Genetic Basis Of Cancer Research Articles

Targeted Therapies in Cancer Treatment: Unveiling the Latest Breakthroughs and Promising Approaches

This review article delves into the realm of cancer treatment, specifically focusing on targeted therapies. It aims to present the most recent breakthroughs and promising approaches in this rapidly evolving field. Targeted therapies have emerged as a revolutionary approach in cancer treatment, aiming to selectively and precisely attack cancer cells while sparing normal tissues. This article explores various targeted therapy strategies, including monoclonal antibodies, small molecule inhibitors, immunotherapies, and gene therapies. In recent years, there have been significant advancements in understanding the molecular and genetic basis of cancer, which has led to the identification of novel therapeutic targets. The article sheds light on these newly discovered targets and highlights their potential in designing more effective and personalized treatment regimens for cancer patients. Furthermore, the review addresses the challenges and limitations associated with targeted therapies, such as resistance mechanisms and the heterogeneity of tumors. Strategies to overcome these obstacles are discussed, including combination therapies and the development of next-generation targeted agents. The role of precision medicine in cancer treatment is also explored, emphasizing the importance of biomarker-guided therapy selection to optimize treatment outcomes. Additionally, the review touches upon the integration of targeted therapies with conventional treatments, such as chemotherapy and radiation therapy, to enhance overall treatment efficacy. Finally, the article examines ongoing clinical trials and preclinical studies that are investigating cutting-edge targeted therapies, showcasing the potential impact of these approaches in transforming cancer care. In conclusion, targeted therapies in cancer treatment represent a rapidly expanding field with remarkable breakthroughs and promising avenues. Understanding the latest advancements and challenges in this domain is essential to harness the full potential of targeted therapies and ultimately improve patient outcomes in the battle against cancer.

Predictors of Population Awareness of Cancer Genetic Tests: Implications for Enhancing Equity in Engaging in Cancer Prevention and Precision Medicine.

A cross-sectional study was conducted from July 2019 to August 2019, with the survey e-mailed to 7,575 adult residents in southeastern Pennsylvania and New Jersey. Constructs from National Cancer Institute Health Information and National Trends Survey assessed cancer attitudes or beliefs, health literacy, and numeracy. Characteristics were summarized with mean ± standard deviation for numeric variables and frequency counts and percentages for categorical variables. Comparison of factors by race or ethnicity (non-Hispanic White and non-Hispanic Black) and sex was conducted by t-tests, chi-square, or Fisher's exact tests. Multivariate logistic regression models were conducted to identify factors independently predictive of GA. Of 1,557 respondents, data from 940 respondents (the mean age was 45 ± 16.2 years, 35.5% males, and 23% non-Hispanic Blacks) were analyzed. Factors associated with higher GA included female gender (P < .001), non-Hispanic White (P < .001), college education (P < .001), middle-higher income (P < .001), stronger belief in genetic basis of cancer (P < .001), lower cancer fatalism (P = .004), motivation for cancer information (P < .001), and higher numeracy (P = .002). On multivariate analysis, college education (odds ratio [OR] 1.79; 95% CI, 1.22 to 2.63), higher motivation for cancer information (OR 1.56; 95% CI, 1.17 to 2.09), stronger belief in genetics of cancer (OR 2.21; 95% CI, 1.48 to 3.30), and higher medical literacy (OR 2.21; 95% CI, 1.34 to 3.65) predicted greater GA. This population-based study conducted in the precision medicine era identified novel modifiable factors, importantly perceptions of cancer genetics and medical literacy, as predictive of GA, which informs strategies to promote equitable engagement in genetically based cancer care.

The Cancer Genomic Atlas – “TO CONQUER CANCER”

The Cancer Genomic Atlas (TCGA) is a publicly accessible cancer data repository and tool that allows us to understand the molecular basis of cancer through the application of genomics and proteomics. So far, researchers have been able to diagnose 33 cancer types including 10 rare cancer types. The key features of TCGA are to make the data collection process publicly accessible for the better understanding of the molecular and genetic basis of cancer and its mechanism of action along with its prevention. Studies on different cancer types along with comprehensive pan cancer analysis have expanded the understanding and purpose of TCGA. Ever since its’ conceptualization, its’ high-throughput approach has provided a platform for the identification of genes and pathways involved in cancers and accurate classification of cancers.

