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Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Coronavirus Disease 2019 (COVID-19) is an acute respiratory syndrome, reported at the end of 2019 in China originally and immediately spread affecting over ten million world population to date. This pandemic is more lethal for the older population and those who previously suffered from other ailments such as cardiovascular diseases, respiratory disorders, and other immune system affecting abnormalities including cancers. Lung cancer is an important comorbidity of COVID-19. In this review, we emphasized the impact of lung tumor microenvironment (TME) on the possibility of enhanced severity of infection caused by the SARS-Co-V2. The compromised lung TME is further susceptible to the attack of viruses. The lung cells are also abundant in the virus entry receptors. Several SARS-Co-V2 proteins can modulate the lung TME by disrupting the fragile immune mechanisms contributing to cytokine storming and cellular metabolic variations. We also discussed the impact of medication used for lung cancer in the scenario of this infection. Since other respiratory infections can be a risk factor for lung cancer, COVID-19 recovered patients should be monitored for tumor development, especially if there is genetic susceptibility or it involves exposure to other risk factors.

BackgroundThe RecQ Like Helicase (RECQL) gene has previously been shown to predispose to breast cancer mainly in European populations, in particular to estrogen receptor (ER) and/or progesterone receptor (PR) positive tumor. Here, we investigated the contribution of pathogenicRECQLgermline variants to hereditary breast cancer in early-onset and familial breast cancer patients from Pakistan.MethodsComprehensiveRECQLvariant analysis was performed in 302BRCA1andBRCA2negative patients with ER and/or PR positive breast tumors using denaturing high-performance liquid chromatography followed by DNA sequencing. Novel variants were classified using Sherloc guidelines.ResultsOne novel pathogenic protein-truncating variant (p.W75*) was identified in a 37-year-old familial breast cancer patient. The pathogenic variant frequencies were 0.3% (1/302) in early-onset and familial breast cancer patients and 0.8% (1/133) in familial patients. Further, three novel variants of unknown significance, p.I141F, p.S182S, and p.C475C, were identified in familial breast cancer patients at the age of 47, 68, and 47 respectively. All variants were absent in 250 controls.ConclusionsOur data suggest that theRECQLgene plays a negligible role in breast cancer predisposition in Pakistan.

Background: Tumors use several immunosuppressive mechanisms to evade immune destruction. Cyclooxygenase-2 (COX-2) expression may be a driver of immunosuppression in breast cancer, but the mechanisms involved remain elusive. COX-2 expression induces the expression of indoleamine 2,3 dioxygenase (IDO) in tumor cells. IDO is an immunosuppressive enzyme which is involved in tumor immune escape mechanisms in breast cancer. Our aim was to evaluate the association between COX-2 and IDO expression to find evidence of immunosuppression in Pakistani breast cancer patients. Methods: Immunohistochemical analysis was performed to evaluate the expression of COX-2, IDO, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) on formalin-fixed paraffin-embedded breast cancer tissues of 100 patients. Univariable and multivariable logistic regression model was used to identify the independent risk factors of COX-2. Results: A total of 100 patients were included with a mean age and standard deviation of 48.28 ± 11.83. A significant association was observed among COX-2, IDO, ER, PR and tumor grade. In multivariable analysis, three variables were identified as significant independent risk factors for high COX-2: IDO expression high; [adjusted odds ratio (AOR) 6.51; 95% confidence interval (CI) (2.00-21.20), p=0.001], ER; [AOR 5.62; 95% CI (1.80-17.84), p=0.002] and age [AOR 1.04; 95% CI (1.00-1.10), p=0.05] respectively. Conclusion: Our data showed that high IDO expression is associated with high COX-2 expression in Pakistani breast cancer patients. The co-expression of both enzymes may suggest their role in disease pathogenesis. Hence the concurrent targeting of COX-2 and IDO may be a promising therapy for breast cancer.

Oral cancer ranks first among males and is the primary cause of cancer-related deaths in Pakistan. We studied the epidemiology and risk factors associated with this cancer. The main risk factors in the Pakistani population include the usage of chewable and non-chewable tobacco, areca nut, betel leaf, poor dental hygiene practices, oncogenic viral infections, and genetic predispositions. The impact of socioeconomic status and the available health resources on the management of oral cancer is also discussed. It is concluded that being a low-middle economy efforts should be primarily focused on awareness for early screening, diagnosis, and prevention strategies.

