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Last Updated: October 16, 2019

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Claims for Patent: 9,340,830

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Summary for Patent: 9,340,830
Title:Optimization of multigene analysis of tumor samples
Abstract: A method of analyzing a tumor sample comprising: (a) acquiring a library comprising a plurality of tumor members from a tumor sample; (b) contacting the library with a bait set to provide selected members; (c) acquiring a read for a subgenomic interval from a tumor member from said library; (d) aligning said read; and (e) assigning a nucleotide value (e.g., calling a mutation) from said read for the preselected nucleotide position, thereby analyzing said tumor sample.
Inventor(s): Lipson; Doron (Chestnut Hill, MA), Otto; Geoffrey Alan (Brookline, MA), Parker; Alexander N. (Boston, MA), Stephens; Philip James (Lexington, MA), Downing; Sean R. (Methuen, MA), Jarosz; Mima (Palo Alto, CA), Shapiro; Mikhail G. (San Francisco, CA), Yelensky; Roman (Newton, MA)
Assignee: FOUNDATION MEDICINE, INC. (Cambridge, MA)
Application Number:13/339,986
Patent Litigation and PTAB cases: See patent lawsuits and PTAB cases for patent 9,340,830
Patent Claims:1. A method of analyzing a tumor sample for a somatic mutation, comprising: (a) acquiring a library comprising a plurality of tumor members from the tumor sample; (b) contacting the library with at least two bait sets to provide selected tumor members, wherein said bait sets hydridize with the tumor members, thereby providing a library catch; (c) sequencing by a next generation sequencing method a subgenomic interval comprising the somatic mutation from a tumor member from said library or library catch, thereby acquiring a read for the subgenomic interval; (d) aligning said read by an alignment method; and (e) assigning a nucleotide value from said read for a preselected nucleotide position, thereby analyzing said tumor sample, wherein the at least two bait sets of step (b) are chosen from two of the following bait sets: (i) a first bait set that selects a high-level target chosen from one or more tumor nucleic acid molecules that comprise a subgenomic interval comprising a somatic mutation that appears at a frequency of about 5% or less of the cells from the tumor sample; (ii) a second bait set that selects a mid-level target chosen from one or more tumor nucleic acid molecules that comprise a subgenomic interval comprising a somatic mutation that appears at a frequency of about 10% or higher of the cells from the tumor sample; (iii) a third bait set that selects a low-level target chosen from one or more nucleic acid molecules that comprise a subgenomic interval chosen from one or more of: a) a pharmacogenomic (PGx) single nucleotide polymorphism (SNP) that distinguishes the ability of a patient to metabolize different drugs, b) a plurality of genomic SNPs that uniquely identify (fingerprint) a patient, or c) a genomic SNP or locus that is used to assess copy number gains or losses of genomic DNA and loss-of-heterozygosity (LOH); (iv) a fourth bait set that selects a nucleic acid molecule that comprises an intron sequence that detects a structural breakpoint; or (v) a fifth bait set that selects a one-copy deletion of several terminal exons, wherein each bait set of said plurality has a unique preselected efficiency for selection for its target as compared with the other bait sets in the plurality.

2. The method of claim 1, wherein the efficiency for selection in step (b) is modified by one or more of: (i) differential representation of different bait sets; (ii) differential overlap of bait subsets; (iii) differential bait parameters; (iv) mixing of different bait sets at different molar ratios to enhance or reduce relative target coverage depths; (v) using different types of oligonucleotide baits.

3. The method of claim 2, wherein different types of oligonucleotide baits are chosen from one or more of: (a) one or more chemically (non-enzymatically) individually synthesized baits, (b) one or more baits synthesized in an array, (c) one or more in vitro transcribed baits, (d) any combination of (a), (b) or (c), (e) one or more naturally or non-naturally occurring DNA oligonucleotides, (f) one or more naturally or non-naturally occurring RNA oligonucleotides, (g) a combination of (e) and (f), or (h) a combination of any of the above.

4. The method of claim 3, wherein the different types of oligonucleotide baits are mixed at a ratio chosen from 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:20, 1:50; 1:100, or 1:1000.

5. The method of claim 4, wherein the ratio of chemically individually synthesized baits to the baits synthesized in an array is chosen from 1:5, 1:10, or 1:20.

