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PubMed2026

A multicenter survey on BRAF screening for the implementation of perioperative cancer genomic medicine for resectable colorectal oligometastases.

BACKGROUND: Genomic screening is an essential, but potentially time-consuming procedure, especially in neoadjuvant settings. We evaluated the preoperative screening of the BRAF V600E mutation for recruitment to a clinical trial among patients with resectable colorectal oligometastases (CRM). METHODS: In April 2022, an investigator-initiated trial was launched to investigate the efficacy and safety of perioperative use of the BEACON triplet regimen for BRAF V600E mutant resectable CRM. BRAF screening was retrospectively conducted in patients with resected colorectal liver metastases in 2019 for planning the trial and prospectively conducted in preoperative patients with resectable CRM from January 2022 to June 2025 for patient recruitment to the trial. RESULTS: BRAF V600E mutation was detected in 12 (3.2%) of 379 postoperative patients retrospectively and in 36 (1.7%) of 2140 preoperative patients prospectively, with 1840 patients (86.0%) carrying the wild-type and 264 patients (12.3%) classified as untested. The detection rate of the BRAF V600E mutation was significantly lower when the screening was performed prospectively in preoperative patients (P&#x2009;<&#x2009;0.001). The untested rates varied across metastatic organs, with 10.3% in the liver, 18.1% in the lungs, 12.0% in the lymph nodes, 16.7% in the peritoneum, and 7.8% in other organs. The untested rates decreased consistently across semiannual comparisons: 28.5% in the first evaluation, followed by 15.0%, 12.0%, 8.4%, 9.1%, 7.3%, and 7.1% (P&#x2009;<&#x2009;0.01 when compared with the first period). CONCLUSION: Raising physician awareness, as reflected by the untested rate, is a crucial factor in conducting clinical trials to implement perioperative cancer genomic medicine.

Humans↗
PubMed2003

Sequence-based cancer genomics: progress, lessons and opportunities.

Technologies that provide a genome-wide view offer an unprecedented opportunity to scrutinize the molecular biology of the cancer cell. The information that is derived from these technologies is well suited to the development of public databases of alterations in the cancer genome and its expression. Here, we describe the synergistic efforts of research programmes in Brazil, the United Kingdom and the United States towards building integrated databases that are widely accessible to the research community, to enable basic and applied applications in cancer research.

Brazil↗
PubMed2026

SeqQC-former: A sequence-quality fusion framework for QC-aware review prioritization of candidate somatic SNVs in cancer genomics.

The accurate prioritization of candidate somatic single-nucleotide variants (SNVs) remains a challenge due to the substantial variability in sequencing quality across genomic loci. SeqQC-Former is a sequence-quality fusion framework that integrates the local nucleotide context with read-level quality-control (QC) covariates derived from matched tumor-normal sequencing data. This integration generates QC-aware prioritization scores for the downstream review of candidate variants. Unlike conventional variant callers, SeqQC-Former is designed not to infer biological truth but to support post-calling review and prioritization under heterogeneous sequencing conditions. The framework was trained and evaluated on a SEQC2-derived dataset comprising 89,447 candidate loci, including 1378 positive and 88,069 negative loci. In chromosome-held-out validation, which aims to reduce potential genomic-position leakage, SeqQC-Former demonstrated strong discrimination (AUROC = 0.9479; AUPRC = 0.9448), indicating good generalization to previously unseen chromosomes. Given that the SEQC2-derived labels contain QC-associated information; these results should be interpreted as an evaluation of QC-aware prioritization capability rather than an independent validation of biological variant correctness. Ablation analyses revealed that structured QC covariates provided the dominant predictive signal under the current SEQC2-derived labeling regime. SeqQC-Former achieved a significantly higher AUROC than classical machine-learning baselines, as determined by DeLong's test (p&#x202f;<&#x202f;0.01). Application to 53,164 glioblastoma variants demonstrated that external predictions were sensitive to QC scaling and threshold selection, underscoring that model outputs should be interpreted as QC-dependent prioritization scores rather than calibrated probabilities or definitive biological classifications. Overall, SeqQC-Former offers a reproducible post-calling QC-aware prioritization framework for large-scale somatic SNV review and underscores the importance of explicitly modeling sequencing-quality information when interpreting structured cancer genomics datasets.

Humans↗
PubMed2005

Apply innovative technologies to explore cancer genome.