The main objective of this research was to investigate the effect of adding polypropylene and steel fibres on flexural behaviour of prestressed concrete girders. Although the construction industry is frequently using prestressed concrete to increase the load-carrying capacity of structures, it can be further enhanced by using fibres. In this paper, experimental work was carried out to encourage the construction industry in utilizing fibres in prestressed concrete members to improve the mechanical properties of these members. As past investigations on fibre-reinforced prestressed beams were limited, the present work was done on small-scale fibre-reinforced I-shaped prestressed concrete girders. Six small-scale prestressed concrete girders were cast comprising a control girder, a hybrid girder, two girders with varying percentages of steel fibres, and two girders with varying percentages of polypropylene fibres. These girders were tested by centre point loading up to failure. It was concluded that, by the addition of small volume fraction of fibres, not only the ductility but also the tensile strength and flexural strength of FRC girders could be improved. It also altered the failure pattern positively by enhancing large strains in concrete and steel. Steel fibre-reinforced concrete showed higher energy absorption and deflection at ultimate loads in comparison to other specimens.

Importance The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P

Reservoirs play a strategic role in the rapid monetary growth of the world by providing numerous benefits. However, the reduction in appropriate sites along with environmental and social apprehensions has resulted in curtailment of new reservoirs around the world in twenty-first century. There is a potential of benefits available from existing reservoirs which can be best capitalized through their optimized operation. Reservoirs Operation Optimization considering Sediment Evacuation (RESOOSE), recently developed model which combines multiple reservoirs operation and sediment evacuation with Genetic Algorithm based optimization module, has been used in the study. The objective of the study was to optimize the irrigation deficit through cascade reservoirs with consideration to hydropower, sediment evacuation and flood damages reduction benefits. The RESOOSE model was applied to optimize the irrigation deficits of Tarbela and Diamer Basha Reservoirs in Pakistan using developed objective function. The article computed and compared the benefits of optimized and existing rule curves. The hydropower benefits of 36.92 Billion Kw, sediment evacuation benefits of 21.534 Million m3 and flood damages of 616.19 Million US$ due to existing rule curves were considered as minimum benefits for achieving the optimized rule curves to minimize irrigation deficits. The developed optimized rule curves reduced the irrigation shortages of case study reservoirs from 6.9 to 5.8 Billion m3 (16% enhancement) annually as compared to existing rule curves. The optimized rule curves minimized the irrigation deficits by maintaining the existing benefits and without lowering the minimum operating levels of case study reservoirs. The study suggests change in existing rule curves of Tarbela and Diamer Basha Reservoirs due to less irrigation shortages. The RESOOSE model can be applied to other cascade reservoirs for optimizing the rule curves.

Nanomedicine application in cancer immunotherapy is currently one of the most challenging areas in cancer therapeutic intervention. Innovative solutions have been provided by nanotechnology to deliver cytotoxic agents to the cancer cells partially affecting the healthy cells of the body during the process. Nanoparticle-based drug delivery is an emerging approach to stimulate the immune responses against cancer. The inhibition of indoleamine 2,3-dioxygenase (IDO) is a pivotal area of research in cancer immunotherapy. IDO is a heme-containing immunosuppressive enzyme, which is responsible for the degradation of tryptophan while increasing the concentration of kynurenine metabolites. Various preclinical studies showed that IDO inhibition in certain diseases may result in significant therapeutic effects. Here, we provide a review of the natural and synthetic inhibitors of IDO. These inhibitors are classified according to their source, inhibitory concentrations, the chemical structure, and the mechanism of action. Tumor-targeted chemotherapy is an advanced technique and has more advantages as compared to the conventional chemotherapy. Search for more efficient and less toxic nanoparticles in conjunction with compounds to inhibit IDO is still an area of interest for several research groups worldwide, especially revealing to be an extensive and a promising area in cancer therapeutic innovations.

Background Pathogenic germline mutations in BRCA1 and BRCA2 (BRCA1/2) account for the majority of hereditary breast and/or ovarian cancers worldwide. To refine the spectrum of BRCA1/2 mutations and to accurately estimate the prevalence of mutation in the Pakistani population, we studied 539 breast cancer patients selected for family history and age of diagnosis. Methods Comprehensive screening for BRCA1/2 germline mutations was performed using state-of-the-art technologies. Results A total of 133 deleterious mutations were identified in 539 families (24.7%), comprising 110 in BRCA1 and 23 in BRCA2. The prevalence of BRCA1/2 small-range mutations and large genomic rearrangements was 55.4% (36/65) for families with breast and ovarian cancer, 27.4% (67/244) for families with two or more cases of breast cancer, 18.5% (5/27) for families with male breast cancer, and 12.3% (25/203) for families with a single case of early-onset breast cancer. Nine mutations were specific to the Pakistani population. Eighteen mutations in BRCA1 and three in BRCA2 were recurrent and accounted for 68.2% (75/110) and 34.8% (8/23) of all identified mutations in BRCA1 and BRCA2, respectively. Most of these mutations were exclusive to a specific ethnic group and may result from founder effects. Conclusions Our findings show that BRCA1/2 mutations account for one in four cases of hereditary breast/ovarian cancer, one in five cases of male breast cancer, and one in eight cases of early-onset breast cancer in Pakistan. Our study suggests genetic testing of an extended panel of 21 recurrent BRCA1/2 mutations for appropriately selected patients and their families in Pakistan.