6. The method of claim 3, wherein the non-naturally occurring DNA or RNA oligonucleotides are chosen from one or more of: a locked nucleic acid (LNA); a peptide nucleic acid (PNA); a DNA or RNA oligonucleotide modified to capture low GC regions; a bicyclic nucleic acid (BNA); a crosslinked oligonucleotide; a modified 5-methyl deoxycytidine; or 2,6-diaminopurine.

7. The method of claim 2, wherein one or more of the following bait parameters are modified: (i) increasing or decreasing bait representation or overlap to enhance or reduce coverage of tumor members, which are under or over-covered relative to other targets in the same category; (ii) for low coverage, hard to capture target sequences comprising high GC content sequences, targeting with the bait sets covering adjacent sequences; (iii) modifying a bait sequence to reduce secondary structure of the bait and enhance its efficiency of selection; (iv) modifying a bait length to equalize melting hybridization kinetics of different baits within the same category; (v) modifying baits of different orientation for the same target region forward and reverse strand, to have different binding efficiencies; (vi) modifying the amount of a binding entity present on each that affects its binding efficiency; (vii) modifying the type of nucleotide used for different baits to affect binding affinity to the target, and enhance or reduce the relative target coverage; or (viii) using modified oligonucleotide baits having more stable base pairing,to equalize melting hybridization kinetics between areas of low or normal GC content relative to high GC content.

8. The method of claim 1, wherein the bait sets are chosen from two or more of: A. a bait set that selects an exon sequence that comprises a single nucleotide alteration associated with a cancerous phenotype; B. a bait set that selects an in-frame deletion of 1 or more codons from a reference nucleotide sequence; C. a bait set that selects an intragenic deletion; D. a bait set that selects an intragenic insertion; E. a bait set that selects a deletion of a full gene; F. a bait set that selects an inversion; G. a bait set that selects an interchromosal translocation; H. a bait set that selects a tandem duplication; I. a bait set that selects a nucleotide sequence of interest flanked by adjacent non-repetitive sequences; J. a bait set that selects one or more subgenomic intervals corresponding to a fusion sequence; K. a bait set that selects a subgenomic interval adjacent to a nucleotide sequence that includes an undesirable feature chosen from a nucleotide sequence of high GC content, or a nucleotide sequence comprising repeated elements, inverted repeats, or both; L. a bait set that selects a genomic rearrangement that comprises an intron sequence; or M. a bait set that selects a subgenomic interval that comprises an exon adjacent to a cancer associated gene fusion.

9. The method of claim 1, wherein the subgenomic interval comprises or consists of one or more of: a single nucleotide position; an intragenic region or an intergenic region; an exon or an intron, or a fragment thereof; a coding region or a non-coding region; a promoter, an enhancer, a 5' untranslated region (5' UTR), or a 3' untranslated region (3' UTR), or a fragment thereof; a cDNA or a fragment thereof; an SNP; a somatic mutation, a germ line mutation or both; a point or a single mutation; a deletion mutation; an in-frame deletion, an intragenic deletion, a full gene deletion; an insertion mutation; an intragenic insertion; an inversion mutation; an intra-chromosomal inversion; a linking mutation; a linked insertion mutation; an inverted duplication mutation; a tandem duplication; an intrachromosomal tandem duplication; a translocation; a chromosomal translocation, a non-reciprocal translocation; a rearrangement; a genomic rearrangement; a rearrangement of one or more introns, or a fragment thereof; a rearranged intron; a 5'- or a 3'-UTR, or a combination thereof.

10. The method of claim 1, wherein the subgenomic interval comprises an altered nucleotide sequence, encodes an altered amino acid sequence, a chromosomal translocation, an intra-chromosomal inversion, a change in copy number, a change in expression level, a change in protein level, a change in protein activity, or a change in methylation status, in a cancer tissue or cancer cell, as compared to a normal, healthy tissue or cell.

11. The method of claim 1, wherein the tumor sample comprises: one or more premalignant or malignant cells; cells from a solid tumor, a soft tissue tumor or a metastatic lesion; tissue or cells from a surgical margin; a histologically normal tissue; one or more circulating tumor cells (CTC); a normal adjacent tissue (NAT); a blood sample from the same subject having or at risk of having the tumor; or an FFPE-sample.

