USO10787712B2 ( 12 ) United States Patent ( 10 ) Patent No .: US 10,787,712 B2 Sjoblom et al . ( 45 ) Date of Patent : * Sep . 29 , 2020 ( 54 ) CONSENSUS CODING SEQUENCES OF ( 56 ) References Cited HUMAN BREAST AND COLORECTAL CANCERS U.S. PATENT DOCUMENTS 5,605,799 A 2/1997 White et al . ( 71 ) Applicant: The Johns Hopkins University , 8,741,573 B2 * 6/2014 Sjoblom C12Q 1/6886 Baltimore , MD (US ) 435 / 6.14 2001/0021502 Al 9/2001 Swift et al . ( 72 ) Inventors: Tobias Sjoblom , Uppsala ( SE ) ; Sian 2007/0017666 Al 1/2007 Song Jones , Baltimore , MD (US ); D. 2010/0316995 Al 12/2010 Sjoblom et al . Williams Parsons , Bellaire, TX ( US ) ; FOREIGN PATENT DOCUMENTS Laura D. Wood , Baltimore, MD ( US ) ; Jimmy Cheng - Ho Lin , Baltimore , MD EP 785216 7/1997 EP 2543739 1/2013 ( US ) ; Thomas Barber , Nobelsville , TN WO WO 199213103 8/1992 ( US ) ; Diana Mandelker , Baltimore , WO WO 200042436 7/2000 MD ( US ) ; Bert Vogelstein , Baltimore , WO WO 2001042504 6/2001 MD ( US ) ; Kenneth W. Kinzler , WO WO 2004082458 9/2004 Baltimore , MD (US ); Victor E. WO WO 2005113824 12/2005 Velculescu, Dayton , MD ( US ) WO WO 2014110408 7/2014 ( 73 ) Assignee : The Johns Hopkins University , OTHER PUBLICATIONS Baltimore , MD (US ) Allen et al . , “ + A2 : D33The role of molecular markers in the adjuvant Subject to any disclaimer , the term of this treatment of colorectal cancer ,” European Journal of Cancer . Supple ( * ) Notice : ment, Pergamon , Oxfor, GB , vol . 3 , No. 3 , Oct. 1 , 2005 . patent is extended or adjusted under 35 Arai et al ., “ The inv ( 11 ) ( p15222) chromosome translocation of de U.S.C. 154 ( b ) by 0 days. novo and therapy -related myeloid malignancies results in fusion of This patent is subject to a terminal dis the nucleoporin gene, NUP98 , with the putative RNA helicase gene , claimer. DDX10 . " , Blood 89 , 3936-3944 , 1997 . Bamford , et . al . , “ The COSMIC ( Catalog of Somatic Mutations in Cancer ) Database and Website , ” British Journal of Cancer, vol . 91 , ( 21 ) Appl. No .: 16 /824,052 No. 2 , Jul. 19 , 2004 , pp . 355-358 . Bardelli et al . , “ Mutational analysis of gene families in human ( 22 ) Filed : Mar. 19 , 2020 cancer ” , Curr Opin Genet Dev 15 , 5-12 , 2005 . Bardelli et al . , “ Mutational analysis of gene families in human ( 65 ) Prior Publication Data cancer , ” Current Opinion in Genetics & Development, Current US 2020/0239970 A1 Jul . 30 , 2020 Biology Ltd , XX , vol . 15 , No. 1 , Feb. 1 , 2005 , pp . 5-12 . Bardelli et al . , “ Mutational analysis of the tyrosine kinome in colorectal cancers . " , Science 300 , 949 , 2003 . Benvenuti et al . , “ Identification of cancer genes by mutational Related U.S. Application Data profiling of tumor genomes, ” Febs Letters, Elsevier , Amsterdam , ( 60 ) Continuation of application No. 16 / 664,505 , filed on NL , vol . 579 , No. 8 , Mar. 21 , 2005 , pp . 1884-1890 . Oct. 25 , 2019 , which is a continuation of application (Continued ) No. 15 / 413,903 , filed on Jan. 24 , 2017 , now abandoned , which is a division of application No. Primary Examiner James Martinell 14 / 224,102 , filed on Mar. 25 , 2014 , now Pat . No. 9,551,037 , which is a division of application No. ( 74 ) Attorney , Agent, or Firm — Fish & Richardson P.C. 12 / 377,073 , filed as application No. PCT /US2007 /017866 on Aug. 13 , 2007 , now Pat. No. ( 57 ) ABSTRACT 8,741,573 . Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an aver ( 60 ) Provisional application No. 60 / 836,944 , filed on Aug. age of ~ 90 mutant genes but that only a subset of these 11 , 2006 , provisional application No. 60 / 842,363 , contribute to the neoplastic process . Using stringent criteria filed on Sep. 6 , 2006 . to delineate this subset , we identified 189 genes ( average of 11 per tumor ) that were mutated at significant frequency. ( 51 ) Int . Ci . The vast majority of these genes were not known to be C12Q 1/68 ( 2018.01 ) genetically altered in tumors and are predicted to affect a GOIN 33/53 ( 2006.01 ) wide range of cellular functions, including transcription , C12Q 1/6886 ( 2018.01 ) adhesion , and invasion . These data define the genetic land ( 52 ) U.S. Cl . scape of two human cancer types , provide new targets for CPC C12Q 1/6886 ( 2013.01 ) ; C12Q 2600/106 diagnostic and therapeutic intervention and monitoring. ( 2013.01 ) ; C12Q 2600/156 ( 2013.01 ) ( 58 ) Field of Classification Search None 20 Claims , 36 Drawing Sheets See application file for complete search history . Specification includes a Sequence Listing . US 10,787,712 B2 Page 2 ( 56 ) References Cited Hinginbotham et al . , “ Activating Point Mutation in Ki - ras Codon 63 in a Chemically Induced Rat Renal Tumor” , Molecular Carcinogenesis, 5 : 136-139 , 1992 . OTHER PUBLICATIONS Hirshman - Jax , et . al ., “ A Distinct ‘ Side Population of Cells with High Drug Efflux Capacity in Human Tumor Cells ,” Proceedings of Bluteau et al . , “ Bi - allelic inactivation of TCF1 in hepatic the National Academy of Sciences of USA , National Academy of adenomas ." , Nat Genet 32 , 312-315 , 2002 . Science , Washington , DC , vol . 101 , No. 39 , Sep. 28 , 2004 , pp . Bos et al . , “ Prevalence of ras gene mutations in human colorectal 14228-14233 . cancers . ” , Nature 327,293-297 , 1987 . Hollstein et al . , " p53 mutations in human cancers ” , Science 253 , Bos , “ RAS Oncogenes in Human Cancer: A Review ” , Jan. 15 , 2014 . 49-53 , 1991 . Brent , “ Genomic biology . ” , Cell 100 , 169-183 , 2000 . Ideker et al. , “ Integrated Genomic and Proteomic Analyses of a cancer.gov' [ online ] “ Table of TCGA Cancer Codes ” , 2017 , Retrieved Systematically Perturbed Metabolic Network ” , Science 292 , 929 from the Internet : URL < https://cancer.gov/research/key-initiatives/ 934 , 2001 . ras / ras -central /blog / 2017 /kras.pdf > . Janakiraman et al . , “ Genomic and biological characterization of Castagnola et al . , “ Mutant KRAS , chromosomal instability and exon 4 KRAS mutations in human cancer ” , Cancer Res ., 70 ( 14 ) : progo in colorectal cancer, Biochimica Biophysica Acta , 5901-5911 , 2010 . 