Cell competition and tumorigenesis in the imaginal discs of Drosophila.

Cancer is a major health issue and the object of investigations in thousands of laboratories all over the world. Most of cancer research is being carried out in in vitro systems or in animal models, generally mice or rats. However, the discovery of the high degree of genetic identity among metazoans has prompted investigation in organisms like Drosophila, on the idea that the genetic basis of cancer in flies and humans may have many aspects in common. Moreover, the sophisticated genetic methodology of Drosophila offers operational advantages and allows experimental approaches inaccessible in other species. Cell competition is a cell-quality control process that aims to identifying and subsequently removing cells within animal tissues that are unfit, abnormal or aberrant, and that may compromise the fitness or the viability of the organism. It was originally described in Drosophila imaginal discs but later work has shown it occurs in mammalian tissues where it fulfils similar roles. One aspect of the surveillance role of cell competition is to eliminate oncogenic cells that may appear during development or the life of an organism. In this review we have focussed on the work on Drosophila imaginal discs relating cell competition and tumorigenic processes. We briefly discuss related work in mammalian tissues.

Molecular Profiling of RNA Tumors Using High-Throughput RNA Sequencing: Overview of Library Preparation Methods.

RNA sequencing (RNA-seq) is revolutionizing the study of cancer by providing a highly sensitive and robust tool to interrogate the transcriptome. It leverages the power of deep sequencing technology and provides global and multidimensional views of transcriptional landscapes in healthy and tumor tissues. Such information is contributing innovative insights to our understanding of the genetic basis of cancer and the progression of the disease. RNA-seq is a superior technology to DNA microarrays in that it provides digital rather than analog information on transcripts and their isoforms. The front end (sequencing library preparation and validation) is technically complex and time intensive. The primary objective in preparing a sequencing library is to eliminate or minimize bias, so that the library is reflective of the input RNA sample in terms of both sequence content and transcript abundance. This chapter describes the RNA-seq approach, and reviews methods and good practices for library preparation and sequencing.

Abstract 2804: Identifying therapeutically relevant mouse and patient-derived xenograft (PDX) models of human cancer using the mouse tumor biology database (MTB) data resource

Abstract The laboratory mouse is the foremost model organism for interrogating the genetic and molecular basis of human cancer and is a powerful platform for identifying therapeutically effective targets for prevention and treatment of cancer. Research using genetically engineered mouse models (GEMMs) have led to important advances in our understanding of the genetic basis of cancer susceptibility, the function of tumor suppressors and oncogenes, and therapy responses in preclinical and co-clinical studies. Patient Derived Xenograft (PDX) models are an increasingly important model system for in vivo studies of human cancer. These models are created by implanting patient tumors into immunodeficient or humanized mouse hosts and are a powerful translational research platform for preclinical and co-clinical studies. The number of GEMM and PDX mouse models increases significantly every year and the diverse cancer-related data about human cancer models tend to be distributed in ways that makes it difficult for researchers to integrate and interpret the information to find the most relevant model for their research. The Mouse Tumor Biology database (http://tumor.informatics.jax.org) is an expertly curated resource for information and data about genetically defined mouse strains and PDX models of human cancer. MTB provides query tools to enable integrated searches and visualization of these varied data, thus facilitating the assessment of novel mouse models of human cancer and potential preventative and therapeutic treatments. Enforcement of controlled vocabularies and standard gene, allele and strain nomenclature within MTB facilitates precise and comprehensive queries of MTB for pertinent mouse models. MTB contains data from spontaneous or endogenously induced tumors from genetically defined mice including tumor classification, incidence, Quantitative Trait Loci, pathology reports, images and genetic changes in the tumor (somatic) and background strain (germline) genomes. The PDX resource enables queries based on tumor type, cancer diagnosis and genomic properties of the engrafted tumors. Information in MTB is obtained from curation of peer-reviewed scientific publications and direct data submissions from individual investigators and large-scale programs. New features in MTB include the Faceted Tumor Search Form and a Reported Mouse Models table linking the most common fatal human cancers to reported equivalent mouse models. MTB contains over 77,000 Tumor Frequencies and over 2,200 Pathology Reports with over 6,600 images from over 4,200 references. MTB provides access to detailed clinical, pathological, expression and genomics data from over 400 PDX models. Information in MTB is integrated with cancer models data from other bioinformatics resources including PathBase, the Gene Expression Omnibus and ArrayExpress. MTB is supported by NCI grant CA089713. Citation Format: Dale A. Begley, Debra M. Krupke, Steven B. Neuhauser, Joel E. Richardson, John P. Sundberg, Janan T. Eppig, Carol J. Bult. Identifying therapeutically relevant mouse and patient-derived xenograft (PDX) models of human cancer using the mouse tumor biology database (MTB) data resource [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2804. doi:10.1158/1538-7445.AM2017-2804

