Copy number analysis of ductal carcinoma in situ with and without recurrence.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer and a frequent mammographic finding requiring treatment. Up to 25% of DCIS can recur and half of recurrences are invasive, but there are no reliable biomarkers for recurrence. We hypothesised that copy number aberrations could predict likelihood of recurrence. We analysed a cohort of pure DCIS cases treated only with wide local excision for genome-wide copy number and loss of heterozygosity using Affymetrix OncoScan MIP arrays. Cases included those without recurrence within 7 years (n = 25) and with recurrence between 1 and 5 years after diagnosis (n = 15). Pure DCIS were broadly similar in copy number changes compared with invasive breast cancer, with the consistent exception of a greater frequency of ERBB2 amplification in DCIS. There were no significant differences in age or ER status between the cases with a recurrence vs those without. Overall, the DCIS cases with recurrence had more copy number events than the DCIS without recurrence. The increased copy number appeared non-random with several genomic regions showing an increase in frequency in recurrent cases, including 20 q gain, ERBB2 amplification and 15q loss. Copy number changes may provide prognostic information for DCIS recurrence, but validation in additional cohorts is required.

Identification of copy number alterations associated with the progression of DCIS to invasive ductal carcinoma.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive ductal carcinoma (IDC). Annotation of the genetic differences between the two lesions may assist in the identification of genes that promote the invasive phenotype. Synchronous DCIS and IDC cells were microdissected from FFPE tissue and analysed by molecular inversion probe (MIP) copy number arrays. Matched IDC and DCIS showed highly similar copy number profiles (average of 83% of the genome shared) indicating a common clonal origin although there is evidence that the DCIS continues to evolve in parallel with the co-existing IDC. Four chromosomal regions of loss (3q, 6q, 8p and 11q) and four regions of gain (5q, 16p, 19q and 20) were recurrently affected in IDC but not in DCIS. CCND1 and MYC showed increased amplitude of gain in IDC. One region of loss (17p11.2) was specific to DCIS. IDC-specific regions include genes with previous links to breast cancer progression and potential therapeutic targets such as AXL, SPHK1 and PLAUR.

Protein kinase C-beta II expression in diffuse large B-cell lymphoma predicts for inferior outcome of anthracycline-based chemotherapy with and without rituximab.

Protein kinase C-beta II (PKC-beta II) expression has been reported to indicate inferior prognosis in diffuse large B-cell lymphoma (DLBCL) treated with anthracycline-based chemotherapy. This study compared prognostic significance of immunohistochemically determined PKC-beta II expression in de novo DLBCL treated with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy with and without rituximab. Outcomes were assessed in 80 consecutive patients, 48 treated with CHOP, and 32 with rituximab plus CHOP (R-CHOP). PKC-beta II expression correlated with inferior overall survival (OS) and progression-free survival (PFS) in CHOP-treated patients with low-risk International Prognostic Index (IPI) disease (0-2 adverse factors), but not in the overall patient group unstratified by IPI. PKC-beta II expression correlated with inferior OS and PFS in R-CHOP-treated patients unstratified by IPI status. Immunohistochemically demonstrated PKC-beta II expression thus identified patient subgroups where alternative treatment strategies may confer superior outcome. We now report that PKC-beta II expression has prognostic significance not only for CHOP therapy in low-risk IPI disease, but also for all patients receiving CHOP plus rituximab.

Evaluation of treatment in 35 cases of bipolar suicide.

OBJECTIVE: The aim of the present study was to evaluate clinical factors relevant to suicide prevention (including treatment) in cases of bipolar suicide with available therapeutic histories. METHOD: Victorian Coroner's Office data enabled identification of suicides that occurred between March 1993 and December 2001. Cases involving sufficient clinical notes to enable diagnosis of DSM-IV bipolar disorder and review of treatment were de-identified and assessed by an expert clinical panel. RESULTS: From 3752 suicides, 35 eligible bipolar subjects (22 men, 13 women) aged 40.3 +/- 1.8 years were identified. Duration of illness was 11.9 +/- 1.1 years. A total of 86% had made at least one previous suicide attempt, and 83% were in the depressed phase of illness. A total of 63% manifested psychosis at some time during lifetime illness. Fourteen per cent were inpatients, and 26% suicided within 6 weeks of hospital discharge. The panel's retrospective risk assessment concluded that only 48% of cases could have been assessed as high risk. In the 4 weeks prior to suicide, treatment was rated as not reaching benchmark standards in 60% of cases. Electroconvulsive therapy had been given to 11%, lithium to 43% (but definitely therapeutic in only 11%), 31% had never been treated with lithium, and psychosocial interventions did not reach adequate standards in 57% during the previous year. CONCLUSIONS: In the majority of bipolar suicide cases in the present case series the subjects did not receive treatment at or above a benchmark standard, often due to illness and situational factors, but also possibly due to inadequate clinical interventions. Strategies to improve treatment may reduce suicide in bipolar disorder.

No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas.

There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinoma-promoting phenotypes of breast and ovarian CAFs.

A molecular diagnostic test for distinguishing lung adenocarcinoma from malignant mesothelioma using cells collected from pleural effusions.

PURPOSE: Patients with malignant mesothelioma or adenocarcinoma of the lung often present with respiratory complications associated with a malignant pleural effusion. Distinguishing between these malignancies is frequently problematic, as many of the clinical, cytologic, and histologic features of the diseases overlap. Following cytologic analysis of pleural effusions, subsequent confirmatory tissue biopsies involve increased patient morbidity and expense. We have therefore designed a gene expression-based test to classify the primary tumor causing a malignant pleural effusion, using cells collected from the effusion itself. EXPERIMENTAL DESIGN: We have used microarray data for 190 lung adenocarcinomas and 33 malignant mesotheliomas to identify genes differentially expressed between the two diseases. Genes expressed in normal mesothelial cells were removed, allowing the development of a PCR-based test to measure the expression of genes that discriminate between mesothelioma and lung adenocarcinoma from cytology specimens. RESULTS: Applying an real-time PCR-based assay involving 17 genes to 13 independent samples from biopsy-proven malignant mesothelioma and lung adenocarcinomas resulted in the correct identification of all samples. CONCLUSIONS: We have developed a test that is able to distinguish between lung adenocarcinoma and mesothelioma in cells collected from pleural effusions.