Women who have germline mutations in the BRCA1 gene are at substantially increased lifetime risk of developing breast and ovarian cancer but are otherwise normal. Currently, early age of onset of ...cancer and a strong family history are relied upon as the chief clues as to who should be offered genetic testing. Certain morphologic and immunohistochemical features are overrepresented in BRCA1-associated breast cancers but these differences have not been incorporated into the current selection criteria for genetic testing.
Each of the 4 pathologists studied 30 known cases of BRCA1- and BRCA2-associated breast cancer from kConFab families. After reviewing the literature, we agreed on a semiquantitative scoring system for estimating the chances of presence of an underlying BRCA1 mutation, based on the number of the reported prototypic features present. After a time lag of 12 months, we each examined a series of 62 deidentified cases of breast cancer, inclusive of cases of BRCA1-associated breast cancer and controls. The controls included cases of BRCA2-associated breast cancer and sporadic cases.
Our predictions had a sensitivity of 92%, specificity of 86%, positive predictive value of 61%, and negative predictive value of 98%. For comparison the sensitivity of currently used selection criteria are in the range of 25% to 30%.
The inclusion of morphologic and immunohistochemical features of breast cancers in algorithms to predict the likelihood of presence of germline mutations in the BRCA1 gene improves the accuracy of the selection process.
BACKGROUND: 10% of sporadic colorectal cancers are characterised by a low level of microsatellite instability (MSI-L). These are not thought to differ substantially from microsatelite-stable (MSS) ...cancers, but MSI-L and MSS cancers are distinguished clinicopathologically and in their spectrum of genetic alterations from cancers showing high level microsatellite instability (MSI-H). AIMS: To study the distribution of molecular alterations in a series of colorectal cancers stratified by DNA microsatellite instability. METHODS: A subset of an unselected series of colorectal cancers was grouped by the finding of DNA MSI at 0 loci (MSS) (n = 51), 1-2 loci (MSI-L) (n = 38) and 3-6 loci (MSI-H) (n = 25). The frequency of K-ras mutation, loss of heterozygosity (LOH) at 5q, 17p and 18q, and patterns of p53 and beta catenin immunohistochemistry was determined in the three groups. RESULTS: MSI-H cancers had a low frequency of K-ras mutation (7%), LOH on chromosomes 5q (0%), 17p (0%) and 18q (12.5%), and a normal pattern of immunostaining for p53 and beta catenin. MSI-L cancers differed from MSS cancers in terms of a higher frequency of K-ras mutation (54% v 27%) (p = 0.01) and lower frequency of 5q LOH (23% v 48%) (p = 0.047). Whereas aberrant beta catenin expression and 5q LOH were concordant (both present or both absent) in 57% of MSS cancers, concordance was observed in only 20% of MSI-L cancers (p = 0.01). CONCLUSIONS: MSI-L colorectal cancers are distinct from both MSI-H and MSS cancers. This subset combines features of the suppressor and mutator pathways, may be more dependent on K-ras than on the APC gene in the early stages of neoplastic evolution, and a proportion may be related histogenetically to the serrated (hyperplastic) polyp.
ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A ...significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may underlie the association. Using cell-based models, we evaluated the correlations between ABCB1 expression, polymorphisms, transporter activity and paclitaxel sensitivity in ovarian cancer (n = 10) and lymphoblastoid (n = 19) cell lines. Close associations between ABCB1 expression, transporter function and paclitaxel sensitivity were found in lymphoblastoid cell lines, although we could not demonstrate an association with common SNPs. In ovarian cancer cell lines, ABCB1 expression was low and the association between expression and function was lost. These results suggest that ABCB1 related survival difference in ovarian cancer patients is more likely to be due to differential whole body paclitaxel clearance mediated by normal cells rather than a direct effect on cancer cells.
Molecular classification of breast carcinoma Alizart, Michelle; Saunus, Jodi; Cummings, Margaret ...