A hierarchical Bayesian design for randomized Phase II clinical trials with multiple groups

ABSTRACTEnhanced knowledge of the biological and genetic basis of cancer is re-defining the target population for new treatments. In oncology, potential targets for a new therapeutic agent often include various solid and hematologic malignancies that share common signaling pathways. New agents are often tested in multiple tumor types across which information can be borrowed. We propose a hierarchical Bayesian design (HBD) to simultaneously test a novel agent in multiple groups for randomized Phase II clinical trials with binary endpoints. Compared to parallel design for individual tumor groups, the HBD has greatly reduced sample size. Therefore, this improves efficiency and decreases the financial cost of conducting randomized Phase II clinical trials. An R package hbdct has been developed to implement the HBD and streamline the sample size calibration.

Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells.

Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease.

Abstract 4743: A population-based approach to address clinical cancer care: The national genomics platform

Abstract Our understanding of the genetic basis for cancer is advancing at a rapid rate due to the application of next generation sequencing (NGS) technologies. It is becoming common to sequence tumors and patients in an attempt to find actionable mutations that could offer the patient a more targeted and effective treatment. However, the genomics of cancer is very complex and only a handful of actionable mutations have been characterized. Larger-scale studies are needed to understand the pathogenic spectrum of cancer variants and deliver reliable clinical decision-making support to providers. Several large-scale sequencing projects are underway to collect NGS data on tumors (e.g. TCGA, ICGC, and TARGET) but a national platform for analysis, interpretation, and reporting does not exist. We propose that a consolidated informatics platform for the collection of outcomes data with genomics and clinical data would accelerate research and provide patients with the opportunity for personalized cancer treatment. In addition, with 1,665,540 new cancer cases predicted in the US for 2014, a national-scale genomics platform is needed, capable of sequencing 3 million genomes per year, storing exabytes of data, while supporting over 20,000 oncologists, researchers, and analysts. At Lockheed Martin, we deliver highly scalable and reliable information systems for a variety of missions and citizen services. Here, we will present our vision for a national cancer genomics platform to include NGS data collection, cost-efficient storage, scalable and modular processing pipelines, and collaborative analytics and data sharing capabilities, within a compliant privacy and security framework. In conclusion, by leveraging the scale of clinical cancer sequencing and capturing these data into a case management system for translational research, this platform provides data at-scale needed for finding actionable mutations, designing effective treatments and implementing prevention strategies, faster. Citation Format: Ogan Abaan, Amrita Basu, Noah Brown, Bret Light, David Deal, Michael Hultner. A population-based approach to address clinical cancer care: The national genomics platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4743. doi:10.1158/1538-7445.AM2015-4743

Now Perceiving: The Complete Genome Package

The genetic basis of cancer has expanded from studying individual gene and molecules to using a systems biology approach in deciphering the onset and development of the disease. The biology of the disease has revealed itself to be more complex than the initial ‘Hallmarks of cancer’ as defined by Hanahan and Weinberg in 2000, wherein the activation of proliferation, metastasis and angiogenesis along with signs of resistance to death and evasion of tumor suppressors, co-exist. Since then a large body of work has elucidated the role of immune cells, inflammation and metabolism within the tumor to be an equal contributing in the genesis and progression of this heterogeneous disease. Cells and molecules in the stroma together comprise the tumor microenvironment and these are known to activate signaling cascades, which help in tumor growth and progression. Cancer development itself has changed its fate as and when new discoveries of tumor suppressor genes, oncogenes and cell types have been validated. The concept of a linear progression of cancer has been significantly altered by the discovery of regulatory molecules, which modulate the driver and passenger mutation in a cell.

