Tracking the Evolution of Non–Small-Cell Lung Cancer …

Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)

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Panel A shows an example of mirrored subclonal allelic imbalance. This occurs when the maternal allele is gained or lost in a subclone in one region and the paternal allele is gained or lost in a different subclone in another region. Such imbalance indicates additional ongoing chromosomal instability and can be inferred through multiregion whole-exome sequencing by using the frequencies at which heterozygous germline single-nucleotide polymorphisms (SNPs) (termed B-allele frequency [BAF]) are detected. The BAF of heterozygous SNPs is plotted in the same color as their parental chromosome of origin. Panel B shows the BAF profile across the genome of a tumor sample obtained from Patient CRUK0062. Areas of BAF in regions (including tumor regions R1 through R7 and a germline [GL] reference region) that have mirrored subclonal allelic imbalance are highlighted in blue or orange. Events that showed mirrored subclonal allelic imbalance were identified in more than 40% of the genome. Panel C shows phylogenetic trees that indicate parallel evolution of driver amplifications detected through the observation of mirrored subclonal allelic imbalance (arrows). Subclones that are colored blue carry a cancer driver event, and those that are colored gray carry no driver event; black outlining of the circles indicates that the subclone appears to be clonal in at least one tumor region.


Tracking the Evolution of Non–Small-Cell Lung Cancer | …

He is also senior investigator at the National Library of Medicine and National Institutes of Health

Regional allelic-imbalance profiling of primary tumors from Patients 3 and 4 provided further evidence of genetic intratumor heterogeneity (Figure 11 in the ). Only 4 of 30 samples from four patients had identical allelic-imbalance profiles (tumor from Patient 3 in R1, R3, R4, and R9). Chromosome 3p aberrations occurred ubiquitously in all regions from all tumors, and allelic imbalances of 10q (in tumor from Patient 2) and in 5q and 6q (in tumor from Patient 4) were ubiquitously present in one case each. These early ubiquitous events were outnumbered by nonubiquitous aberrations, indicating that the majority of chromosomal events occurred after tumors diverged, providing further evidence of branching evolution. Ploidy profiling detected intratumor heterogeneity in tumor from Patient 4 (Figure 10 in the ), and Sanger sequencing of in Patients 3 and 4 revealed intratumor heterogeneity in Patient 4: seven regions of tumor sharing a frameshift mutation harbored absent trimethylated H3K36 staining, whereas a single region with wild-type but mutant harbored strong tumor-cell trimethylated H3K36 staining (Figure 14 in the ).


How to Analyze DNA Microarray Data | HHMI …

From the Cancer Research UK Lung Cancer Centre of Excellence (M.J.-H., G.A.W., N. McGranahan, N.J.B., S.V., S.S., D.H.J., R.R., S.-M.L., M.D.F., C.A., S.M.J., C.D., C.S.), London and Manchester, Good Clinical Laboratory Practice Facility, University College London (UCL) Experimental Cancer Medicine Centre (H.L.L., J.A.H.), Bill Lyons Informatics Centre (J.H.), and Cancer Immunology Unit (S.A.Q.), UCL Cancer Institute, the Translational Cancer Therapeutics Laboratory (G.A.W., N. McGranahan, N.J.B., T.B.K.W., A.R., T.C., S. Turajlic, H.X., C.T.H., C.S.), Department of Bioinformatics and Biostatistics (R.M., M.S., S.H., M.E., A.S.), Advanced Sequencing Facility (N. Matthews), and Cancer Genomics Laboratory (S.D., P.V.L.), Francis Crick Institute, the Renal and Skin Units, Royal Marsden Hospital (S. Turajlic), the Departments of Medical Oncology (M.J.-H., S.-M.L., M.D.F., T.A., C.A., C.S.), Pathology (M.F., E.B., T.M.), Cardiothoracic Surgery (D.L., M.H., S. Kolvekar, N.P.), Respiratory Medicine (S.M.J., R.T.), and Radiology (A.A.), UCL Hospitals, Lungs for Living, UCL Respiratory, UCL (S.M.J.), the Department of Radiotherapy, North Middlesex University Hospital (G.A.), the Department of Respiratory Medicine, Royal Free Hospital (S. Khan), and UCL Cancer Research UK and Cancer Trials Centre (N.I., H.B., Y.N., A.H.), London, Cancer Studies, University of Leicester (D.A.M., D.A.F., J.A.S., J.L.Q.), the Department of Thoracic Surgery, Glenfield Hospital (A.N., S.R.), and the Medical Research Center Toxicology Unit (J.L.Q.), Leicester, the Institute of Cancer Studies, University of Manchester (F.B.), the Christie Hospital (F.B., Y.S.), the Departments of Cardiothoracic Surgery (R.S.) and Pathology (L.J., A.M.Q.) and the North West Lung Centre (P.A.C.), University Hospital of South Manchester, and Cancer Research UK Manchester Institute (C.D.), Manchester, the Departments of Thoracic Surgery (B.N.) and Cellular Pathology (G.L., S. Trotter), Birmingham Heartlands Hospital, Molecular Pathology Diagnostic Services, Queen Elizabeth Hospital (P.T., B.O.), and Institute of Immunology and Immunotherapy, University of Birmingham (G.M.), Birmingham, the Departments of Medical Oncology (M.N.), Cardiothoracic Surgery (H.R.), Pathology (K.K.), Respiratory Medicine (M.C.), and Radiology (L.G.), Aberdeen University Medical School and Aberdeen Royal Infirmary, Aberdeen, the Department of Respiratory Medicine, Barnet and Chase Farm Hospitals, Barnet (S. Khan), the Department of Respiratory Medicine, Princess Alexandra Hospital, Harlow (P.R.), the Department of Clinical Oncology, St. Luke’s Cancer Centre, Guildford (V.E.), the Departments of Pathology (B.I.), Respiratory Medicine (M.I.-S.), and Radiology (V.P.), Ashford and St. Peters’ Hospitals, Surrey, the Department of Clinical Oncology, Velindre Hospital (J.F.L.), the Departments of Radiology (H.A.) and Respiratory Medicine (H.D.), University Hospital Llandough, the Departments of Pathology (R.A.) and Cardiothoracic Surgery (M.K.), University Hospital of Wales, and Cardiff University (R.A.), Cardiff, and Wellcome Trust Sanger Institute, Hinxton, and Big Data Institute, University of Oxford, Oxford (S.D.) — all in the United Kingdom; the Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby (Z.S.); the Computational Health Informatics Program, Boston Children’s Hospital and Harvard Medical School, Boston (Z.S.); MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary (Z.S.); Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin (R.F.S.); and the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.).

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Trimethylated H3K36 staining was absent from tumor cells in regions with frameshift or missense mutations (Figure 12 in the ), indicating that both mutations together with a 3p deletion confer convergent loss of function. Regions with either a splice-site mutation or a missense mutation in a negative regulator of the PI3 kinase–Akt pathway located on chromosome 10, showed increased phospho-Akt staining, as compared with wild-type regions (Figure 13 in the ), consistent with loss of PTEN function and convergent phenotypic evolution.