BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged ...DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates but the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors.
Germline TP53 mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or ...Li-Fraumeni-like (LFL) features. However, in Asia and in many low resource settings, it is challenging to obtain accurate family history and we, therefore, sought to determine whether the presence of early-onset breast cancer is an appropriate selection criteria for germline TP53 testing.
A total of 100 patients with early-onset breast cancer (≤ 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues.
We identified 11 BRCA1 (11%) and 6 BRCA2 (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers.
Our study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers.
Background: Isosulfan blue is not available for clinical use in Malaysia. This study describes the use of methylene blue as an alternative to isosulfan blue in colorectal sentinel node mapping.
...Methods: Methylene blue dye was injected around colonic and rectal tumours and the first blue‐stained nodes were suture tagged and harvested after standard colorectal resection. Standard histopathological examination was then carried out to detect nodal metastasis. All negative sentinel lymph nodes (SLN) were subjected to 10 further step sectioning and immunoperoxidase staining for cytokeratin 20 to detect tumour deposits.
Results: Thirty‐one patients were enrolled from August 2005 to July 2006. Twenty‐five attempts at identifying the SLN were successful (80.7%). Of the 18 (58.1%) who had nodal metastases (stage III), 3 had negative SLN but positive other lymph nodes (false‐negative rate of 21.4%). In one (4%), the SLN was the exclusive site of metastasis.
Conclusion: Methylene blue can be used as an alternative sentinel node marker for rectal cancer (above the peritoneal reflection) and colonic cancer.
Breast cancer treatment is highly dependent on the carcinoma stage, which was obtained by evaluating the pathological slides and the estrogen receptor status. The Allred score has been manually ...calculated by the pathologists to represent the percentage and intensity of tumor nuclei. The task can be automated by enabling digital pathology, by classifying the nuclei using learning-based method. We present here a comprehensive analysis of 32 pretrained deep learning models from DenseN et, EfficientN et, InceptionResN et, Inception, ResN et, MobileNet, NasNet, VGG and Xception. The aim of this exper-iment is to identify the best pre-trained model for classifying the negative, weak, moderate and strong nuclei taken from 44 whole slide images of estrogen receptor immunohistochemistry stained histopathology. The highest test accuracy is achieved by DenseNet169 with the measure of 94.91 %. This study will be a basis for the future development of more complex deep learning models with cascading or any combination of the tested models.
Hormone receptor status in breast carcinoma is determined primarily to identify patients who may benefit from hormonal therapy. Estrogen receptor (ER) is one of the hormone receptor positive factors ...which have been recognized as a marker for which women with breast cancer would respond to hormone treatment. We propose a system to classify cells in ER-stained whole slide breast carcinoma images according to their staining strength using convolutional neural network (CNN). The proposed CNN multiclass classifier was tested on a region of 1200 cells, and achieved very promising results, with overall accuracy of 88.8% and AUC score of 97.5%. The proposed system is useful for use in hormone receptor testing, where the outcomes are used to decide whether the cancer is likely to respond to hormonal therapy or other treatments.
The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved ...categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving > or = 50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.
The classification of glomerulonephritis in systemic lupus erythematosus revisited.The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus ...nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving ≥50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.
Abstract Background: Adjuvant! Online is a free web-based tool which predicts 10-year breast cancer outcomes and the efficacy of adjuvant therapy in patients with breast cancer. As its prognostic ...performance has only been validated in high income Caucasian populations, we validated the model in a middle income Asian setting. Methods: Within the University Malaya Hospital-Based Breast Cancer Registry, all 631 women who were surgically treated for invasive non-metastatic breast cancer between 1993 and 2000 were identified. The discriminative performance of Adjuvant! Online was tested using receiver operating characteristic (ROC) analysis. Calibration of the model was evaluated by comparing predicted 10-year overall survival with observed 10-year survival. Findings: Adjuvant! Online was fairly capable in discriminating between good and poor survivors, as attested by the area under ROC curve of 0.73 (95% Confidence Interval: 0.69–0.77). Overall, Adjuvant! Online predicted 10 year survival (70.3%) was significantly higher than the observed 10 year survival (63.6%, difference of 6.7%; 95% CI: 3.0–10.4%). The model was especially overoptimistic in women under 40 years and in women of Malay ethnicity, where survival was overestimated by approximately 20% (95% CI: 9.8–29.8%) and 15% (95% CI: 5.3–24.5%) respectively. Interpretation: Even though Adjuvant! Online is capable of discriminating between good and poor survivors, it systematically overestimates survival. These findings suggest that the model requires adaptation prior to use in Asian settings.
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