Higher Than Reported Response Rates to Decitabine Observed in Indian AML Patients - Is There a Genomic Basis

Between May 2012 and May 2014, 15 elderly patients (median 64yrs, range 54-80yrs) who presented with acute myeloid leukemia (AML) with comorbidities preventing them from receiving standard induction, were treated with decitabine at a dose of 20 mg/m2 for 5 days at monthly intervals. All patients received a minimum of 3 cycles of decitabine with a range of 3-9 cycles. Bone marrow examination was conducted at the end of 3 cycles to assess response. As opposed to the 40% CR rate reported by Ritchie et al (2013) in an elderly western population, we observed a response rate of 60% in our cohort. 9 out of 15 patients achieved remission, with 7 of the 9 patients regaining normal blood counts. The median clinical follow-up was 375 days with a range of 74-800 days. All 9 patients who responded positively to decitabine are alive and well.This 50% higher response rate to decitabine in Indian patients led us to examine the genetic basis for this observed difference. We conducted an observational prospective study of 14 Indian AML patients either at diagnosis or at relapse. Whole genome expression data from bone marrow aspirate samples was analyzed using PeCaSo™ (APT Life Sciences, Bangalore, India). PeCaSo is a genetic interaction network analysis platform that provides a ranked list of chemotherapeutic agents, as well as other approved pharmaceutical agents which can potentially be used as adjuvant therapy. For the 14 patients enrolled in the study, we looked at their response to decitabine as predicted by PeCaSo (see figure). As a comparison, PeCaSo was also used to retrospectively analyze whole genome expression data of Caucasian AML patients (n=16) available at The Cancer Genome Atlas (TCGA). [Display omitted] PeCaSo’s genomic network analysis indicates a higher response rate to decitabine for the Indian AML cohort when compared with a Caucasian cohort, strongly suggesting a potential genetic basis for the clinically observed difference.This study provides supportive evidence for considering decitabine for induction therapy of AML in Indian patients. Our study’s genomic approach confirms that the heterogeneity and genetic basis of cancer has to be factored in prescribing personalized protocols for the treatment of cancer. DisclosuresDamodar:APT Life Sciences, Bangalore, India: Research Funding. KS:APT Life Sciences, Bangalore, India: Research Funding. Purnaiya:APT Life Sciences, Bangalore, India: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Kumar:APT Life Sciences, Bangalore, India: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Nagaraj:APT Life Sciences, Bangalore, India: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Ram:APT Life Sciences, Bangalore, India: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

The Somatic Cancer Genome

New genome sequencing technologies have led to an explosion of cancer genome sequence information, resulting in new insights into the genetic basis of cancer. This talk will review recent advances in somatic cancer genome analysis, with particular emphasis on hematological malignancies including diffuse large B-cell lymphoma and multiple myeloma. New analytical approaches have led to both a refined ability to distinguish true drivers of cancer from mere passenger mutations and to a better understanding of what scale of cancer genome sequencing will be required to “complete” a cancer genome atlas of mutations. While many of the recurrently mutated genes in cancer have known function, many remain uncharacterized. As such, a new kind of follow-up research activity is required – one that can bring systematic, high throughput biology methods to bear on elucidating mutant allele function and their potential as therapeutic targets. Efforts to pilot such a “Target Accelerator” will be presented, with particular emphasis on use of the Connectivity Map/Library of integrated cellular signatures (LINCS) resource to systematically connect mutant alleles to pathways and to potential therapeutic strategies. Disclosures Golub: Foundation Medicine, Inc.: Consultancy, Equity Ownership.

History of cancer in Iran.