PURPOSE OF REVIEW: Molecular genetic alterations characterize the development of human cancer. Recent advances in molecular genetic technology and the success of the human genome project have empowered investigators with new tools in dissecting the cancer genome for discovery of new cancer-associated genes. The purpose of this review is to highlight the emerging molecular genetic methodologies and summarize their principles, applications, and potential technical challenges. The critical issue in sample preparation and a strategy that combines different molecular techniques to facilitate the identification of novel cancer-associated genes will be discussed. RECENT FINDINGS: Digital karyotyping and array-based techniques including array comparative genomic hybridization and representational oligonucleotide microarray analysis have been recently developed to study the genomic landscape in human cancer. These innovations provide tools to quantitatively measure DNA copy number changes in cancer and to map those changes directly onto the human genome. Digital karyotyping is based on counting the sequence tags that are distributed in the human genome and thus, it provides a digital readout to precisely outline the amplified and deleted chromosomal regions. Array-based technologies, on the other hand, compare the content of cancer and reference genomes followed by localizing the amplified or deleted signals in chromosomal regions using an array hybridization technique. In addition, a high-throughput mutational analysis platform has been available for a large-scale mutational analysis by using an automated capillary sequencing device and sophisticated bioinformatic tools. A number of examples have demonstrated the promise of these new molecular genetic approaches in identifying several potential new oncogenes and tumor suppressors. SUMMARY: As compared with conventional cytogenetics methods, digital karyotyping, array comparative genomic hybridization, and representational oligonucleotide microarray analysis provide an unprecedented mapping resolution that allows a precise localization of the amplified and deleted chromosomal regions. These technologies can be combined with gene expression profiling and high-throughput mutational analysis to facilitate the search for new cancer-associated genes. It is expected that applying these new technologies will lead to discovery of a host of novel oncogenes and tumor suppressors, which will have a significant impact in our understanding of tumorigenesis and in the clinical management of cancer patients.

Cytogenetics↗
PubMed2000

Expression-based genetic/physical maps of single-nucleotide polymorphisms identified by the cancer genome anatomy project.

SNPs (Single-Nucleotide Polymorphisms), the most common DNA variant in humans, represent a valuable resource for the genetic analysis of cancer and other illnesses. These markers may be used in a variety of ways to investigate the genetic underpinnings of disease. In gene-based studies, the correlations between allelic variants of genes of interest and particular disease states are assessed. An extensive collection of SNP markers may enable entire molecular pathways regulating cell metabolism, growth, or differentiation to be analyzed by this approach. In addition, high-resolution genetic maps based on SNPs will greatly facilitate linkage analysis and positional cloning. The National Cancer Institute's CGAP-GAI (Cancer Genome Anatomy Project Genetic Annotation Initiative) group has identified 10,243 SNPs by examining publicly available EST (Expressed Sequence Tag) chromatograms. More than 6800 of these polymorphisms have been placed on expression-based integrated genetic/physical maps. In addition to a set of comprehensive SNP maps, we have produced maps containing single nucleotide polymorphisms in genes expressed in breast, colon, kidney, liver, lung, or prostate tissue. The integrated maps, a SNP search engine, and a Java-based tool for viewing candidate SNPs in the context of EST assemblies can be accessed via the CGAP-GAI web site (http://cgap.nci.nih.gov/GAI/). Our SNP detection tools are available to the public for noncommercial use.

Chromosome Mapping↗
PubMed2003

Gene discovery in oral squamous cell carcinoma through the Head and Neck Cancer Genome Anatomy Project: confirmation by microarray analysis.

The near completion of the human genome project and the recent development of novel, highly sensitive high-throughput techniques have now afforded the unique opportunity to perform a comprehensive molecular characterization of normal, precancerous, and malignant cells, including those derived from squamous carcinomas of the head and neck (HNSCC). As part of these efforts, representative cDNA libraries from patient sets, comprising of normal and malignant squamous epithelium, were generated and contributed to the Head and Neck Cancer Genome Anatomy Project (HN-CGAP). Initial analysis of the sequence information indicated the existence of many novel genes in these libraries [Oral Oncol 36 (2000) 474]. In this study, we surveyed the available sequence information using bioinformatic tools and identified a number of known genes that were differentially expressed in normal and malignant epithelium. Furthermore, this effort resulted in the identification of 168 novel genes. Comparison of these clones to the human genome identified clusters in loci that were not previously recognized as being altered in HNSCC. To begin addressing which of these novel genes are frequently expressed in HNSCC, their DNA was used to construct an oral-cancer-specific microarray, which was used to hybridize alpha-(33)P dCTP labeled cDNA derived from five HNSCC patient sets. Initial assessment demonstrated 10 clones to be highly expressed (>2-fold) in the normal squamous epithelium, while 14 were highly represented in the malignant counterpart, in three of the five patient sets, thus suggesting that a subset of these newly discovered transcripts might be highly expressed in this tumor type. These efforts, together with other multi-institutional genomic and proteomic initiatives are expected to contribute to the complete understanding of the molecular pathogenesis of HNSCCs, thus helping to identify new markers for the early detection of preneoplastic lesions and novel targets for pharmacological intervention in this disease.

Aged↗
PubMed2004

OCGR array: an oral cancer genomic regional array for comparative genomic hybridization analysis.