12. The method of claim 1, wherein the methods comprises sequencing of a cDNA derived from an RNA acquired from the tumor sample.

13. The method of claim 12, further comprising a step chosen from one or more of: detecting a change in the level of a gene or gene product comprising the somatic mutation, enriching a sample for a target RNA, or depleting the sample of certain high abundance RNAs.

14. The method of claim 1, further comprising one or more of: (i) fingerprinting the tumor sample; (ii) quantifying the abundance of a gene or gene product; (iii) quantifying the relative abundance of a transcript in the tumor sample; (iv) identifying the tumor sample as belonging to a particular subject; (v) identifying a genetic trait in the tumor sample comprising one or more of a subject's genetic make-up, ethnicity, race, or familial traits; (vi) determining the ploidy in the tumor sample; (vii) determining a loss of heterozygosity in the tumor sample; (viii) determining the presence or absence of a gene duplication event in the tumor sample; (ix) determining the presence or absence of a gene amplification event in the tumor sample; or (x) determining the level of tumor/normal cellular admixture in the tumor sample.

15. The method of claim 1, wherein the method comprises sequencing a subgenomic interval chosen from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or all of the following: A) at least five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty or more subgenomic intervals from a mutated or wild-type gene or gene product chosen from at least five or more of: ABL1, AKT1, AKT2, AKT3, ALK, APC, AR, BRAF, CCND1, CDK4, CDKN2A, CEBPA, CTNNB1, EGFR, ERBB2, ESR1, FGFR1, FGFR2, FGFR3, FLT3, HRAS, JAK2, KIT, KRAS, MAP2K1, MAP2K2, MET, MLL, MYC, NF1, NOTCH1, NPM1, NRAS, NTRK3, PDGFRA, PIK3CA, PIK3CG, PIK3R1, PTCH1, PTCH2, PTEN, RB1, RET, SMO, STK11, SUFU, or TP53; B) at least five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty, thirty-five, forty, forty-five, fifty, fifty-five, sixty, sixty-five, seventy, seventy-five, eighty, eighty-five, ninety, ninety-five, one hundred, one hundred and five, one hundred and ten, one hundred and fifteen, one hundred and twenty or more of subgenomic intervals from a mutated or wild type gene or gene product chosen from at least five or more of: ABL2, ARAF, ARFRP1, ARID1A, ATM, ATR, AURKA, AURKB, BAP1, BCL2, BCL2A1, BCL2L1, BCL2L2, BCL6, BRCA1, BRCA2, CBL, CARD11, CBL, CCND2, CCND3, CCNE1, CD79A, CD79B, CDH1, CDH2, CDH20, CDH5, CDK6, CDK8, CDKN2B, CDKN2C, CHEK1, CHEK2, CRKL, CRLF2, DNMT3A, DOT1L, EPHA3, EPHA5, EPHA6, EPHA7, EPHB1, EPHB4, EPHB6, ERBB3, ERBB4, ERG, ETV1, ETV4, ETV5, ETV6, EWSR1, EZH2, FANCA, FBXW7, FGFR4, FLT1, FLT4, FOXP4, GATA1, GNA11, GNAQ, GNAS, GPR124, GUCY1A2, HOXA3, HSP90AA1, IDH1, IDH2, IGF1R, IGF2R, IKBKE, IKZF1, INHBA, IRS2, JAK1, JAK3, JUN, KDM6A, KDR, LRP1B, LRP6, LTK, MAP2K4, MCL1, MDM2, MDM4, MEN1, MITF, MLH1, MPL, MRE11A, MSH2, MSH6, MTOR, MUTYH, MYCL1, MYCN, NF2, NKX2-1, NTRK1, NTRK2, PAK3, PAX5, PDGFRB, PKHD1, PLCG1, PRKDC, PTPN11, PTPRD, RAF1, RARA, RICTOR, RPTOR, RUNX1, SMAD2, SMAD3, SMAD4, SMARCA4, SMARCB1, SOX10, SOX2, SRC, TBX22, TET2, TGFBR2, TMPRSS2, TNFAIP3, TNK, TNKS2, TOP1, TSC1, TSC2, USP9X, VHL, or WT1; C) at least five, six, seven, eight, nine, ten, fifteen, twenty, or more subgenomic intervals from a gene or gene product according to Table 1, 1A, 2, 3, or 4; D) at least five, six, seven, eight, nine, ten, fifteen, twenty, or more subgenomic intervals from a gene or gene product chosen from one or more of: ABL1, AKT1, ALK, AR, BRAF, BRCA1, BRCA2, CEBPA, EGFR, ERBB2, FLT3, JAK2, KIT, KRAS, MET, NPM1, PDGFRA, PIK3CA, RARA, AKT2, AKT3, MAP2K4, NOTCH1, or TP53; E) at least five, six, seven, eight, nine, ten, or more subgenomic intervals including a mutated or a wild type codon chosen from one or more of: codon 315 of the ABL1 gene; codon 1114, 1338, 1450 or 1556 of APC; codon 600 of BRAF; codon 32, 33, 34, 37, 41 or 45 of CTNNB1; codon 719, 746-750, 768, 790, 858 or 861 of EGFR; codon 835 of FLT3; codon 12, 13, or 61 of HRAS; codon 617 of JAK2; codon 816 of KIT; codon 12, 13, or 61 of KRAS; codon 88, 542, 545, 546, 1047, or 1049 of PIK3CA; codon 130, 173, 233, or 267 of PTEN; codon 918 of RET; or codon 175, 245, 248, 273, or 306 of TP53; F) at least five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty, or more subgenomic intervals from a mutated or wild type gene or gene product chosen from: ABCB1,BCC2, ABCC4, ABCG2, C1orf144, CYP1B1, CYP2C19, CYP2C8, CYP2D6, CYP3A4, CYP3A5, DPYD, ERCC2, ESR2, FCGR3A, GSTP1, ITPA, LRP2, MAN1B1, MTHFR, NQO1, NRP2, SLC19A1, SLC22A2, SLCO1B3, SOD2, SULT1A1, TPMT, TYMS, UGT1A1, or UMPS; G) at least five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty, or more subgenomic intervals from a mutated or wild type PGx gene or gene product associated with one or more of: (i) better survival of a cancer patient treated with a drug; (ii) paclitaxel metabolism; (iii) toxicity to a drug; or (iv) a side effect to a drug; H) a translocation alteration of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 110 or more genes or gene products according to Table 3; I) a translocation alteration of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 110 or more genes or gene products according to Table 3 in a solid tumor sample from the cancer types specified therein; J) a translocation alteration of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200 or more genes or gene products according to Table 4; K) a translocation alteration of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200 or more genes or gene products according to Table 4 in a heme tumor sample from the cancer types specified therein; L) at least five genes or gene products selected from the genes in any of Table 1, 1A, 2, 3, or 4, wherein an allelic variation is associated with a preselected type of tumor and wherein said allelic variation is present in less than 5% of the cells in said tumor type; M) at least five genes or gene products selected from the genes in any of Table 1, 1A, 2, 3, or 4, which are embedded in a GC-rich region; or N) at least five genes or gene products indicative of a genetic factor for developing cancer chosen from one or more of BRCA1, BRCA2, EGFR, HRAS, KIT, MPL, ALK, PTEN, RET, APC, CDKN2A, MLH1, MSH2, MSH6, NF1, NF2, RB1, TP53, VHL, or WT1.

16. A method of claim 1, wherein the method comprises sequencing a subgenomic interval from at least twenty, twenty-five, thirty or more genes or gene products from the sample, wherein the genes or gene products are chosen from: ABL1, AKT1, AKT2, AKT3, ALK, APC, AR, BRAF, CCND1, CDK4, CDKN2A, CEBPA, CTNNB1, EGFR, ERBB2, ESR1, FGFR1, FGFR2, FGFR3, FLT3, HRAS, JAK2, KIT, KRAS, MAP2K1, MAP2K2, MET, MLL, MYC, NF1, NOTCH1, NPM1, NRAS, NTRK3, PDGFRA, PIK3CA, PIK3CG, PIK3R1, PTCH1, PTCH2, PTEN, RB1, RET, SMO, STK11,SUFU, or TP53.

17. The method of claim 15, wherein the method further comprises providing a report in electronic, web-based, or paper form, to a patient or to another person or entity, a caregiver, a physician, an oncologist, a hospital, clinic, third-party payor, insurance company or government office.