The history of human and animal cancers date back to antiquity. The earliest written document on cancer appeared on Egyptian papyrus. For centuries, the theory of "four humors" was the primary hypothesis that explained the cause for cancer. Finally, in the 19th century a new era began with the detection of the cellular origin of cancer; in due course, the nature of this lethal disease was better recognized and led to further achievements in cancer treatment. During the 20th century researchers investigated several risk factors for cancer such as tobacco smoking and environmental chemicals, in addition to the carcinogenic role of certain viruses, occupational association of cancer, its relationship with certain hormones and dietary habits, and the genetic basis of cancer. These investigations resulted in more efficient cancer management. After the advent of radiotherapy and chemotherapy as two complementary therapeutic modalities to surgery, the campaign against cancer has improved. However, cancer remains a major health challenge that accounts for substantial morbidity and mortality worldwide. The present paper briefly reviews the history of cancer in Iran, particularly during the last decades of the 20th century.

Personalized Cancer Treatment for Ovarian Cancer

Recently there have been numerous advances in understanding the genetic basis of cancer which have resulted in more appropriate treatments. In this paper we describe the experience of the Burzynski Clinic, involved in treatment of numerous patients based on personalized approach using novel combinations for difficult-to-treat malignancies, with gynecological cancers. This retrospective study was conducted by extracting data from Burzynski Clinic's medical records and comprehensive review. Among the advanced refractory ovarian cancers cases (N=33), an objective response (OR) was found in 42.4%. We anticipate that with improved technology and novel therapeutics this rate will increase and adverse events will be reduced.

Gene Therapy - The use of DNA as a Drug

GENE therapy represents a fundamentally new way to treat a disease. The use of genetic material (genes), which can express a protein in the cell or interfere with the synthesis of a protein in the cell, in order to treat a disease, is gene therapy. Replacing a defective gene with a normal gene and thus restoring the lost gene function in the patient's body is the essence of gene therapy. Originally conceived as an approach to treat autosomal recessive Mendelian disorders, it is now being applied to a broad range of acquired conditions such as cancers, infections and degenerative disorders. With the understanding of the genetic basis of cancer, an entirely new approach to the treatment of cancer using gene transfer techniques has evolved. DNA is now slated to be used as a therapeutic agent to replace defective genes in patients suffering from genetic disorders or to kill tumor cells in cancer patients.

L3.3 Role of Biomarkers in the Development of Targeted Cancer Therapeutics

ABSTRACT Success rates in oncology drug development have been challenging for a number of reasons, including issues with drugability and target validation, determination of the appropriate dose and schedule, tumor and patient heterogeneity, and drug resistance mechanisms. With an increased understanding of the genetic basis of cancer, the identification of specific biomarkers that help predict drug response in specific patient populations has become of critical importance. Drug development efforts are focusing on both pharmacodynamic markers to determine the ability of drugs to inhibit their specific target and predictive biomarkers to define subpopulations of patients who will respond to specific targeted agents. Predictive markers, including HER2 amplification in breast cancer, EGFR mutation and EML4-ALK translocation in lung cancer, BRAF V600E mutation in melanoma, and K-ras mutations in colorectal cancer, have been critical to the development of agents that target these genetic changes in tumors. A better understanding of cancer biology, specifically tumor heterogeneity coupled with novel technologies, will help facilitate the identification of patient populations more likely to respond to targeted therapeutics. Improving the application and utility of this detailed understanding of disease will increase both the success rate in cancer clinical development and the benefit to specific patients. This presentation will review efforts to better understand tumor heterogeneity and the development of novel cancer therapeutics and associated biomarkers. One example of this is the Asian Cancer Research Group (ACRG) which is a pre-competitive consortium comprised of Lilly, Merck and Pfizer that was initiated in 2009 to study genomic profiling and clinical outcomes of prevalent cancers in Asia, including HCC, NSCLC and gastric cancer. The recent results of an ACRG HCC analysis, and the potential impact on drug development, will be presented. Next, the development of biomarkers for cancer therapeutics will be discussed, with a focus on targets involved in the regulation of the tumor microenvironment and tumor invasion, including cMET and TGFb. This discussion will include Lilly Oncology's approach to biomarker co-development with specific therapeutics against these targets.