Background:BRCA1/BRCA2 mutations are associated with an increased lifetime risk for hereditary breast and ovarian cancer (HBOC). Compared with the Western developed countries, genetic testing and risk assessment for HBOC in Asia are less available, thus prohibiting the appropriate surveillance, clinical strategies and cancer management. Methods: The current status of HBOC management in 14 Asian countries, including genetic counselling/testing uptakes and clinical management options, was reviewed. We analysed how economic factors, healthcare and legal frameworks, and cultural issues affect the genetic service availability in Asia. Results: In 2012, only an estimated 4,000 breast cancer cases from 14 Asian countries have benefited from genetic services. Genetic testing costs and the absence of their adoption into national healthcare systems are the main economic barriers for approaching genetic services. Training programmes, regional accredited laboratories and healthcare professionals are not readily available in most of the studied countries. A lack of legal frameworks against genetic discrimination and a lack of public awareness of cancer risk assessment also provide challenges to HBOC management in Asia. Conclusions: The Asian BRCA Consortium reports the current disparities in genetic services for HBOC in Asia and urges the policy makers, healthcare sectors and researchers to address the limitations in HBOC management.

Breast cancer is a heterogeneous disease. Several genetic, environmental and lifestyle factors are involved in the aetiology of this disease. Genetic risk factors include alterations (mutations) in genes conferring risks to develop breast cancer. Depending on the associated lifetime risks of this malignancy, these genes are categorised into high-, moderate- and low-risk genes. Women carrying mutations in these genes are at an increased risk to develop breast cancer, ovarian cancer and several other malignancies. Breast carcinoma is the most reported malignancy in Pakistani females. Pakistan is a developing country with most of its population living in rural areas; hence, optimal healthcare facilities are inadequate for the early diagnosis and prevention of this disease. Hence, identification of individuals carrying mutations is clinically relevant as different strategies are available for the early detection, risk reduction and better management of this malignancy. This review summarises the findings of the major studies conducted in Pakistan to investigate the contribution of breast cancer predisposing genes. Furthermore, implications of the current studies and future research potentials are discussed.Key words: Breast cancer gene 1/2, breast cancer, checkpoint kinase 2, genetic susceptibility, Pakistan, RAD51C, tumour Protein p53, Vitamin D receptor

CIMBA Consortium et al., PMID: 25849179, [Importance]: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. [Objective]: To identify mutation-specific cancer risks for carriers of BRCA1/2. [Design, Setting, and Participants]: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. [Exposures]: Mutations of BRCA1 or BRCA2. [Main Outcomes and Measures]: Breast and ovarian cancer risks. [Results]: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. [Conclusions and Relevance]: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations., Dr Antoniou and the CIMBA data management are funded by Cancer Research UK. Dr Easton is a Principal Research Fellow of Cancer Research UK. Dr Rebbeck is supported by R01-CA083855, R01-CA102776, and P50-CA083638 from the National Institutes of Health (NIH). Dr Rebbeck, Dr Nathanson, Ms Friebel, and Dr Domchek are supported by the Basser Research Center at the University of Pennsylvania. Dr Nathanson is supported by the Breast Cancer Research Foundation. Drs Domchek and Nathanson are supported by the Rooney Family Foundation. Dr Poppe is supported by R01-CA112520 from NIH. Cancer Research UK provided financial support for this work. Dr Antoniou is a Senior Cancer Research UK Cancer Research Fellow. Dr Phillips is a National Breast Cancer Foundation (Australia) Practitioner Fellow.