Genetic alterations have been recognized as important events in the carcinogenesis of oral squamous cell carcinoma (OSCC) and have been used as predictors of progression risk. In this study, we have designed an oral cancer-specific human bacterial artificial chromosome (BAC) array, called the oral cancer genomic regional array (OCGR), to detect and fine map copy number alterations in OSCC. This array contains a total of approximately 45 Mbp coverage of nine chromosomal regions reported to be involved in the progression of oral cancer. We demonstrate the detection of copy number alterations in 14 microdissected clinical specimens in each of the nine regions. These include both copy number increases and decreases. Although the number of regions selected for this first generation array is small, we observed multiple segmental changes. In some cases, we observed single BAC clone alterations at 7p11 and 11q13 which contain EGFR and cyclin D1 respectively highlighting the need for high resolution detection techniques. Array comparative genomic hybridization (CGH) complements traditional methods for detecting genetic alterations in OSCC (such as microsatellite and CGH analysis) by improving the detection of segmental copy number alterations to single BAC clone resolution. This work represents the first attempt at the construction of an oral cancer-specific CGH array.

Acid Anhydride Hydrolases↗
PubMed2004

Colon cancer: genomics and apoptotic events.

Colon cancer is the third most common cancer globally. The risk of developing colon cancer is influenced by a number of factors that include age and diet, but is primarily a genetic disease, resulting from oncogene over-expression and tumour suppressor gene inactivation. The induction and progression of the disease is briefly outlined, as are the cellular changes that occur in its progression. While colon cancer is uniformly amenable to surgery if detected at the early stages, advanced carcinomas are usually lethal, with metastases to the liver being the most common cause of death. Oncogenes and genetic mutations that occur in colon cancer are featured. The molecules and signals that act to eradicate or initiate the apoptosis cascade in cancer cells, are elucidated, and these include caspases, Fas, Bax, Bid, APC, antisense hTERT, PUMA, 15-LOX-1, ceramide, butyrate, tributyrin and PPARgamma, whereas the molecules which promote colon cancer cell survival are p53 mutants, Bcl-2, Neu3 and COX-2. Cancer therapies aimed at controlling colon cancer are reviewed briefly.

Apoptosis↗
PubMed2006

CancerGenes: a gene selection resource for cancer genome projects.

The genome sequence framework provided by the human genome project allows us to precisely map human genetic variations in order to study their association with disease and their direct effects on gene function. Since the description of tumor suppressor genes and oncogenes several decades ago, both germ-line variations and somatic mutations have been established to be important in cancer-in terms of risk, oncogenesis, prognosis and response to therapy. The Cancer Genome Atlas initiative proposed by the NIH is poised to elucidate the contribution of somatic mutations to cancer development and progression through the re-sequencing of a substantial fraction of the total collection of human genes-in hundreds of individual tumors and spanning several tumor types. We have developed the CancerGenes resource to simplify the process of gene selection and prioritization in large collaborative projects. CancerGenes combines gene lists annotated by experts with information from key public databases. Each gene is annotated with gene name(s), functional description, organism, chromosome number, location, Entrez Gene ID, GO terms, InterPro descriptions, gene structure, protein length, transcript count, and experimentally determined transcript control regions, as well as links to Entrez Gene, COSMIC, and iHOP gene pages and the UCSC and Ensembl genome browsers. The user-friendly interface provides for searching, sorting and intersection of gene lists. Users may view tabulated results through a web browser or may dynamically download them as a spreadsheet table. CancerGenes is available at http://cbio.mskcc.org/cancergenes.

Databases, Genetic↗
PubMed2001

Prostate cancer genomics.

The molecular processes contributing to cancer of the human prostate gland are under intensive investigation. Methods used for discovering genetic alterations involved in prostate neoplasia include family studies designed to map hereditary disease loci, chromosomal studies to identify aberrations that may locate oncogenes or tumor suppressor genes, and comprehensive gene expression studies. These studies determine how various molecular signaling pathways influence or reflect the process of carcinogenesis. However, a comprehensive overview of the cell is necessary to understand all of the dynamic interactions between genes, their protein products, and the network of cellular processes resulting in tumorigenesis. Unraveling the complexity of these systems in a timely manner involves the integration of computers, miniaturization, and automation into molecular biology. New biotechnologies such as the development of automated DNA sequencing and complementary DNA microarrays allow for a systematic, "discovery-driven" approach. These and other technologies afford a comprehensive view of biology and pathology that have the potential to fully characterize the processes involved in neoplasia and therefore provide potential targets for the therapy of prostate and other cancers.

Genetic Therapy↗
PubMed2006

Decoding the fine-scale structure of a breast cancer genome and transcriptome.

