common to the majority of breast cancers, or that they have not yet been identified. In striking contrast, we now show that 19 of 19 stage I breast tumors tested with the functional unscheduled DNA synthesis assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls (n = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis. By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples versus normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNase protection. These results were confirmed at the protein level for five NER gene products. Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early-stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis-platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium. human primary breast cell explant culture | human breast tumor explant culture | breast epithelial attached epispher | hypermutability doi/ 10.1073/pnas.0914772107

Abstract Background Screening mammography has had a positive impact on breast cancer mortality but cannot detect all breast tumors. In a small study, we confirmed that low power magnetic resonance imaging (MRI) could identify mammographically undetectable tumors by applying it to a high risk population. Tumors detected by this new technology could have unique etiologies and/or presentations, and may represent an increasing proportion of clinical practice as new screening methods are validated and applied. A very important aspect of this etiology is genomic instability, which is associated with the loss of activity of the breast cancer-predisposing genes BRCA1 and BRCA2. In sporadic breast cancer, however, there is evidence for the involvement of a different pathway of DNA repair, nucleotide excision repair (NER), which remediates lesions that cause a distortion of the DNA helix, including DNA cross-links. Case presentation We describe a breast cancer patient with a mammographically undetectable stage I tumor identified in our MRI screening study. She was originally considered to be at high risk due to the familial occurrence of breast and other types of cancer, and after diagnosis was confirmed as a carrier of a Q1200X mutation in the BRCA1 gene. In vitro analysis of her normal breast tissue showed no differences in growth rate or differentiation potential from disease-free controls. Analysis of cultured blood lymphocyte and breast epithelial cell samples with the unscheduled DNA synthesis (UDS) assay revealed no deficiency in NER. Conclusion As new breast cancer screening methods become available and cost effective, patients such as this one will constitute an increasing proportion of the incident population, so it is important to determine whether they differ from current patients in any clinically important ways. Despite her status as a BRCA1 mutation carrier, and her mammographically dense breast tissue, we did not find increased cell proliferation or deficient differentiation potential in breast epithelial cells from this patient which might have contributed to her cancer susceptibility. Although NER deficiency has been demonstrated repeatedly in blood samples from sporadic breast cancer patients, analysis of blood cultured lymphocytes and breast epithelial cells for this patient proves definitively that heterozygosity for inactivation of BRCA1 does not intrinsically confer this type of genetic instability. These data suggest that the mechanism of genomic instability driving the carcinogenic process may be fundamentally different in hereditary and sporadic breast cancer, resulting in different genotoxic susceptibilities, oncogene mutations, and a different molecular pathogenesis.

* Context.--Cervical screening in the United States increasingly involves newer US Food and Drug Administration-approved cytologic methods and adjunctive high-risk human papillomavirus (hrHPV) DNA testing. Objective.--To document cervical screening test performance preceding histopathologic cervical intraepithelial neoplasia (CIN) 2/3 diagnoses. Design.--Preceding screening test results with computer-imaged, liquid-based cytology (LBC) and hrHPV results were analyzed for 2827 patients with histopathologic CIN 2/3 diagnoses. Results.--Of 2827 patients with CIN 2/3 diagnoses, 2074 (73.4%) had system LBC findings within 4 months of CIN 2/3 diagnoses: high-grade squamous intraepithelial lesion (n = 862; 41.6%), low-grade squamous intraepithelial lesion (n = 464; 22.4%), atypical squamous cells of undetermined significance (n = 445; 21.5%), atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (n = 288; 13.9%), and atypical glandular cells/adenocarcinoma in situ (n = 15; 0.7%). Of the 2827 patients, 1488 (52.6%) also had earlier system LBC results at more than 4 months to 3 years before CIN 2/3 diagnoses: one or more abnormal LBC results (n = 978; 65.7%), one or more negative LBC results (n = 911; 61.2%), both abnormal and negative LBC (n = 401; 26.9%). Of 807 patients with hrHPV cotest results within 4 months of CIN 2/3 diagnoses, 786 (97.4%) had hrHPV+ results. Of 454 patients who also had earlier hrHPV results at more than 4 months to 3 years before CIN 2/3 diagnoses: 377 (83.0%) had one or more [hrHPV.sup.+] result, 110 (24.2%) had one or more hrHPV' result, and 33 (7.3%) had both positive and negative HPV results. Conclusion.--Patients with histopathologic CIN 2/3 had recent abnormal LBC results, most often, high-grade squamous intraepithelial lesions. Among cotested patients, 97.4% (786 of 807) tested hrHP[V.sup.+}]. However, a significant number of patients tested during an extended period of several years had earlier negative Papanicolaou or negative HPV test results, suggesting the recent development of some CIN 2/3 lesions and supporting the value of cotesting for enhanced detection of other developing, small, inaccessible, or nondiagnostic precursor lesions. (Arch Pathol Lab Med. 2013;137:942-947; doi:10.5858/arpa.2012-0307-OA), The primary goal of cervical screening is the identification and removal of intraepithelial precancerous lesions, which, if left untreated, would, at some future time, become invasive cervical cancer. (1) The [...]

Herein, we present a case of a 76-year-old Caucasian man with a very large fungating, ulcerating mass, involving the right neck and parotid area, which developed while he was being treated for chronic lymphocytic leukemia/small lymphocytic lymphoma. Resection of the fungating right neck tumor, right modified radical neck dissection, and right superficial parotidectomy with flap reconstruction were performed. The final pathological diagnosis was high-grade leiomyosarcoma of the skin and the subcutaneous tissue, with invasion into the skeletal muscle, skin, and soft tissue. Additionally, the sarcoma had metastasized to the lymph nodes that were involved diffusely by lymphoma. The most interesting fact for this case is coincidence of three rare occurrences which were soft tissue sarcomas of subcutaneous leiomyosarcoma form and its metastasis to same lymph nodes that were involved with lymphoma. [ABSTRACT FROM AUTHOR]