18. The method of claim 17, wherein said report comprises one or more of: (a) output from the method, comprising the identification of nucleotide values, the indication of the presence or absence of an alteration, mutation, or wild-type sequence for sugenomic intervals associated with a tumor of the type of the sample; (b) information on the role of a sequence, an alteration, mutation, or wild-type sequence, in a disease, wherein said information comprises information on prognosis, resistance, or potential or suggested therapeutic options; (c) information on the likely effectiveness of a therapeutic option, the acceptability of a therapeutic option, or the advisability of applying the therapeutic option to a patient having a sequence, alteration or mutation identified in the report; (d) information, or a recommendation on, the administration of a drug, the administration at a preselected dosage or in a preselected treatment regimen, in combination with other drugs, to the patient; (e) wherein not all mutations identified in the method are identified in the report, the report can be limited to mutations in genes having a preselected level of correlation with the occurrence, prognosis, stage, or suseptability of the cancer to treatment, with a preselected therapeutic option; or (f) is provided to the patient or to another person or entity within 7, 14, or 21 from receipt of the sample by the entity practicing the method.

19. The method of claim 1, wherein a nucleotide value assigned for a nucleotide position in each of X unique subgenomic intervals is assigned by a unique calling method and X is at least 2, and wherein unique subgenomic interval means different from the other X-1 subgenomic intervals, and wherein unique calling method means different from the other X-1 calling methods.

20. The method of claim 19, wherein: (i) assigning said nucleotide value is a function of a value which is or represents a prior expectation of observing said read showing a preselected variant at said preselected nucleotide position in a tumor of type; or (ii) assigning said nucleotide value is a function of a set of values which represent the probabilities of observing a read showing a preselected variant at said preselected nucleotide position if the variant is present in the sample at a frequency of at least 1%, at least 5%, at least 10%, or more, or if the variant is absent.

21. The method of claim 19, wherein the calling method comprises: acquiring, for a preselected nucleotide position in each of said X unique subgenomic intervals: (i) a first value which is or represents a prior expectation of observing a read showing a preselected variant at said preselected nucleotide position in a type of tumor; and (ii) a second set of values which represent the probabilities of observing a read showing said preselected variant at said preselected nucleotide position if the variant is present in the sample at a frequency of at least 1%, at least 5%, at least 10%, or more, or if the variant is absent; responsive to said values, assigning a nucleotide value from said reads for each of said preselected nucleotide positions by weighing the comparison among the values in the second set using the first value, thereby analyzing said sample.

22. The method of claim 21, wherein the method comprises assigning a nucleotide value for at least X, where X is 10 preselected nucleotide positions, wherein each assignment is a function of a unique value which is or represents the prior expectation of observing a read showing a preselected variant at said preselected nucleotide position in a tumor of type, wherein unique value means different from the values for the other X-1 assignments.

23. The method of claim 22, wherein the preselected nucleotide position and the type of tumor are according to Tables 6, 9 and 10.

24. The method of claim 19, wherein the unique calling methods differ by relying on different Bayesian prior values.

25. The method of claim 19, comprising one or more or all of: (i) assigning a nucleotide value for at least 10 preselected nucleotide positions, wherein each assignment is based on a unique first or second value, as compared with the values for the other assignments; (ii) the assignment of method of (i), wherein at least 10 of the assignments are made with first values which are a function of a probability of a preselected variant being present in less than 5, 10, or 20% of the cells in a preselected type of tumor; (iii) assigning a nucleotide value for at least X preselected nucleotide positions, each of which is associated with a preselected variant having a unique probability of being present in the tumor of preselected type as compared with the probability for the other X-1assignments, wherein each of said X assignments is based on a unique first or second value as compared with the values for the other X-1assignments, wherein X=10; or (iv) assigning a nucleotide value at a first and a second nucleotide position, wherein the likelihood of a first preselected variant at said first nucleotide position being present in a tumor of preselected type is at least 2 times greater than the likelihood of a second preselected variant at said second nucleotide position being present, wherein each assignment is based on a unique first and/or second value as compared with the values for the other assignments.

