BRCA-Associated Cancer Risk May Vary by Mutation Type

“Researchers have used observational study data to better define risks for breast and ovarian cancers associated with mutations in the BRCA1 or BRCA2 genes in an attempt to improve risk assessment and cancer prevention among women who carry these mutations.

“ ‘This study is the first step in defining differences in risk associated with location and type of BRCA1 and BRCA2 mutations,’ wrote Timothy R. Rebbeck, PhD, of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues in JAMA. ‘Pending additional mechanistic insights into the observed associations, knowledge of mutation-specific risks could provide important information for clinical risk assessment among BRCA1/2 mutation carriers, but further systematic studies will be required to determine the absolute cancer risks associated with different mutations.’

“Rebbeck and colleagues conducted an observational study of women found to have BRCA1 (n = 19,851) or BRCA2 (n = 11,900) mutations between 1937 and 2011. Data were collected from 55 centers in 33 countries.”


Gene Marker may Predict Breast Cancer Response to Tamoxifen

The gist: Oncologists can sometimes check a patient’s tumor for specific genetic mutations that indicate how well different treatment options might work. Researchers recently discovered a genetic mutation found in some breast cancer tumors that could help oncologists predict how well the drug tamoxifen will work for a patient with ER-positive breast cancer. Further studies are needed to explore just how useful the discovery might be.

“Researchers have identified genes that may help predict whether a patient with estrogen receptor (ER)-positive breast cancer is likely to benefit from tamoxifen therapy, according to a study published in the July 15 issue of Cancer Research.

“Hendrika M. Oosterkamp, M.D., of The Netherlands Cancer Institute in Amsterdam, and colleagues conducted a large-scale loss-of-function genetic screen in ZR-75-1 luminal breast cancer cells to identify candidate genes for tamoxifen resistance.

“The researchers found that loss of function in the deubiquitinase USP9X prevented proliferation arrest by tamoxifen, but not by the ER downregulator fulvestrant. RNAi-mediated attenuation of USP9X stabilized ERα on chromatin in the presence of tamoxifen, and this caused a global activation of ERα-responsive genes driven by tamoxifen. A gene signature defined by differential expression after USP9X attenuation in the presence of tamoxifen was used to identify patients with ERα-positive breast cancer experiencing a poor outcome after adjuvant therapy with tamoxifen. Correlation of the gene signature with survival was not observed in patients with breast cancer who did not receive endocrine therapy.

” ‘Overall, our findings identify a gene signature as a candidate biomarker of response to tamoxifen in breast cancer,’ the authors write.”


Scientific Breakthrough Could Lead to New Ovarian Cancer Treatments

“The cause of a rare type of ovarian cancer that most often strikes girls and young women has been uncovered by an international research team led by the Translational Genomics Research Institute (TGen), according to a study published online by the renowned scientific journal, Nature Genetics.

“By applying its groundbreaking work in genomics, TGen led a study that included Mayo Clinic, Johns Hopkins University, St. Joseph’s Hospital and Medical Center; Evergreen Hematology and Oncology, Children’s Hospital of Alabama, the Autonomous University of Barcelona, British Columbia Cancer Agency, University of British Columbia, and the University Health Network-Toronto.

“The findings revealed a “genetic superhighway” mutation in a gene found in the overwhelming majority of patients with small cell carcinoma of the ovary, hypercalcemic type, also known as SCCOHT.”

Editor’s note: While this story does not highlight any immediate new treatment strategy for women with SCCOHT, it describes the discovery of a genetic mutation that may be the underlying cause of the disease, and could soon lead to better treatments.


Non-Uniform Genetic Mutations Identified in Lung Cancers Could Lead to Targeted Treatment

“The research, published in the journal Oncotarget, explored tumour heterogeneity – where different cells have different appearances or their own DNA signatures within the same cancer. Such differences could make it difficult to design effective, targeted treatment strategies.