Abstract 108: Functional characterization of WAC, a candidate tumor suppressor gene in colorectal cancer

Abstract Broadening our understanding of the genetic basis of cancer will facilitate construction of relevant pre-clinical models and provide novel targets for drug development. To identify genes that contribute to the initiation or progression of colorectal cancer (CRC) when mutated or dysregulated, we recently conducted a set of forward genetic screens using transposon insertional mutagenesis to drive intestinal tumor formation in mice. These studies were designed to identify novel cancer genes that function in a wildtype genetic context or cooperate with known predisposing alleles (ApcMin/+ or Trp53R270H/+). Over 150 genes were identified, including several known to be important in human CRC (eg. APC, PTEN, and FBXW7) and many novel candidate cancer genes. WW domain containing adaptor with coiled-coil (WAC), is a gene not previously associated with cancer that was identified in all three screens. While the function of WAC is incompletely understood, previous reports indicate that the WAC protein participates in multiple cellular processes, including golgi biogenesis, modulation of gene expression, and induction of p21CIP1 expression and cell cycle arrest in response to DNA damage. In this study, we evaluated the role of WAC in cellular transformation by depleting WAC in mouse colonic epithelial cells conditionally immortalized by expression of a temperature sensitive SV40 large T antigen. In this model, loss of WAC expression increased anchorage-independent growth of colonic epithelial cells in cooperation with mutant APC. In human CRC samples, resequencing the WAC gene identified non-silent mutations in 2 of 74 samples. Further, CRC-associated WAC mutants were found to be functionally deficient in induction of p21CIP1 in a zebrafish embryo model. These data are consistent with the model that WAC functions as a tumor suppressor in the colonic epithelium. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 108. doi:1538-7445.AM2012-108

LKB1, TP16, EGFR, and KRAS somatic mutations in lung adenocarcinomas from a Chiba Prefecture, Japan cohort

The discovery of somatic mutations in cancer-related genes has been applied to understand the genetic basis of cancer. Here we report somatic mutations of two tumor suppressor genes: LKB1 (exons 1, 4, and 8) and TP16 (CDKN2A) (exons 1 and 2); and two oncogenes: epidermal growth factor receptor EGFR (exons 18-21) and KRAS (exon 2) in 97 lung adenocarcinoma tissues in a cohort from the Kujukuri coast area of Chiba, Japan. In the LKB1 gene, only F354L substitutions were observed in 14 of the 97 tissue samples (14.4%). In the TP16 gene, only two deletions were observed in contrast to previous reports. On the other hand, the EGFR gene was highly mutated (38.1%) and mainly L858R substitutions occurred (23.7%) as well as insertions and deletions. In the KRAS gene, 10 substitutions at codon 12 were observed (10.3%). Co-occurrence of EGFR and KRAS somatic mutations was identified in one patient, those of EGFR and LKB1 were in three patients, and those of KRAS and LKB1 were in four patients. The lower rates of LKB1, TP16, and KRAS somatic mutations in lung adenocarcinomas are characteristic of the Kujukuri cohort as compared to Caucasians.

Loss of A-type lamin expression compromises nuclear envelope integrity in breast cancer

Through advances in technology, the genetic basis of cancer has been investigated at the genomic level, and many fundamental questions have begun to be addressed. Among several key unresolved questions in cancer biology, the molecular basis for the link between nuclear deformation and malignancy has not been determined. Another hallmark of human cancer is aneuploidy; however, the causes and consequences of aneuploidy are unanswered and are hotly contested topics. We found that nuclear lamina proteins lamin A/C are absent in a significant fraction (38%) of human breast cancer tissues. Even in lamin A/C–positive breast cancer, lamin A/C expression is heterogeneous or aberrant (such as non-nuclear distribution) in the population of tumor cells, as determined by immunohistology and immunofluorescence microscopy. In most breast cancer cell lines, a significant fraction of the lamin A/C– negative population was observed. To determine the consequences of the loss of lamin A/C, we suppressed their expression by shRNA in non-cancerous primary breast epithelial cells. Down-regulation of lamin A/C in breast epithelial cells led to morphological deformation, resembling that of cancer cells, as observed by immunofluorescence microscopy. The lamin A/C–suppressed breast epithelial cells developed aneuploidy as determined by both flow Cytometry and fluorescence in situ hybridization. We conclude that the loss of nuclear envelope structural proteins lamin A/C in breast cancer underlies the two hallmarks of cancer aberrations in nuclear morphology and aneuploidy.

Genetic Basis of Cancer

Genetic Basis of Cancer