AUA: Prostate Cancer Studies Highlight DNA Repair Gene Involvement

Excerpt:

“Two new studies presented at the Annual Scientific Meeting of the American Urological Association (AUA) offer an improved understanding of some genetic underpinnings of prostate cancer. In one, researchers found that BRCA mutations may raise the risk of the malignancy substantially, while another found a high rate of mutations among other DNA repair genes as well.

” ‘These studies reveal new insights into the role genetic mutations play in the development of prostate cancer, particularly metastatic disease,’ said Scott Eggener, MD, of the University of Chicago Medicine, who moderated the session with these studies, in a press release.”

Go to full article.

If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our ASK Cancer Commons service.


Study Finds Incidence of Mutations in DNA-Repair Genes Significantly Higher in Men With Metastatic Prostate Cancer

Excerpt:

“The incidence of mutations in DNA-repair genes was significantly higher among men with metastatic prostate cancer than among men with localized disease (11.8% vs 4.6%), according to a study by Pritchard et al reported in The New England Journal of Medicine. In addition, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer did not differ significantly according to age at diagnosis or family history of prostate cancer. ”

Go to full article.

Do you have questions about this story? Let us know in a comment below. If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our Ask Cancer Commons service.


Study Finds Gene Mutations Sensitize Tumors to Specific Cancer Drugs

“Mutations in ARID1a, which are common in many cancer types, disrupt DNA damage repair in cancer cells, allowing the cancer to progress. This gene may also be an Achilles’ heel when treating certain tumors, according to a team of researchers at The University of Texas MD Anderson Cancer Center.

“The study, published in Cancer Discovery, discovered that certain mutations in ARID1a (AT-rich interactive domain-containing protein 1a), a gene recently implicated in cancer progression, sensitize some tumors to PARP inhibitor drugs, such as olaparib, veliparib and BMN673, which block DNA damage repair pathways.

” ‘Our results showed, particularly in the ARID1a deficient cells, PARP inhibitors are more effective than in other cancer cells,’ says Guang Peng, M.D., Ph.D, assistant professor, Clinical Cancer Prevention, and senior author of the study. ‘Based on the mechanism we’ve discovered, we propose a new approach for targeting these mutant cancer cells.’ ”


German Breast Group (GBG) Studies Demonstrate Subanalyses of Tumor DNA Repair Mutations Can Help Guide Treatment Selection and Predict Response in Preoperative Breast Cancer

“The German Breast Group (GBG) presented two analyses that can serve as predictors of response to treatment by further subdividing preoperative (neoadjuvant) patients with HER 2 positive breast cancer and those with triple negative breast cancer based on tumor DNA repair capabilities and related factors.

“Prof. Dr. Gunter von Minckwitz, president of the GBG Research Institute, noted, ‘Taken together these studies demonstrate that a deeper understanding of the variations among breast cancer types that go beyond hormone response and BRCA gene mutations can inform treatment options with increased precision.’

“One study (Abstract No: 1004) fromlead author Dr. von Minckwitz found cancer-related BRCA mutations in the tumor are more common (30.3%) than inherited BRCA mutations (19.8%) in patients with triple-negative breast cancer. The homologous recombination (HR) assay measures DNA repair capacity beyond those related to BRCA mutation. HR deficiency defined as having either a BRCA mutation of the tumor or a high HR score was found in 70.5% of the patients. These findings can affect treatment options. Patients with a tumor BRCA mutation and/or a high HR score showed a high complete response to preoperative (neoadjuvant) chemotherapy. Our findings suggest those patients are also benefiting more from the additional use of carboplatin than tumors without HR deficiency.”


AstraZeneca's Olaparib May Also Work in Prostate Cancer: Expert

“AstraZeneca’s new cancer drug olaparib, which won a green light from European regulators last month for inherited ovarian cancer, could also be used much more widely to treat prostate cancer, according to a leading oncologist.

“Johann de Bono, professor of experimental cancer therapeutics at the Institute of Cancer Research in London, told a conference on Tuesday the drug had produced “encouraging” preliminary results in clinical tests against prostate cancer.

“Olaparib works by blocking an enzyme involved in cell repair and is designed for patients with hereditary BRCA gene mutations, which are also found in breast and gastric cancer.

“While AstraZeneca believes the drug has the potential to sell $2 billion a year, the company has so far only talked about its promise in ovarian, breast and gastric cancer.

“However, de Bono told the National Cancer Research Institute that olaparib might also work in patients who have not inherited BRCA mutations but do carry mutations to DNA repair genes within their tumors.

To test the theory, de Bono and colleagues have assessed olaparib in advanced prostate cancer tests, including a mid-stage Phase II clinical trial, the first part of which has now closed.

“ ‘Although PARP inhibitors like olaparib have generally been trailed in women with inherited BRCA mutations, these exciting new trials could give them a whole other lease of life in advanced prostate cancer and other tumors with DNA repair mutations,’ de Bono said.

” ‘It is too early to say whether they will prove to be beneficial in prostate cancer but the initial results from our preliminary trials have been encouraging.’ “


Androgen Receptor Signaling Fuels DNA Repair and Radioresistance in Prostate Cancer

“Successful treatment by genotoxic modalities including radiotherapy is commonly hampered by treatment resistance in advanced cancers. Two new studies now reveal that androgen receptor signaling transcriptionally upregulates a large subset of DNA repair genes, thereby enhancing the repair capacity and promoting radioresistance of prostate cancer. These results provide a mechanistic rationale for a combined treatment by ionizing radiation and androgen deprivation therapy.”


Mutational Landscape and Significance Across 12 Major Cancer Types

“The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/ carcinogen influences, and DNA repair defects. Using the integrated data sets, weidentified 127 significantly mutated genes fromwell-known (for example,mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase,Wnt/b-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.”


Mutational Landscape and Significance Across 12 Major Cancer Types

“The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/ carcinogen influences, and DNA repair defects. Using the integrated data sets, weidentified 127 significantly mutated genes fromwell-known (for example,mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase,Wnt/b-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.”


Mutational Landscape and Significance Across 12 Major Cancer Types

“The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/ carcinogen influences, and DNA repair defects. Using the integrated data sets, weidentified 127 significantly mutated genes fromwell-known (for example,mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase,Wnt/b-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.”