Breast carcinoma and Lynch syndrome: molecular analysis of tumors arising in mutation carriers, non-carriers, and sporadic cases.

INTRODUCTION: Breast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. This study aimed to settle the question as to whether breast carcinoma belongs to the LS tumor spectrum. METHODS: MMR status and epigenetic profiles were determined for all available breast carcinomas identified among 200 LS families from a nation-wide registry (23 tumors from mutation carriers and 18 from non-carriers). Sporadic breast carcinomas (n = 49) and other cancers (n = 105) from MMR gene mutation carriers were studied for comparison. RESULTS: The proportion of breast carcinomas that were MMR-deficient based on absent MMR protein, presence of microsatellite instability, or both was significantly (P = 0.00016) higher among breast carcinomas from mutation carriers (13/20, 65%) compared to non-carriers (0/14, 0%). While the average age at breast carcinoma diagnosis was similar in carriers (56 years) and non-carriers (54 years), it was lower for MMR-deficient versus proficient tumors in mutation carriers (53 years versus 61 years, P = 0.027). Among mutation carriers, absent MMR protein was less frequent in breast carcinoma (65%) than in any of seven other tumor types studied (75% to 100%). Tumor suppressor promoter methylation patterns were organ-specific and similar between breast carcinomas from mutation carriers and non-carriers. CONCLUSIONS: Breast carcinoma from MMR gene mutation carriers resembles common breast carcinoma in many respects (for example, general clinicopathological and epigenetic profiles). MMR status makes a distinction: over half are MMR-deficient typical of LS spectrum tumors, while the remaining subset which is MMR-proficient may develop differently. The results are important for appropriate surveillance in mutation carriers and may be relevant for LS diagnosis in selected cases.

Securin predicts aneuploidy and survival in breast cancer.

AIMS: Securin is known to participate in maintaining chromosomal integrity during the cell cycle through regulation of metaphase-anaphase transition, DNA damage repair, and apoptosis. The aim of this study was to investigate the role of securin in aneuploidy and prognosis in human breast cancer. METHODS AND RESULTS: The study was based on 603 breast cancer patients with up to 20 years of follow-up. DNA content was determined by image cytometry on cell imprints, and securin immunohistochemistry was performed on tissue microarrays of breast cancer tissue. We show, for the first time in human breast cancer, that high-level securin expression predicts abnormal DNA content, with up to 9.8-fold odds for aneuploid DNA content (P = 0.0007). Securin also shows strong independent prognostic value for disease-specific survival, with a significant difference in survival time between patients with low-level and high-level securin expression. CONCLUSIONS: The main result of the present study is the association of aneuploidy and securin expression. According to our results, securin immunohistochemistry is also a potential new prognosticator for treatment decisions concerning breast cancer patients.

Mesangial proliferative glomerulonephritis after autologous stem cell transplantation.

Although glomerulonephritis and renal failure have been observed after allogenic stem cell transplantation, only a few such reports were published about patients undergoing autologous stem cell transplantation. We report a case of mesangial proliferative glomerulonephritis developing 4 months after autologous stem cell transplantation for chronic lymphatic leukemia. Serological test results, together with histological, immunohistochemical, and electronic microscopic findings of a kidney biopsy specimen, confirmed the diagnosis of mesangial proliferative glomerulonephritis in our patient. Complement and immunoglobulin A were not present in the kidney biopsy specimen. An abnormal clone, not previously reported, with the translocation t(5;11)(q31;q13) in blood and bone marrow was observed. The reason for and whether progenitor cells in stem cell transplantations could contribute to the development of glomerulonephritis remain open questions. Kidney biopsy should be performed in patients with microscopic hematuria and/or proteinuria after autologous stem cell transplantation.

The Expression of Cohesin Subunit SA2 Predicts Breast Cancer Survival.

Cohesin is one of the main regulators of sister chromatid separation during the metaphase/anaphase transition. It is a multiprotein complex consisting of 4 core subunits, one of those being the SA2 subunit. SA2 plays the final role in dismantling the cohesion complex from the sister chromatids and also functions in DNA double-strand break repair and gene regulation. There is increasing evidence regarding the involvement of both overexpression and underexpression of cohesin in cancer. Here, we present expression patterns of SA2 in different types of human breast tissue, and the prognostic analysis in the material from breast cancer patients with long-term follow-up. SA2 immunoexpression was evaluated in benign, precancerous, and malignant breast tissue, and was classified into low-intensity or high-intensity groups. The DNA content was determined by image cytometry on breast cancer cell imprints. Prognostic analyses were based on 445 breast cancer patients with upto 20 years' follow-up. SA2 immunoexpression was equally high in both benign and precancerous breast tissue. Instead, 72% of the invasive breast cancers showed deficient SA2 expression. These patients were also associated with an unfavorable outcome as indicated by a 1.6-fold risk of breast cancer death (P=0.0208). The majority (75%) of the patients with low SA2 expression were alive 6.0 years after the diagnosis, whereas the majority of the patients with high SA2 expression survived 17.6 years after the diagnosis. No statistically significant association could be detected between SA2 immunoexpression and DNA aneuploidy. Our results and previous literature indicate that decreased SA2 immunoexpression is associated with malignant breast disease and a particularly unfavorable course of disease.