The paper develops a new methodology and RESOOSE model for optimizing operation of multiple reservoirs considering sediment evacuation for multiple objectives consisting of maximization of irrigation, hydropower, storage conservation and minimization of flood damages. The optimization and sediment evacuation modules of the model are based on Genetic Algorithm and Tsinghua equation respectively. According to the criteria developed for selection of reservoirs, three reservoirs on Indus River of Pakistan have been selected. The model has been calibrated and validated for Tarbela and Chashma Reservoirs. The calibrated model has been applied to Diamer Basha (proposed) and Tarbela Reservoirs. Eight scenarios comprising of combined and individual objectives were developed. The optimized results of different scenarios have been compared with existing rule curves. The optimization results reveal that objective function for hydropower, irrigation, and storage conservation benefits would be enhanced by 11, 13 and 84 % respectively while flood damages would reduce by 80 %. Similarly the optimized rule curves will increase the benefits up to 579, 960, 533 and 648 million US$ per year (on 2012 prices) for all the four components respectively. The maximum value of US$ 977 million per year has been found for the scenario 5 which gives equal priority weight to all the four sectors. The developed model can be applied to other two reservoirs (in series) for optimization of rule curves.

Pathogenic BRCA1/2 germline mutations confer high risks of breast and ovarian cancer to women of European ancestry. Characterization of BRCA1/2 mutations in other ethnic groups is also medically important. We comprehensively screened 68 Colombian breast/ovarian cancer families for small-range mutations, 221 families for large-genomic rearrangements, and 1,022 unselected breast cancer cases for Colombian founder mutations in BRCA1/2. The risk of cancer among relatives of mutation carriers and the mutation penetrance were estimated by survival analysis. Identified BRCA2 mutations included 6310delGA and the recurrent 1991del4 mutations. A novel large BRCA2 deletion was found in 0.9% of the screened families. Among unselected breast cancer cases, 3.3% tested positive for BRCA1/3450del4, 2.2% for BRCA1/A1708E, 1.1% for BRCA2/3034del4, and 0.4% for BRCA2/1991del4. Female relatives of carriers of BRCA1/2 founder mutations showed a 5.90 times higher risk of breast cancer, when the woman herself carried a BRCA1 mutation compared to a non-carrier (95% CI 2.01–17.3). The estimated cumulative risk of breast cancer by age 70 years for BRCA1 mutations carriers was 14% (95% CI 5–38) compared to 3% for the general Colombian population (relative risk of breast cancer 4.05). Together with known founder mutations, reported novel variants may ease a cost-effective BRCA1/2 screening in women with Colombian ancestry.

Dams are strategic assets as they provide water for irrigation, hydropower generation and control floods for rapid economic growth. However, due to lack of suitable sites as well as socio-environmental concerns, the development of new reservoirs has reduced, which necessitates better management of existing ones with consideration to sediment removal for storage conservation. This study presents an analysis of sediment management options available in the literature for Tarbela Reservoir. RESCON model has been used for technical and economical viability of flushing, dredging, trucking and hydrosuction processes. It is found that dredging and trucking are technically feasible but economically non-feasible, whereas, hydrosuction is technically non-feasible for Tarbela Reservoir. Reservoir flushing has been found technically and economically viable for this dam. HEC-RAS model has been used in the present study for carrying out Tarbela Reservoir sedimentation analysis to evaluate the options of: (i) sediment management through appropriate reservoir operation and (ii) constructing the proposed multipurpose Diamer Basha Dam, located at the upstream. The simulations lead to the conclusion that both the options are feasible. The reservoir storage depletion can be reduced and its life can be extended up to 27 years by lowering the minimum operation level from 457 to 401 m. The storage conservation may enhance the irrigation benefits and will reduce the devastations due to floods. Further studies are recommended to envisage the impact of high sediment outflows on turbines, tunnels and downstream reaches for Tarbela Reservoir operation at lower minimum operating levels and flushing.