A comprehensive understanding of cancer is predicated upon knowledge of the structure of malignant genomes underlying its many variant forms and the molecular mechanisms giving rise to them. It is well established that solid tumor genomes accumulate a large number of genome rearrangements during tumorigenesis. End Sequence Profiling (ESP) maps and clones genome breakpoints associated with all types of genome rearrangements elucidating the structural organization of tumor genomes. Here we extend the ESP methodology in several directions using the breast cancer cell line MCF-7. First, targeted ESP is applied to multiple amplified loci, revealing a complex process of rearrangement and co-amplification in these regions reminiscent of breakage/fusion/bridge cycles. Second, genome breakpoints identified by ESP are confirmed using a combination of DNA sequencing and PCR. Third, in vitro functional studies assign biological function to a rearranged tumor BAC clone, demonstrating that it encodes anti-apoptotic activity. Finally, ESP is extended to the transcriptome identifying four novel fusion transcripts and providing evidence that expression of fusion genes may be common in tumors. These results demonstrate the distinct advantages of ESP including: (1) the ability to detect all types of rearrangements and copy number changes; (2) straightforward integration of ESP data with the annotated genome sequence; (3) immortalization of the genome; (4) ability to generate tumor-specific reagents for in vitro and in vivo functional studies. Given these properties, ESP could play an important role in a tumor genome project.

Breast Neoplasms↗
PubMed2001

Scoring a bull's-eye against cancer genome targets.

New anticancer drugs are increasingly targeted to specific abnormalities in the sequence and expression of a series of genes that operate in a stepwise, combinatorial manner to drive the progression of human cancer. These new-generation molecular therapeutics are expected to be more effective and less toxic than the broadly antiproliferative cytotoxic drugs of the previous era, which still dominate medical treatment of cancer today. Molecular and genomic technologies, particularly the availability of the human genome sequence and the ongoing sequencing of cancer genomes, are now having a major impact on target discovery and validation. Over the past year, the progress of three novel anticancer agents in particular (Herceptin, Glivec and Iressa) has exemplified the potential utility of innovative molecular therapeutics in the clinic. Drugs acting on a range of new genome-based molecular targets are now in preclinical and clinical development.

Arylamine N-Acetyltransferase↗
PubMed2006

Integrated breast cancer genomics.

Predicting survival and therapy responses of breast cancer patients is a significant challenge. Two studies in this issue of Cancer Cell present a novel integrated analysis of genomic and transcriptomic profiles of 145 primary breast cancers and 51 established cell lines. Data from clinical tumors highlighted mechanisms of disease and facilitated identification of potential therapeutic targets and prognostic biomarkers. An extensive well-characterized cancer cell line resource opens up opportunities to explore the determinants of cellular responses to existing and emerging therapies. Taken together, these studies illustrate how integrated molecular profiling may one day significantly impact diagnosis and therapeutic choice in human breast cancer.

Breast Neoplasms↗
PubMed2002

Cancer genomics.

The draft human genome sequence and the dissemination of high throughput technology provides opportunities for systematic analysis of cancer cells. Genome-wide mutation screens, high resolution analysis of chromosomal abberations and expression profiling all give comprehensive views of genetic alterations in cancer cells. From these analyses will come a complete list of the genetic changes that drive malignant transformation and of the therapeutic targets that may be exploited for clinical benefit.

Cell Transformation, Neoplastic↗
PubMed2001

Colorectal cancer genomics: evidence for multiple genotypes which influence survival.

Colorectal cancer (CRC) is a leading cause of cancer death and the mechanism for variable outcome in this disease is not yet fully understood. It is hypothesized that differences in the genetic make-up of tumours may be partially responsible for the differences observed in survival among same staged individuals for this disease. In this study the tumour genomes of 29 consecutive patients undergoing surgery for Dukes' C CRC were assessed by comparative genomic hybridization (CGH). In addition, the CGH profiles from the tumours were compared with those from eight colorectal cell lines. Great variation in genetic grade (all detectable aberrations i.e., loss + gain) was observed in 29 Dukes' C colorectal tumours by CGH (median four aberrations per tumour, range 0-20). Gain was found in 76% and loss in 41% of tumours. The most frequently observed regions of gain were 13q (27.6%), 20q (27.6%), 7p (24.1%), 8q (24.1%), and 1q (20.7%) and loss were 18q (31%), 4q (20.7%), 17p (20.7%), 18p (20.7%), and 15q (20.1%). None of these specific genomic aberrations were associated with patient survival. However, patients with more than two aberrations had a better survival than patients with fewer regions of loss and gain (P = 0.02). CRC cell lines had similar regions of loss or gain as the tumours. However, the frequency of genomic aberrations was much greater in the CRC cell lines. Although genomic change in CRC is relevant to the survival of patients with Dukes' C CRC, careful analysis is required to identify cell lines which are representative models of CRC genomics.

Aged↗