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(12) Patent Application Publication (10) Pub. No.: US 2005/0287544A1 Bertucci Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2005/0287544A1 Bertucci Et Al US 20050287544A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0287544A1 Bertucci et al. (43) Pub. Date: Dec. 29, 2005 (54) GENE EXPRESSION PROFILING OF COLON Related U.S. Application Data CANCER WITH DNA ARRAYS (60) Provisional application No. 60/525,987, filed on Dec. 1, 2003. (76) Inventors: Francois Bertucci, Marseille (FR); Remi Houlgatte, Marseille (FR); Publication Classification Daniel Birnbaum, Marseille (FR); (51) Int. Cl. ................................................... C12O 1/68 Stephane Debono, Marseille (FR) (52) U.S. Cl. .................................................................. 435/6 (57) ABSTRACT Correspondence Address: IP GROUP OF DLA PIPER RUDNICK GRAY Differential gene expression associated with histopathologic CARY US LLP features of colorectal disease can be performed with nucleic 1650 MARKET ST acid arrayS. Such arrays can comprise a pool of polynucle SUTE 4900 otide Sequences from colon tissues, and the detection of the overexpression or underexpression of polynucleotide PHILADELPHIA, PA 19103 (US) Sequences (or Subsequences or complements thereof) from (21) Appl. No.: 11/000,688 this pool can provide information relating to the detection, diagnosis, Stage, classification, monitoring, prediction, pre (22) Filed: Dec. 1, 2004 vention or treatment of colorectal disease. Patent Application Publication Dec. 29, 2005 Sheet 1 of 5 US 2005/0287544A1 866 Meta - 899 EMeta - 785 Meta - 905 eta - D Group A 8031 feta - D 835 fetal - ) 8582 feta - ) 74421 Meta - D - 8208 letta - D 750S Eleta - A 8252. Roeta - A 9 Roeta - A 7943. Noneta - A 6992T ?eta - A 6952 Roeta - A Group B 692. Foeta - A 848 Roeta - A G94T Roleta - A 8646. Raeta - A 9118 Roeta - A 650 feta - A 694 NoMeta - A aeses FIG. 1A FIG 1B F.G. 1C Patent Application Publication Dec. 29, 2005 Sheet 3 of 5 US 2005/0287544A1 FG. 3B Months Months FIG. 3C Patent Application Publication Dec. 29, 2005 Sheet 5 of 5 US 2005/0287544A1 . FIG. 5C A's t ran as y of “. ) s' So . e. On 9 : a a poo. .348 as as . e. g. W - SS is a a 5 to of b ? to w m pe a in a - - - -r- - - - ------------- - - - - sa, a toy asto awe r be VC at a - - - se. a t ral & 4, 8 . G.. 36.3's. a p at a 49 W8 e . As so da - Sl . to wo gy . a W. ofis . W.) a". w is w8 rv1 2 e as eup, asa asa . 8t W) . P y try 4 a 0 as O - a . up O a war s w80 rupiah O 2O 40 50 30 OO Months after diagnosis F.G. 5A US 2005/0287544A1 Dec. 29, 2005 GENE EXPRESSION PROFILING OF COLON 0007 DNA microarray technology allows the measure of CANCER WITH DNA ARRAYS the mRNA expression level of thousands of genes Simulta neously in a Single assay, thus providing a molecular defi 0001. This Application claims the benefit of co-pending nition of a Sample adapted to address the combinatory and U.S. provisional patent application Ser. No. 60/525,987, complex nature of cancers (Bertucci, 2001; Ramaswamy, filed Dec. 1, 2003, the entire disclosure of which is herein 2002; Mohr, 2002). Gene expression profiling may reveal incorporated by reference. biologically and/or clinically relevant Subgroups of tumors (Alizadeh, 2000; Garber, 2001; Kihara, 2001; Beer, 2002; SEQUENCE LISTING Bertucci, 2002; Devillard, 2002; Singh, 2002) and signifi 0002 The instant application contains a “lengthy' cantly improve current mechanistic understanding of onco Sequence Listing which has been submitted via CD-R in lieu genesis. of a printed paper copy, and is hereby incorporated by reference in its entirety. Said CD-R, recorded on May 5, 0008 Gene expression profiling-based studies of CRC 2005, are labeled CRF, “Copy 1” and “Copy 2", respec have So far compared normal to tumor tissue Samples, or tively, and each contains only one identical 3.63 Mb file described the molecular heterogeniety in different Stages of NAMED 1423RO3APP. colorectal disease (Alon, 1999; Notterman, 2001; Lin, 2002; Backert, 1999; Zou, 2002; Agrawal, 2002; Kitahara, 2001; FIELD OF THE INVENTION Williams, 2003; Tureci, 2003; Birkenkamp-Demtroder, 0003. The present invention relates to polynucleotide 2002; Frederiksen, 2003), but none have directly addressed analysis and, in particular, to polynucleotide expression the issue of prognosis or MSI phenotype. profiling of colorectal carcinomas using arrays of polynucle otides. SUMMARY OF THE INVENTION BACKGROUND 0009 DNA microarrays may be utilized to elucidate 0004 Colorectal carcinoma (CRC) is a frequent and discrete gene Sets to improve the prognostic classification of deadly disease. Different groups of tumors have been CRC, identify novel potential therapeutic targets of carcino defined according to aggressiveness, anatomical localization genesis, describe new diagnostic and/or prognostic markers, and putative genetic