Expression of DNA mismatch repair gene MSH2 in cytological material from lung cancer patients

Mismatch repair genes encode for proteins responsible for the correction of bases incorrectly paired in the DNA. Loss of DNA mismatch repair activity has been associated with various cancers including tumors of the lung. In the present study, we have analyzed by immunocytochemistry the expression of MSH2 DNA repair gene in cytological material obtained by fine needle aspiration from a panel of 42 primary lung cancer patients. Specimens included 13 adenocarcinomas, 11 small cell carcinomas and 18 squamous cell carcinomas. Loss of expression or low expression was detected in 6 out of 13 (46%) adenocarcinomas and in 7 out of 18 (39%) of squamous cell carcinomas, although all 11 small cell carcinomas expressed MSH2. Our results suggest that loss of MSH2 expression is frequent in nonsmall cell carcinomas of the lung (P < 0.01, chi2 test). Evaluation of MSH2 expression can be applied for the screening of cytological material from fine needle aspirations from the lung.     

Allogeneic blood transfusion as a risk factor for the subsequent development of non-Hodgkin's lymphoma

In summary, it is impossible to reconcile the contradictory results of the studies of the association between previous blood transfusion and subsequent development of NHL (Figs 1 and 2). Most of the studies were of high quality, and the authors discussed the possible sources of bias that might have generated a spurious association or concealed a true relationship. Although recall bias, detection bias, and allogeneic blood transfusions given because of the onset of NHL could be responsible for the reported positive associations, these explanations were considered by the investigators, and they seem unlikely. Multiple comparisons may account for the association between transfusion history and NHL in individual studies, but they are less likely to explain the association noted in all the positive studies considered together. Random misclassification and Berkson's bias might explain some of the null results, but they are unlikely to account for disagreements of the magnitude shown in Figures 1 and 2. Alexander discussed the superior quality of the design of the case-control study of Adami et al but was unable to explain the disagreements among the reported studies (Figs 1 and 2). He concluded that there is no proof that allogeneic blood transfusion does not increase the risk of NHL; one can, however, be reassured that the evidence so far points to--at worst--a doubling of risk, and--at best--no increase in risk after a previous transfusion. Along these lines, Figure 1 shows the results of the 3 cohort studies, which were remarkably consistent in reporting a 2-fold increase in the risk of developing NHL after a blood transfusion; and Figure 2 shows the results of the 6 case-control studies, which usually observed no increased risk. If allogeneic blood transfusion does have an immunosuppressive effect, this effect is probably transient and weak, compared with the severity of the immunosuppression encountered in the posttransplantation situation. Immune impairment may be the common determinant for the increased risk of NHL observed in transplanted and transfused patients, and--if this were the case--the difference in the duration and intensity of the immunosuppressive state would be logically congruent with the observed patterns of lymphoma development: that is, the risk of NHL is increased 20- to 120-fold in the transplanted patients, as compared with only 2-fold in the previously transfused patients. The association between allogeneic blood transfusion and subsequent development of NHL is biologically plausible, whether the mechanism is transfusion-associated immunosuppression, transmission of oncogenic viruses, or viral activation in a setting of transfusion-associated immunosuppression. Also, if allogeneic blood transfusion is a risk factor for the subsequent development of NHL, the increased use of allogeneic blood transfusion since the 1950s might account, at least in part, for the increase in the incidence of NHL over the last half of this century. Blood transfusions are commonly used worldwide, and--based on at least some studies--they show a weak association with NHL (i.e., at worst, a doubling of risk; Fig 1). Common exposures that have a weak association with NHL are more likely to account for the current epidemic of NHL in the elderly, compared with rare exposures that increase the risk of NHL by manyfold. However, no evidence regarding a causal relationship between history of an allogeneic blood transfusion and the subsequent development of NHL has been presented. The available studies are observational, and they cannot determine whether any increase in risk, observed in association with allogeneic blood transfusion, is due to the transfusion itself or to other factors occurring in association with the transfusion. In conclusion, allogeneic blood transfusion from healthy donors may be associated with a small increase in the risk of development of NHL after the transfusion. This hypothesis is biologically plausible and is     