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) account for the majority of hereditary breast and/or ovarian cancers. Pakistan has one of the highest rates of breast cancer incidence in Asia, where BRCA1/2 small-range mutations account for 17% of early-onset and familial breast/ovarian cancer patients. We report the first study from Pakistan evaluating the prevalence of BRCA1/2 large genomic rearrangements (LGRs) in breast and/or ovarian cancer patients who do not harbor small-range BRCA1/2 mutations. Both BRCA1/2 genes were comprehensively screened for LGRs using multiplex ligation-dependent probe amplification in 120 BRCA1/2 small-range mutations negative early-onset or familial breast/ovarian cancer patients from Pakistan (Group 1). The breakpoints were characterized by long-range PCR- and DNA-sequencing analyses. An additional cohort of 445 BRCA1/2 negative high-risk patients (Group 2) was analyzed for the presence of LGRs identified in Group 1. Three different BRCA1 LGRs were identified in Group 1 (4/120; 3.3%), two of these were novel. Exon 1–2 deletion was observed in two unrelated patients: an early-onset breast cancer patient and another bilateral breast cancer patient from a hereditary breast cancer (HBC) family. Novel exon 20–21 deletion was detected in a 29-year-old breast cancer patient from a HBC family. Another novel exon 21–24 deletion was identified in a breast-ovarian cancer patient from a hereditary breast and ovarian cancer family. The breakpoints of all deletions were characterized. Screening of the 445 patients in Group 2 for the three LGRs revealed ten additional patients harboring exon 1–2 deletion or exon 21–24 deletion (10/445; 2.2%). No BRCA2 LGRs were identified. LGRs in BRCA1 are found with a considerable frequency in Pakistani breast/ovarian cancer cases. Our findings suggest that BRCA1 exons 1–2 deletion and exons 21–24 deletion should be included in the recurrent BRCA1/2 mutations panel for genetic testing of high-risk Pakistani breast/ovarian cancer patients.

Background Women harboring BRCA1/2 germline mutations have high lifetime risk of developing breast/ovarian cancer. The recommendation to pursue BRCA1/2 testing is based on patient’s family history of breast/ovarian cancer, age of disease-onset and/or pathologic parameters of breast tumors. Here, we investigated if diagnosis of triple-negative breast cancer (TNBC) independently increases risk of carrying a BRCA1/2 mutation in Pakistan. Methods Five hundred and twenty-three breast cancer patients including 237 diagnosed ≤ 30 years of age and 286 with a family history of breast/ovarian cancer were screened for BRCA1/2 small-range mutations and large genomic rearrangements. Immunohistochemical analyses were performed at one center. Univariate and multiple logistic regression models were used to investigate possible differences in prevalence of BRCA1/2 mutations according to patient and tumor characteristics. Results Thirty-seven percent of patients presented with TNBC. The prevalence of BRCA1 mutations was higher in patients with TNBC than non-TNBC (37 % vs. 10 %, P

Background Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS) account for a significant proportion of inherited gynecologic malignancies, mainly caused by pathogenic germline mutations in the BRCA1 and BRCA2 genes or in mismatch repair (MMR) genes, such as MLH1 and MSH2. Women harboring deleterious mutations in these genes have increased life-time risks of developing a number of malignancies including ovarian cancer. Since there is a phenotypic overlap of HBOC and LS, timely identification of individuals at-risk of a particular syndrome is crucial in order to optimize cancer risk management. Case presentation We report a novel pathogenic MSH2 mutation, c.2656G > T, which was identified in a 67-year-old female patient with breast cancer, who had previously tested negative for a deleterious mutation in the breast cancer susceptibility genes BRCA1, BRCA2, CHEK2 or RAD51C. The patient reported a personal history of endometrial cancer diagnosed at age 48, and a strong family history of breast and ovarian cancer, as well as several other malignancies within the spectrum of LS. The novel mutation was also found in the index patient’s daughter and a niece, who were diagnosed with endometrial and ovarian cancer, respectively. Breast and endometrial tumors from c.2656G > T mutation carriers showed loss of MSH2 and MSH6 protein expression. The mutation was absent in the control population. Conclusions Our finding suggests that testing for MMR genes may be of benefit to BRCA1/2 negative families with overlapping HBOC and LS phenotype in Pakistan. It is clinically significant to identify individuals harboring mutations in genes linked with a particular syndrome so that they can benefit from targeted life-saving cancer surveillance and preventive strategies.

Article, Background Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P, published version, peerReviewed

Metaplastic breast carcinoma (MBC) is a relatively rare subtype of breast cancer that encompasses a pathologically heterogeneous group of tumors. Pathogenic germ line mutations in the major breast cancer susceptibility genes BRCA1 and BRCA2 genes have been rarely found or described in MBC. We report the identification of the BRCA1 185delAG mutation in a 22-year-old Pakistani woman with triple-negative MBC that showed biphasic morphological features, including sarcomatous and malignant epithelial components. A comprehensive description of the clinical, histopathological, morphological, and immunohistochemical features of the tumor and the patient's treatment course is presented.

Introduction The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0474-y) contains supplementary material, which is available to authorized users.