Diagnostic histopathology (Oxford, England : 2008),
03/2012, Letnik:
18, Številka:
3
Journal Article
Recenzirano
Abstract Breast cancer is a complex disease encompassing multiple tumour entities each with a characteristic morphology and behaviour. Current clinical practice relies on the recognition of various ...pathology prognostic factors to guide patient management, including histological type and grade, stage and biomarker receptor status. However, there is increasing concern that these parameters are of limited value for the accurate prediction of individual patient outcome. The introduction of genome-wide microarray-based expression profiling studies has allowed better understanding of the molecular underpinning of several characteristics of breast cancer, including histological grade and metastatic potential. Expression profiling has also facilitated the identification of prognostic and predictive gene expression signatures and novel therapeutic targets. Here we review the evolution of molecular classification of breast cancer, including special types, the implications for clinical management, limitations of findings thus far and predictions for the future.
Apoptosis CUMMINGS, M. C; WINTERFORD, C. M; WALKER, N. I
The American journal of surgical pathology,
1997, 1997-Jan, 1997-01-00, 19970101, Letnik:
21, Številka:
1
Journal Article
Reply to J. Moline et al Buchanan, Daniel D; Tan, Yen Y; Walsh, Michael D ...
Journal of clinical oncology,
2014-Jul-20, 2014-07-20, 20140720, Letnik:
32, Številka:
21
Journal Article
Performance measures for Australian laboratories reporting cervical cytology are a set of quantifiable measures relating to the profile and accuracy of reporting. This study reviews aggregate data ...collected over the ten years in which participation in the performance measures has been mandatory.
Laboratories submit annual data on performance measures relating to the profile of reporting, including reporting rates for technically unsatisfactory specimens, high grade or possible high grade abnormalities and abnormal reports. Cytology-histology correlation data and review findings of negative smears reported from women with histological high grade disease are also collected. Suggested acceptable standards are set for each measure.
This study reviews the aggregate data submitted by all laboratories for the years 1998–2008 and examines trends in reporting and the performance of laboratories against the suggested standards.
The performance of Australian laboratories has shown continued improvement over the study period. There has been a fall in the proportion of laboratories with data outside the acceptable standard range in all performance measures.
Laboratories are reporting a greater proportion of specimens as definite or possible high grade abnormality. This is partly attributable to an increase in the proportion of abnormal results classified as high grade or possible high grade abnormality. Despite this, the positive predictive value for high grade and possible high grade abnormalities has continued to rise.
Performance measures for cervical cytology have provided a valuable addition to external quality assurance procedures in Australia. They have documented continued improvements in the aggregate performance, as well as providing benchmarking data and goals for acceptable performance for individual laboratories.
Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer. Endometrial cancers display hyperactivation of the MAPK and PI3K pathways, the result of ...somatic aberrations in genes such as
, and
The FGFR2 and PI3K pathways, have emerged as potential therapeutic targets in endometrial cancer. Activation of the PI3K pathway is seen in more than 90% of FGFR2
endometrial cancers. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719. We assessed synergy in three FGFR2
endometrial cancer cell lines (AN3CA, JHUEM2, and MFE296), and the combination of BGJ398 and GDC-0941 or BYL719 showed strong synergy. A significant increase in cell death and decrease in long-term survival was seen when PI3K inhibitors were combined with BGJ398. Importantly, these effects were seen at low concentrations correlating to only partial inhibition of AKT. The combination of BGJ398 and GDC-0941 showed tumor regressions
, whereas each drug alone only showed moderate tumor growth inhibition. BYL719 alone resulted in increased tumor growth of AN3CA xenografts but in combination with BGJ398 resulted in tumor regression in both AN3CA- and JHUEM2-derived xenografts. These data provide evidence that subtherapeutic doses of PI3K inhibitors enhance the efficacy of anti-FGFR therapies, and a combination therapy may represent a superior therapeutic treatment in patients with FGFR2
endometrial cancer.
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