The genomic profile of HER2-amplified breast cancers: the influence of ER status

Expression profiling studies have suggested that HER2-amplified breast cancers constitute a heterogeneous group that may be subdivided according to their ER status: HER2-amplified ER-positive breast carcinomas that fall into the luminal B cluster; and HER2-amplified ER-negative cancers which form a distinct molecular subgroup, known as the erbB2 or HER2 subgroup. ER-negative breast cancer differs significantly from ER-positive disease in the pattern, type, and complexity of genetic aberrations. Here we have compared the genomic profiles of ER-positive and ER-negative HER2-amplified cancers using tiling path microarray-based comparative genomic hybridization (aCGH). Validation of the differentially amplified regions was performed in an independent series of 70 HER2-amplified breast cancers. Although HER2-amplified cancers had remarkably complex patterns of molecular genetic aberrations, ER-positive and ER-negative HER2-amplified breast carcinomas shared most molecular genetic features as defined by aCGH. Genome-wide Fisher's exact test analysis revealed that less than 1.5% of the genome was significantly differentially gained or lost in ER-positive versus ER-negative HER2-amplified cancers. However, two regions of amplification were significantly associated with ER-positive carcinomas, one of which mapped to 17q21.2 and encompassed GJC1, IGFBP4, TNS4, and TOP2A. Chromogenic in situ hybridization analysis of an independent validation series confirmed the association between ER status and TOP2A amplification. In conclusion, although hormone receptor status does not determine the overall genetic profile of HER2-amplified breast cancers, specific genetic aberrations may be characteristic of subgroups of HER2 breast cancers.     

Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection

The mechanisms underlying the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast are yet to be fully elucidated. Several hypotheses have been put forward to explain the progression from DCIS to IDC, including the selection of a subpopulation of cancer cells with specific genetic aberrations, and the acquisition of new genetic aberrations or non-genetic mechanisms mediated by the tumour microenvironment. To determine whether synchronously diagnosed ipsilateral DCI and IDCs have modal populations with distinct repertoires of gene copy number aberrations and mutations in common oncogenes, matched frozen samples of DCIS and IDC were retrieved from 13 patients and subjected to microarray-based comparative genomic hybridization (aCGH) and Sequenom MassARRAY (Oncocarta v 1.0 panel). Fluorescence in situ hybridization and Sanger sequencing were employed to validate the aCGH and Sequenom findings, respectively. Although the genomic profiles of matched DCI and IDCs were similar, in three of 13 matched pairs amplification of distinct loci (ie 1q41, 2q24.2, 6q22.31, 7q11.21, 8q21.2 and 9p13.3) was either restricted to, or more prevalent in, the modal population of cancer cells of one of the components. Sequenom MassARRAY identified PIK3CA mutations restricted to the DCIS component in two cases, and in a third case the frequency of the PIK3CA mutant allele reduced from 49% in the DCIS to 25% in the IDC component. Despite the genomic similarities between synchronous DCIS and IDC, our data provide strong circumstantial evidence to suggest that in some cases the progression from DCIS to IDC is driven by the selection of non-modal clones that harbour a specific repertoire of genetic aberrations.     

The impact of familial risk for schizophrenia or bipolar disorder on cognitive control during episodic memory retrieval

Episodic memory impairment is a robust correlate of familial risk for schizophrenia (SZ) and bipolar disorder (BD); still much is unknown about the processes that underlie this deficit and how they may be implicated in BD and SZ. We examined the possibility that (a) episodic memory impairment may arise from abnormalities in the cognitive control of interference between task-relevant and task-irrelevant memories during retrieval; inability to suppress task-irrelevant representations could give rise to intrusions of inappropriate memories and increased rate of forgetting, (b) cognitive control deficits during retrieval may be differentially affected by familial predisposition to SZ or BD. We examined episodic memory in relatives of patients with SZ (SZ-R) (n=15) or BD (BD-R) (n=17) compared to healthy controls (n=23) using the California Verbal Learning Test (CVLT) and the Doors and People Test (DPT). All relatives were free of any psychiatric morbidity and were matched to controls on age, sex, educational achievement and general intellectual ability. During the CVLT, both relatives' groups made significantly more perseverative recall errors than controls. However, intrusion errors were significantly increased in SZ-R only. SZ-R also showed increased rate of forgetting in the DPT while BD-R were comparable to controls. Familial predisposition to SZ, compared to that of BD, was associated with significantly greater impairment in cognitive control processes during episodic memory retrieval with some evidence of specificity for SZ in connection with mechanisms relating to increased forgetting.     

Evaluation of a Dual ALK/ROS1 Fluorescent In Situ Hybridization Test in Non–Small-cell Lung Cancer

Background

Several therapeutics targets have emerged to treat patients with non–small-cell lung carcinoma (NSCLC), with numerous biomarkers available to test for treatment choices. Minimum tumor wastage is necessary to permit the analysis of every potentially relevant target. Searching for targetable ALK and ROS1 rearrangements is now mandatory in NSCLC. In the present study, we evaluated the performance of a dual ALK/ROS1 fluorescent in situ hybridization (FISH) probe that concurrently analyzed the 2 oncogenes on a same FISH slide.