“Firstly they confirmed the mutual exclusivity between the EGFR mutation and either the KRAS or BRAF mutation. Secondly, they found that lung cancers driven by the EGFR gene mutation have that specific mutation present uniformly throughout the tumour, regardless of microscopic appearance. In stark contrast, they discovered that some tumours, with either KRAS or BRAF gene mutations, do not have the mutation present in all parts of the tumour.
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Editor’s note: In recent years, lung cancer treatment has focused on the use of targeted therapy drugs. These drugs kill tumor cells that have certain cancer-causing genetic mutations, while generally leaving healthy cells unharmed. Oncologists use genetic testing to see if a patient’s tumor has any specific genetic mutations that can be targeted by a specific drug. According to the research described here, different parts of a tumor may have different mutations that can be targeted by different drugs. This makes treatment more complicated, but continued research could lead to more effective treatments.


Inherited Mutated Gene Raises Lung Cancer Risk for Women, Those Who Never Smoked

“People who have an inherited mutation of a certain gene have a high chance of getting lung cancer—higher, even, than heavy smokers with or without the inherited mutation, according to new findings by cancer researchers at UT Southwestern Medical Center. Although both genders have an equal risk of inheriting the mutation, those who develop lung cancer are mostly women and have never smoked, the researchers found.

“People with the rare inherited T790M mutation of the epidermal growth factor receptor (EGFR) gene who have never smoked have a one-in-three chance of developing lung cancer, researchers found. This risk is considerably greater than that of the average heavy smoker, who has about a one-in-eight chance of developing lung cancer – about 40- fold greater than people who have never smoked and do not have the mutation.”


Squamous Lung Cancer ‘Master Protocol’ Brings Cancer Research into the 21st Century


Clinical trials help determine whether new cancer treatments are safe and effective, and they provide access to cutting-edge drugs that patients wouldn’t otherwise be able to have. But the clinical trial system is notoriously inefficient, slow, expensive, and laborious. Now, a new and ambitious clinical trial design called the Lung Cancer Master Protocol seeks to overhaul the system, promising to benefit patients and drug companies alike. Continue reading…


Melanoma: A 2013 ‘Progress Report’


The past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013: Continue reading…


Genome-wide Consequences of Deleting Any Single Gene

“Loss or duplication of chromosome segments can lead to further genomic changes associated with cancer. However, it is not known whether only a select subset of genes is responsible for driving further changes. To determine whether perturbation of any given gene in a genome suffices to drive subsequent genetic changes, we analyzed the yeast knockout collection for secondary mutations of functional consequence. Unlike wild-type, most gene knockout strains were found to have one additional mutant gene affecting nutrient responses and/or heat-stress-induced cell death. Moreover, independent knockouts of the same gene often evolved mutations in the same secondary gene. Genome sequencing identified acquired mutations in several human tumor suppressor homologs. Thus, mutation of any single gene may cause a genomic imbalance, with consequences sufficient to drive adaptive genetic changes. This complicates genetic analyses but is a logical consequence of losing a functional unit originally acquired under pressure during evolution.”


Genome-wide Consequences of Deleting Any Single Gene

“Loss or duplication of chromosome segments can lead to further genomic changes associated with cancer. However, it is not known whether only a select subset of genes is responsible for driving further changes. To determine whether perturbation of any given gene in a genome suffices to drive subsequent genetic changes, we analyzed the yeast knockout collection for secondary mutations of functional consequence. Unlike wild-type, most gene knockout strains were found to have one additional mutant gene affecting nutrient responses and/or heat-stress-induced cell death. Moreover, independent knockouts of the same gene often evolved mutations in the same secondary gene. Genome sequencing identified acquired mutations in several human tumor suppressor homologs. Thus, mutation of any single gene may cause a genomic imbalance, with consequences sufficient to drive adaptive genetic changes. This complicates genetic analyses but is a logical consequence of losing a functional unit originally acquired under pressure during evolution.”