Tumor cells induce an immunosuppressive microenvironment which leads towards tumor immune escape. Understanding the intricacy of immunomodulation by tumor cells is essential for immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme which mediates tumor immune escape in various cancers including hepatocellular carcinoma (HCC). IDO up-regulation in HCC may lead to recruitment of regulatory T-cells into tumor microenvironment and therefore inhibit local immune responses and promote metastasis. HCC associated fibroblasts stimulate natural killer cells dysfunction through prostaglandin E2 and subsequently IDO promotes favorable condition for tumor metastasis. IDO up-regulation induces immunosuppression and may enhance the risk of hepatitis C virus and hepatitis B virus induced HCC. Therefore, IDO inhibitors as adjuvant therapeutic agents may have clinical implications in HCC. This review proposes future prospects of IDO not only as a therapeutic target but also as a prognostic marker for HCC.

To the editor About 80% of breast and ovarian cancer families and about 50% of site-specific breast cancer families are due to germ line mutations in either BRCA1 (MIM 113705) or BRCA2 (MIM 600185) [1–3]. Women carrying a pathogenic mutation in BRCA1 or BRCA2 face average lifetime risks of 65% and 45%, respectively, of developing breast cancer, and corresponding ovarian cancer risks of 39% and 11% [4]. In humans, almost all BRCA carriers have been found to be heterozygous [5, 6]. The lack of viable homozygous BRCA mutation carriers in humans suggests that homozygous fetuses may be more susceptible to spontaneous abortions. Further evidence for this hypothesis comes from in vivo animal studies showing that mice homozygous for mutations in the BRCA1 or BRCA2 gene die early in embryogenesis [7, 8]. Two recent studies have explored the impact of BRCA mutation status on the occurrence of miscarriages. One study included BRCA carriers of Ashkenazi Jewish descent [9], and the other included mutation carriers from United States and Canada [10]. Neither study found a significant difference in the rate of miscarriage between BRCA carriers and non-carriers. We conjectured that miscarriages may occur more frequently in BRCA carriers from consanguineous parents since their offspring are more often homozygous by descent compared to those of unrelated parents, and living homozygous BRCA mutation carriers have not been observed. To explore this question, we studied the rates of miscarriages in Pakistani BRCA mutation carriers and non-carriers with a history of parental consanguinity. Pakistan has one of the highest rates of consanguinity in the world (range 60–70%) [11, 12]. Breast and/or ovarian cancer families were recruited at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, between June 2001 and November 2004. Of the 165 female index patients, 30 carried a deleterious BRCA mutation, and 135 were without any identifiable mutation. All families, screening methods and mutations have been described previously [13]. Four additional families carrying a deleterious BRCA mutation identified recently were also included in this study. Relevant information regarding potential breast cancer risk factors including family history of cancer, hormone use, reproductive history, medical history and life style factors was collected by interview-administered questionnaires. Detailed information on the outcome of each pregnancy (year of each pregnancy, number of miscarriages including spontaneous and therapeutic abortions, number of still and live born), and parental consanguinity was collected. Spontaneous abortion was defined as loss of a pregnancy before the completion of 20 gestational weeks from the M. U. Rashid F. Rasheed F. Sultan Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan

Breast cancer is the most common cancer among women worldwide. Approximately 5–10 % of breast cancers are hereditary, and caused by monoallelic germ line mutations in high-, moderate-, and low-penetrance breast cancer susceptibility genes. Several of these genes such as BRCA1, BRCA2, PALB2, BRIP1, and genes of the RAD51 family play an important role in maintenance of genomic stability and are functionally linked with homologous recombination-mediated DNA damage repair. Breast cancer susceptibility is connected with the Fanconi anemia (FA) pathway, since biallelic mutations in at least four genes, BRCA2 (FANCD1) [1], PALB2 (FANCN) [2], BRIP1 (FANCJ) [3], and RAD51C (FANCO) [4] have been shown to also cause FA. Recently, Kiiski and colleagues identified the FA complementation group M (FANCM) gene as a novel breast cancer susceptibility gene [5]. A nonsense mutation in exon 20, c.5101C[T (p.Q1701X), was identified by exome sequencing of germline DNA samples from 24 breast cancer patients from eleven BRCA1/2-negative Finnish breast cancer families. Further genotyping of a large sample set of breast or ovarian cancer cases and controls revealed a 3.5-fold increased frequency among triple-negative breast cancer (TNBC) cases and an approximately twofold increased mutation frequency among all breast cancer cases compared with controls. Given that deleterious mutations in other FA genes including FANCD1 (BRCA2) and FANCO (RAD51C) have previously been identified among TNBC patients from Pakistan [6, 7], we investigated whether the FANCM c.5101C[T mutation is associated with TNBC in Pakistan. Constitutional genomic DNA of 117 BRCA1/2-negative TNBC patients and 188 controls from Pakistan were screened for the FANCM c.5101C[T mutation. Of the TNBC cases, 75 were diagnosed with early-onset disease (B30 years of age), 37 belonged to families with C2 breast cancer cases, and five to breast–ovarian cancer families (Table 1). The median age of diagnosis was 28 years (range 18–67). Forty-four of the cases have been previously described [7]. Screening for the c.5101C[T mutation was performed using denaturing high-performance liquid chromatography (DHPLC) analyses followed by DNA sequencing of variant fragments. PCR primer sequences were as previously described [5]. DHPLC running conditions are available upon request. A positive mutation control was included in all DHPLC runs. The c.5101C[T mutation was not identified in any of the 117 TNBC cases and 188 controls implying that this mutation does not or rarely contributes to TNBC in this population. In line with our data, this mutation was also not detected in previous studies among 965 Icelandic unselected breast cancer patients including 92 BRCA1/2negative familial cases [5], 95 BRCA1/2-negative familial cases from Spain [8], and 3409 BRCA1/2-negative familial cases and 3896 controls from Italy, Netherland, Australia, and Spain [9]. The findings of these studies suggest that the c.5101C[T may be specific to the Finnish population. In the current study, we identified two other FANCM missense mutations. A mutation, c.4931G[A (p.R1644Q), & Muhammad U. Rashid usmanr@skm.org.pk