instability based on conventional his and guide physician decisions on appropriate patient care. topathological and immunohistopathological analysis. How 0010. The invention thus provides a method for analyzing ever, these aforementioned diagnostic tools are not Sufficient differential gene expression associated with histopathologic to accurately diagnose and predict Survival. Gene expression features of colorectal disease, comprising the detection of microarrays improve these classifications and bring new the overexpression or underexpression of a pool of poly insights on the underlying molecular mechanisms involved nucleotide Sequences in colon tissues, Said pool comprising throughout colorectal tumorigenic progression. all or part of the polynucleotide Sequences, Subsequences or 0005. Despite global scientific efforts to effectively treat complements thereof, Selected from each of predefined colon cancer, little progreSS has been made during the last polynucleotide Sequence Sets I through 644 Set forth in Table decade and colorectal cancer (CRC) remains one of the most 1. frequent and deadly neoplasias in western countries. Current 0011. The invention further provides a method or prog prognostic models based on histoclinical parameters inad nosis or diagnosis of colon cancer, or for monitoring the equately describe the heterogeneity of CRC, and are not treatment of a Subject with a colon cancer. This method Sufficient to predict prognosis and guide clinical treatment in comprises the steps of 1) obtaining colon tissue nucleic acids the individual patients. Tumors with different genetic alter from a patient; and 2) detecting the overexpression or ation with similar clinical presentation follow different evo underexpression of a pool of polynucleotide Sequences in lutions. One goal of molecular analysis is to identify, among colon tissues. The pool of polynucleStide Sequences com complex networks of genes involved in tumorigenic pro prises all or part of the polynucleotide Sequences, Subse gression, markers that could differentiate Subgroups of quences or complements thereof, Selected from each of tumors with prognosis, hence providing physicians with a predefined polynucleotide Sequnce Sets 1 through 644, as Set clinically useful diagnostic tool to treat individual patients forth in Table 1. based on molecular gene Sets as previously described. 0012. The invention further provides a polynucleotide 0006 Previous studies have been largely focused on library, comprising a pool of polynucleotide Sequences individual candidate genes of disease, contrasting with the molecular complexity of cancer. The multi-step progression either overexpressed or underexpressed in colon tissue, Said of CRC is accompanied by a number of genetic alterations pool corresponding to all or part of the polynucleotide KRAS, APC, P53 and mismatch repair (MMR) genes, sequences of SEQ ID Nos. 1 through 1596. WNT and TGF-alpha pathways that accumulate and inter 0013 The invention still further provides a method of act in heterogenous complex ways to exert their tumor detecting differential gene expression, comprises 1) obtain promoting effects (Vogelstein, 1988; Fearon, 1990). Despite ing a polynucleotide Sample from a Subject; 2) reacting said the large number of published studies, the clinical utility of polynucleotide sample obtained in Step (1) with a polynucle these disparate observations and reports remain limited for otide library of the invention; and 3) detecting the reaction CRC patients. For example, little is known about molecular product of Step (2). alterations associated with the prognostic heterogeneity of disease or the microsatellite instability (MSI) phenotype, 0014. The invention still further provides a method of and no single molecular marker has been validated to assigning a therapeutic regimen to Subject with histopatho accurately predict prognoSOSiS in clinical practice. New logical features of colorectal disease, comprising 1) classi models based on a precise molecular understanding of fying the Subject as having a "poor prognosis” or a "good disease are required to improve Screening, diagnosis, treat prognosis on the basis of the method of differential gene ment, and ultimately Survival of patients. expression analysis according to the invention, and 2) US 2005/0287544A1 Dec. 29, 2005 assigning the Subject a therapeutic regimen. The therapeutic numerous (e.g., ~8,000) genes in cancerous and non-can regimen will either (i) comprise no adjuvant chemotherapy cerous colon tissue or cell Samples. UnSupervised hierarchi if the Subject is lymph node negative and is classified as cal clustering can be used to identify putative gene expres having a good prognosis, or (ii) comprise chemotherapy if Sion patterns that are precisely correlated to Subgroups of Said patient has any other combination
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