Low cdc27 and high securin expression predict short survival for breast cancer patients.

Cell cycle regulators cdc27 and securin participate in control of the mitotic checkpoint and survey the mitotic spindle to maintain chromosomal integrity. This is achieved by their functions in metaphase-anaphase transition, DNA damage repair, enhancement of mitotic arrest and apoptosis. We report on the roles of cdc27 and securin in aneuploidy and prognosis of breast cancer. The study comprises 429 breast cancer patients with up to 22 years of follow-up. DNA content was determined by image cytometry, and immunopositivity for cdc27 and securin was based on tissue microarrays. An inverse association between cdc27 and securin expression was observed in both image cytometric and immunohistochemical analyses. Low cdc27 and high securin expression identified patients with significant difference in disease outcome. Cdc27 and securin immunoexpression identified patients at risk of early cancer death within five years from diagnosis. In multivariate analysis, the combination of cdc27 and securin immunohistochemistry was the strongest predictor of cancer death after lymph node status. We demonstrate, for the first time in human breast cancer, the prognostic value of cdc27 and securin immunohistochemistry. Cdc27 and securin appear promising biomarkers for applications in predicting disease progression, prognostication of individual patients and potential in anti-mitotic drug development.

Absence of cytomegalovirus from the gastrointestinal tract of patients with active Crohn's disease.

BACKGROUND: Cytomegalovirus (CMV) infection reportedly is detectable in the gastrointestinal mucosa of patients with chronic inflammatory bowel disease. One view is that CMV infection is of clinical significance in patients with Crohn's disease with severe colitis not responding to steroid therapy. In this study, we evaluated the prevalence of CMV infection in our own patients with Crohn's disease treated with colon resection. PATIENTS AND METHODS: The study included 16 consecutive patients with Crohn's disease with colitis who underwent surgery for colonic disease. Histology and immunohistochemistry were used to examine the CMV infection in their surgical specimens by means of enzymatic antigen retrieval, mouse monoclonal antibody, clone CMV01, and a sensitive polymer detection system. RESULTS: All 16 patients underwent colon resection, three of them undergoing emergency surgery. No CMV infection was found in their surgical specimens. CONCLUSION: CMV infection seems not to play a major role in the pathogenesis of Crohn's colitis requiring surgery. However, further prospective studies with larger number of patients are needed to determine the role of CMV in active Crohn's colitis.

Global gene expression profiles in skeletal muscle of monozygotic female twins discordant for hormone replacement therapy.

Aging is accompanied by inexorable loss of muscle tissue. One of the underlying causes for this is the massive change in the hormonal milieu of the body. The role of a female sex steroid - estrogen - in these processes is frequently neglected, although the rapid decline in its production coincides with a steep deterioration in muscle performance. We recruited 54- to 62-year-old monozygotic female twin pairs discordant for postmenopausal hormone replacement therapy (HRT, n=11 pairs; HRT use 7.3 ± 3.7 years) from the Finnish Twin Cohort to investigate the association of long-term, estrogen-based HRT with skeletal muscle transcriptome. Pathway analysis of muscle transcript profiles revealed significant HRT-induced up-regulation of a biological process related to regulation of cell structure and down-regulation of processes concerning, for example, cell-matrix interactions, energy metabolism and utilization of nutrients (false discovery rate < 0.15). Lending clinical relevance to the findings, these processes explained a significant fraction of the differences observed in relative proportion of muscle within thigh and in muscle performance (R(2) =0.180-0.257, P=0.001-0.023). Although energy metabolism was affected through down-regulation of the transcripts related to succinate dehydrogenase complex in mitochondria, no differences were observed in mtDNA copy number or oxidative capacity per muscle cross section. In conclusion, long-term use of HRT was associated with subtle, but significant, differences in muscle transcript profiles. The better muscle composition and performance among the HRT users appeared to be orchestrated by improved regulatory actions on cytoskeleton, preservation of muscle quality via regulation of intramuscular extracellular matrix and a switch from glucose-oriented metabolism to utilization of fatty acids.