Women from Pakistan and India are more often diagnosed with early-onset breast cancer than Caucasian women. Given that only 12% of Pakistani women diagnosed with breast cancer at or before 30 years of age have previously been shown to harbor germ line mutations in the breast cancer susceptibility genes BRCA1 and BRCA2, the genetic causes of the majority of early-onset cases are unexplained. Since germ line mutations in the tumor suppressor gene TP53 predispose women to early-onset breast cancer, we assessed the prevalence of TP53 mutations in 105 early-onset breast cancer patients from Pakistan, who had previously been found to be negative for BRCA1 and BRCA2 germ line mutations. The patient group included 67 women diagnosed with early-onset breast cancer at or before age 30 with no family history of breast or ovarian cancer (EO30NFH group) and 38 women diagnosed with breast cancer at or before age 40 with one or more first- or second-degree relatives with breast or ovarian cancer (EO40FH group). Mutation analysis of the complete TP53 coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. One deleterious mutation, c.499-500delCA in exon 5, was identified in the 105 breast cancer patients (1%). This mutation is novel in the germ line and has not been described in other populations. It was detected in a 28-year-old patient with no family history of breast or ovarian cancer. This mutation is rare as it was not detected in additional 157 recently recruited non-BRCA1 and non-BRCA2-associated early-onset breast cancer patients. Our findings show that TP53 mutations may account for a minimal portion of early-onset breast cancer in Pakistan.

Background Vitamin D is postulated to decrease the risk of breast cancer by inhibiting cell proliferation via the vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNPs) in the VDR gene, rs1544410 (BsmI) and rs2228570 (FokI), are inconsistently associated with breast cancer risk in Caucasian populations, while data for Asians are scarce. Here, we investigated the possible contribution of these SNPs to breast cancer risk in Pakistani breast cancer patients and in controls participating in a hospital-based breast cancer case-control study (PAK-BCCC). Methods Genotyping of the BsmI and FokI SNPs was performed by PCR-based restriction fragment length polymorphism (RFLP) analysis of 463 genetically enriched female breast cancer cases with known BRCA1/2 status and in 1,012 controls from Pakistan. The association between SNP genotypes and breast cancer risk was investigated by logistic regression adjusted for potential breast cancer risk factors and stratified by BRCA1/2 status and family history. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. Results The b allele of the BsmI was associated with an increased breast cancer risk (per b allele OR 1.28, 95% CI 1.09–1.49, P = 0.003). Subgroup analysis revealed that this effect was restricted to BRCA1/2 non-carriers (per b allele OR 1.33, 95% CI 1.11–1.59, P = 0.002) and was stronger in those who reported a positive family history of breast and/or ovarian cancer (per b allele OR 1.64, 95% CI 1.20–2.22, P = 0.002). No association with breast cancer risk was detected for the FokI SNP. Conclusions The BsmI polymorphism in the VDR gene may be associated with an increased breast cancer risk in Pakistani women negative for BRCA1/2 germline mutations.