1756 : 115-125 , ( 2005 ) . Kem et al . , “ Elegance , silence and nonsense in the mutations Conlin et al . , “ The prognostic significance of K - ras , p53 , and APC literature for solid tumors ” , Cancer Biol Ther 5 , 349-359 , 2006 . mutations in colorectal carcinoma, ” Gut, 54 : 1283-1286 , 2005 . Kim et al . , “ Absence of FES exon 16 and 17 mutation in the Costello et al . , “ Aberrant CpG - island methylation has non - random colorectal carcinomas in Korean patients , ” Digestive and Liver and tumour - type - specific patterns .” , Nat Genet 24 , 132-138 , 2000 . Disease , W.B. , Saunders , GB , vol . 38 , No. 3 , Mar. 1 , 2006 , pp . Der et al . , “ rasH Mutations Deficient in GTP Binding ” , Molecular 213-214 . and Celluar Biology, 3291-3294 , 1986 . Kinzler et al . , “ Identification of an amplified , highly expressed gene Dulak et al . , “ Exome and whole genome sequencing of esophageal in a human glioma. " , Science 236 , 70-73 , 1987 . encarcinoma identifies recurrent driver events and mutatna Ku et al . , “ Genetic alterations of the TGF - b signaling pathway in complexity ” Nat. Genet ., 45 ( 5 ) : 478-486,213 . Duval et al. , “ Frequent frameshift mutations of the TCF - 4 gene in colorectal cancer cell lines : A novel mutation in Smad3 associated colorectal cancers with microsatellite instability .” , Cancer Res 59 , with the inactivation of TGF - b - induced transcriptional activation ” , 4213-4215 , 1999 . Cancer Lett, 247 : 283 ( 2007 ). Eddy, “ Multiple alignment using hidden Markov models . ” , 3 : Landis et al . , “ GTPase inhibiting mutations activate the alpha chain 114-120 , 1995 . of Gs and stimulate adenylyl cyclase in human pituitary tumours . ” , Edkins et al . , “ Recurrent KRAS Codon 146 Mutations in Human Nature 340 , 692-696 , 1989 . Colorectal Cancer Cancer Biology & Therapy , 5 : 8 , pp.228-936 , Lengauer et al . , “ Genetic instabilities in human cancers . ” , Nature Aug. 2006 . 396,643-649 , 1998 . Eppert et al . , “ MADR2 maps to 18q21 and encodes a TGFbeta Lievre et al . , “ KRAS Mutation Status is Predictive of Response to regulated MAD - related protein that is functionally mutated in Cetuximab Therapy in Colorectal Cancer ” , Cancer Res . 66 ( 8 ) , colorectal carcinoma . " , Cell 86,543-552 , 1996 . 2006 , pp . 3992-3995 , 2006 . Ewing et al . , “ Base - calling of automated sequencer traces using Lin et al . , “ A multidimensional analysis of genes mutated in rbeast phred . II . Error probabilities . ” , Genome Res 8 , 186-194 , 1998 . and colorectal cancers , " Genome Research , vol . 17 , No. 9 , Jul. 25 , Extended European Search Report dated Mar. 23 , 2010 in Appli 2007 , pp . 1304-1318 . cation No. 07811279.4 . Lin , et . al ., “ Discovery of Estrogen Receptor Alpha Target Genes Extended European Search Report issued in related European and Response Elements in Breast Tumor Cells , " Genome Biology Application No. 12176466.6 , dated Dec. 11 , 2012 . 2004 , vol . 5 , Issue 9 , Article R66 , Aug. 12 , 2004 , 18 pages . Comic.com online ) Extract from the Comdatabase ( anger Loeb , “ A mutator phenotype in cancer . ” , Cancer Res 61 , 3230-3239 , Institute ) for mutation ID COSM28519 , [retrieved on Apr. 4 , 2019 ] , 2001 . available on or before Apr. 12 , 2018 , retrieved from : URL : https : // Maglott et al ., “ Entrez Gene : gene - centered information at NCBI” , cancer.sanger.ac.uk/cosmic/mutation/overview?id=87808808/ > . Nucleic Acids