Cancer Genome Sequencing Will Mean More Targeted Therapies

“As the cost of DNA sequencing plummets, the possibility of testing all cancer patients’ tumor genomes is becoming a reality. For just $1000 or so, a doctor might submit most any malignant specimen for a complete genetic work-up. The sample might be a core needle biopsy taken from a breast, a blood sample from a person with leukemia, or a snippet of a sarcoma removed in an operating room. In principle, checking a tumor for genetic changes should be straightforward, do-able.

“But most cancer patients undergo surgery and other treatment long before their doctors consider sending a biopsy for full molecular evaluation. A recent published survey among oncologists at two prestigious Boston teaching hospitals suggests that a significant proportion of specialists have a low level of confidence about their knowledge of cancer genomics. Aside from some kinds of lymphoma and leukemia, some lung cancers and a few other malignancies, examining cancer cells for genetic mutations is not routine in oncology practice.

“ ‘Genomic testing of cancer cells seems like it should be available to all patients,’ said Lori Marx-Rubiner. At age 48, she’s carried a diagnosis of metastatic breast cancer for five years. She lives in Los Angeles with her husband and teenage son, and blogs about her condition at Regrounding. Recently she took the helm at Metavivor, a non-profit organization that advocates for research in metastatic disease.

“ ‘Now I learn as much as possible about my condition and treatment options,’ she said. Marx-Rubiner, who holds a master’s degree in social work, participates in scientific meetings and advocates for research in metastatic disease. Most of her treatments so far have been selected to interfere with hormone signaling. That’s because her biopsy – evaluated with old pathology methods when she received her initial, stage 2 diagnosis back in 2002 – showed high levels of estrogen receptors in the tumor cells.”

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A Pilot Study Using Next-Generation Sequencing in Advanced Cancers: Feasibility and Challenges

“New anticancer agents that target a single cell surface receptor, up-regulated or amplified gene product, or mutated gene, have met with some success in treating advanced cancers. However, patients’ tumors still eventually progress on these therapies. If it were possible to identify a larger number of targetable vulnerabilities in an individual’s tumor, multiple targets could be exploited with the use of specific therapeutic agents, thus possibly giving the patient viable therapeutic alternatives.”


A Pilot Study Using Next-Generation Sequencing in Advanced Cancers: Feasibility and Challenges

“New anticancer agents that target a single cell surface receptor, up-regulated or amplified gene product, or mutated gene, have met with some success in treating advanced cancers. However, patients’ tumors still eventually progress on these therapies. If it were possible to identify a larger number of targetable vulnerabilities in an individual’s tumor, multiple targets could be exploited with the use of specific therapeutic agents, thus possibly giving the patient viable therapeutic alternatives.”


A Pilot Study Using Next-Generation Sequencing in Advanced Cancers: Feasibility and Challenges

“New anticancer agents that target a single cell surface receptor, up-regulated or amplified gene product, or mutated gene, have met with some success in treating advanced cancers. However, patients’ tumors still eventually progress on these therapies. If it were possible to identify a larger number of targetable vulnerabilities in an individual’s tumor, multiple targets could be exploited with the use of specific therapeutic agents, thus possibly giving the patient viable therapeutic alternatives.”


Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome

“Aneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here, we develop Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8,200 tumor-normal pairs, we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.”


Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome

“Aneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here, we develop Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8,200 tumor-normal pairs, we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.”


Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome

“Aneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here, we develop Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8,200 tumor-normal pairs, we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.”


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.”