If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2*1100delC should be ∼5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be ∼9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2*1100delC carriers was 6.43 (95% confidence interval, 4.33-9.56; P < 0.0001), significantly greater than the published estimate for a first primary (P < 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (Ptrend = 0.0003) and Finland (Ptrend = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2*1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2*1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2*1100delC and other moderate penetrance alleles in women with a family history of breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(1):230–4)

Background: The Breast Cancer Association Consortium (BCAC) is an international collaboration that was established to provide large sample sizes for examining genetic associations. We conducted combined analyses on all single-nucleotide polymorphisms (SNPs) whose associations with breast cancer have been investigated by at least three participating groups. Methods: Data from up to 12 studies were pooled for each SNP ( ADH1C I350V, AURKA F31I, BRCA2 N372H, CASP8 D302H, ERCC2 D312N, IGFBP3 −202 c > a , LIG4 D501D, PGR V660L, SOD2 V16A, TGFB1 L10P, TP53 R72P, XRCC1 R399Q, XRCC2 R188H, XRCC3 T241M, XRCC3 5′ UTR, and XRCC3 IVS7-14). Genotype frequencies in case and control subjects were compared, and genotype-specific odds ratios for the risk of breast cancer in heterozygotes and homozygotes for the rare allele compared with homozygotes for the common allele were estimated with logistic regression. Statistical tests were two-sided. Results: The total number of subjects for analysis of each SNP ranged from 12 013 to 31 595. For five SNPs— CASP8 D302H, IGFBP3 −202 c > a , PGR V660L, SOD2 V16A, and TGFB1 L10P—the associations with breast cancer were of borderline statistical significance ( P = .016, .060, .047, .056, and .0088 respectively). The remaining 11 SNPs were not associated with breast cancer risk; genotype-specific odds ratios were close to unity. There was some evidence for between-study heterogeneity ( P

CHEK2 *1100delC is associated with a twofold increased breast cancer risk. This was shown in a collaborative analysis of European populations, but not in other populations from Europe and the US. Accordingly, there is a need to clarify the role of CHEK2 *1100delC in breast cancer. We established its prevalence in two German populations GENICA (Northrhine-Westphalia, n = 724) and KORA (Bavaria, n = 600) and in women with breast cancer. The latter included cases ( n = 688) from the GENICA breast cancer case-control study, patients with early-onset breast cancer ( n = 86) and patients with familial breast cancer ( n = 71). The latter patient groups were previously investigated for BRCA1/2 -mutations and tested negative. Mutation analysis was performed by combined PCR/DHPLC methodology. CHEK2 *1100delC was found in 0.9% of GENICA controls and was absent in the KORA controls indicating a significant difference between the two populations ( P = 0.03). The frequency of CHEK2 *1100delC in age-matched cases of the GENICA collection was 0.8% and thus not different from controls (OR 0.88, 95% CI 0.21–3.50). In patients with early-onset disease CHEK2 *1100delC was found at a frequency of 2.3% referring to an increased breast cancer risk of 2.56 (95% CI 0.25–14.58). In patients with familial disease the frequency was 1.4% referring to an increased risk of 1.53 (95% CI 0.03–12.93). Our data showed variations in CHEK2 *1100delC prevalence within German populations suggesting possible inaccuracies in breast cancer risk assessments from non population-based studies. In patients with a high-risk profile however, CHEK2 *1100delC was indicative for this risk and highest for early-onset breast cancer.

BackgroundLess than 20% of Pakistani women with early-onset or familial breast/ovarian cancer harbor germ line mutations in the high-penetrance genesBRCA1,BRCA2andTP53. Thus, mutations in other genes confer genetic susceptibility to breast cancer, of whichCHEK2is a plausible candidate.CHEK2encodes a checkpoint kinase, involved in response to DNA damage.MethodsIn the present study we assessed the prevalence ofCHEK2germ line mutations in 145BRCA1/2-negative early-onset and familial breast/ovarian cancer patients from Pakistan (Group 1). Mutation analysis of the completeCHEK2coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments.ResultsTwo potentially deleterious missense mutations, c.275C>G (p.P92R) and c.1216C>T, (p.R406C), were identified (1.4%). The c.275C>G mutation is novel and has not been described in other populations. It was detected in a 30-year-old breast cancer patient with a family history of breast and multiple other cancers. The c.1216C>T mutation was found in a 34-year-old ovarian cancer patient from a family with two breast cancer cases. Both mutations were not detected in 229 recently recruitedBRCA1/2-negative high risk patients (Group 2).ConclusionOur findings suggest thatCHEK2mutations may not contribute significantly to breast/ovarian cancer risk in Pakistani women.