Breast cancer risk associated with genes encoding DNA repair MRN complex: a study from Punjab, Pakistan

Abstract

Background

Variants of DNA repair genes are extensively reported to cause genetic instability and increase the risk of breast cancer. In combination with NBS1, MRE11 and RAD50 constitute an MRN (MRE11–RAD50–NBS1) complex that repairs DNA damage. However, certain genetic alterations in MRE11 and RAD50 produce abnormal protein that affects the repairing process and may result in malignancy. We aimed to investigate the association of MRE11 and RAD50 polymorphisms with breast risk in the female population of Punjab, Pakistan.

Methods

We collected blood samples of 100 breast cancer patients and 100 tumor-free females selected as controls. Extracted DNA was genotyped by tetra ARMS-PCR followed by gel electrophoresis. Results were analyzed by SPSS and SNPstats to analyze the association of different clinical factors and SNPs (single nucleotide polymorphisms) with the risk of breast cancer.

Results

We found that the increased risk of breast cancer is associated with MRE11 variant rs684507 (odds ratio-OR 3.71, 95% confidence interval-CI 1.68–8.18, p value < 0.0001), whereas, RAD50 variant rs28903089 appeared to have protective effect (OR 0.55, CI 0.29–1.02, p value = 0.003). Additionally, clinical factors such as positive family history, life style, and marital status also play significant roles in breast cancer development.

Conclusion

In the present study, strong risk of breast cancer was associated with MRE11 gene. However, RAD50 showed protective effect. Additionally, clinical factors are also pivotal in risk assessment. We anticipate that targeting specific genetic variations confined to ethnic groups would be more effective in future therapeutic approaches for prevention and treatment of breast cancer.

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Atrial septal defect in a patient with congenital disorder of glycosylation type 1a: a case report

Atrial septal defect often become more severe when encountered in genetic syndromes. Congenital disorder of glycosylation type 1a is an inherited metabolic disorder associated with mutations in PMM2 gene and can ...

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Homeobox C10 knockdown suppresses cell proliferation and promotes cell apoptosis in osteosarcoma cells through regulating caspase 3

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Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Opinion statement

Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20 years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment. High-dose interleukin-2 (HDIL-2) therapy remains a reasonable treatment option in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0–1 and have minimal comorbid conditions. In the near future, these agents are likely to be surpassed by cabozantinib and by combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab. Independent review has recently confirmed superiority of first-line cabozantinib over sunitinib in a phase 2 trial of 157 patients with intermediate or poor risk mccRCC (progression-free survival [PFS] 8.6 vs 5.3 months, hazard ratio [HR] 0.48, p = 0.0008). In a separate study of 1096 patients treated with either upfront sunitinib or the combination of nivolumab and ipilimumab, those with intermediate and poor risk had significant improvement in both PFS (11.6 vs 8.4 months, HR 0.82, p = 0.0331) and OS (not reached vs 26 months, p < 0.0001). Responses were greater in patients with positive programmed death receptor ligand-1 (PD-L1) tumor staining, and pending regulatory approval may become standard of care in untreated patients with intermediate to poor risk disease with positive PD-L1 status. This likely represents the beginning of additional novel immunotherapy combinations for the first-line treatment of mccRCC.

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Evolving Treatment Paradigms in Non-clear Cell Kidney Cancer

Opinion Statement

With no therapy specifically approved for non-clear cell cancers of the kidney, this disease remains an orphan site. Clear cell renal cancers (ccRCC) have seen a flurry of activity with multiple agents gaining Food and Drug Administration (FDA) approval in recent years. Simultaneously, non-clear cell RCC (ncRCC) have also seen a fair share of activity and exploration of new agents in development but no specific FDA approvals. Non-clear cell RCC is a mixed bag of multiple types of tumors originating in the kidney with distinct clinical molecular and genetic characteristics that vary significantly from clear cell carcinoma of the kidney. Conventionally, non-clear cell RCC have been treated with the same therapies as clear cell RCC. The clinical trials are typically conducted in ccRCC and the FDA approval covers non-clear cell cancer as well. Few randomized clinical trials have been conducted specifically for ncRCC. With the advent of molecular and tumor genomic testing, leading to discovery of targets and associated therapies for ncRCC, a specific review of the state of management of this disease is timely and clinically relevant.

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Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Opinion statement

Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20 years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment. High-dose interleukin-2 (HDIL-2) therapy remains a reasonable treatment option in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0–1 and have minimal comorbid conditions. In the near future, these agents are likely to be surpassed by cabozantinib and by combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab. Independent review has recently confirmed superiority of first-line cabozantinib over sunitinib in a phase 2 trial of 157 patients with intermediate or poor risk mccRCC (progression-free survival [PFS] 8.6 vs 5.3 months, hazard ratio [HR] 0.48, p = 0.0008). In a separate study of 1096 patients treated with either upfront sunitinib or the combination of nivolumab and ipilimumab, those with intermediate and poor risk had significant improvement in both PFS (11.6 vs 8.4 months, HR 0.82, p = 0.0331) and OS (not reached vs 26 months, p < 0.0001). Responses were greater in patients with positive programmed death receptor ligand-1 (PD-L1) tumor staining, and pending regulatory approval may become standard of care in untreated patients with intermediate to poor risk disease with positive PD-L1 status. This likely represents the beginning of additional novel immunotherapy combinations for the first-line treatment of mccRCC.

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Evolving Treatment Paradigms in Non-clear Cell Kidney Cancer

Opinion Statement

With no therapy specifically approved for non-clear cell cancers of the kidney, this disease remains an orphan site. Clear cell renal cancers (ccRCC) have seen a flurry of activity with multiple agents gaining Food and Drug Administration (FDA) approval in recent years. Simultaneously, non-clear cell RCC (ncRCC) have also seen a fair share of activity and exploration of new agents in development but no specific FDA approvals. Non-clear cell RCC is a mixed bag of multiple types of tumors originating in the kidney with distinct clinical molecular and genetic characteristics that vary significantly from clear cell carcinoma of the kidney. Conventionally, non-clear cell RCC have been treated with the same therapies as clear cell RCC. The clinical trials are typically conducted in ccRCC and the FDA approval covers non-clear cell cancer as well. Few randomized clinical trials have been conducted specifically for ncRCC. With the advent of molecular and tumor genomic testing, leading to discovery of targets and associated therapies for ncRCC, a specific review of the state of management of this disease is timely and clinically relevant.

http://ift.tt/2F8f3Ri