26. The method of claim 19, comprising assigning a nucleotide value to a plurality of preselected nucleotide positions, wherein said plurality comprises an assignment for variants falling into at least 3, or all, of the following probability ranges: less than 0.01%; greater than 0.01 and less than or equal to 0.02%; greater than 0.02 and less than or equal to 0.03%; greater than 0.03 and less than or equal to 0.04%; greater than 0.04 and less than or equal to 0.05%; greater than 0.05 and less than or equal to 0.1%; greater than 0.1 and less than or equal to 0.2%; greater than 0.2 and less than or equal to 0.5%; greater than 0.5 and less than or equal to 1.0%; greater than 1.0 and less than or equal to 2.0%; greater than 2.0 and less than or equal to 5.0%; greater than 5.0 and less than or equal to 10.0%; greater than 10.0 and less than or equal to 20.0%; greater than 20.0 and less than or equal to 50.0%; and greater than 50 and less than or equal to 100.0%; wherein, a probability range is the range of probabilities that a preselected variant at a preselected nucleotide position is present in a tumor of preselected type or the probability that a preselected variant at a preselected nucleotide position is present in the cells in a tumor sample, a library from the tumor sample, or library catch from that library, for a preselected type, and wherein each assignment is based on a unique first or second value, wherein unique first or second value means different from the values for the other assignments in a probability range or different from the first or second value for one or more or all of the other probability ranges.

27. The method of claim 19, comprising one or both of: (i) assigning a nucleotide value for at least 3 preselected nucleotide positions each, independently, having a preselected variant present in less than 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0.2, or 0.1% of the DNA in said sample, wherein each assignment is based on a unique first and/or second value as compared with the values for the other assignments; or (ii) assigning a nucleotide value at a first and a second nucleotide position, wherein the likelihood of a preselected variant at the first position in the DNA of said sample is at least 2 times greater than the likelihood of a preselected variant at said second nucleotide position in the DNA of said sample, wherein each assignment is based on a unique first or second value as compared with the values for the other assignments.

28. The method of claim 19, comprising assigning a nucleotide value to at least 3 preselected nucleotide positions having a preselected variant present in X % of the cells in said sample, of the nucleic acid in a library from said sample, or the nucleic acid in a library catch from that library, wherein X is independently chosen from less than 1.0%; between and equal to 1.0-2.0%; greater than 2.0% and less than or equal to 3%; greater than 3.0% and less than or equal to 4%; greater than 4.0% and less than or equal to 5%; greater than 5.0% and less than or equal to 10%; greater than 10.0% and less than or equal to 20%; greater than 20.0% and less than or equal to 40%; greater than 40.0% and less than or equal to 50%; or greater than 50.0% and less than or equal to 100%, of the cells in said sample, of the nucleic acid in a library from said sample, or the nucleic acid in a library catch from that library; wherein each assignment is based on a unique first or second value, wherein unique means different from the values for the other assignments in the range in (i) of less than 1% or different from a first or second values for a determination in one or more or all of the other ranges.

29. The method of claim 19, comprising assigning a nucleotide value at each of X nucleotide positions, each nucleotide position, independently, having a likelihood of a preselected variant being present in the DNA of said sample that is unique as compared with the likelihood for a preselected variant at the other X-1 nucleotide positions, wherein X is equal to or greater than 1, 2, 3, 5, 10, 20, 40, 50, 60, 70, 80, 90, or 100, and wherein each assignment is based on a unique first or second value as compared with the values for the other assignments.

30. The method of claim 19, said method comprising assigning a nucleotide value at each of at least 3 preselected nucleotide positions, each having, independently, a first value that is a function of a probability that is less than 0.5.

31. The method of claim 19, said method comprising assigning a nucleotide value at each of at least X nucleotide positions, each independently having a first value that is unique as compared with the other X-1 first values, and wherein each of said X first values is a function of a probability that is less than 0.5%, wherein X is equal to or greater than 3.

32. The method of claim 19, wherein a nucleotide position in at least 20 genes from Table 1 or 1A is assigned a nucleotide value.

33. The method of claim 32, wherein a unique first value, second value, or both values are applied to subgenomic intervals in each of at least 10% of said genes analyzed.

34. The method of claim 32, wherein a nucleotide position in at least 10 genes from Table 1 or 1A having the priority 1 annotation is assigned a nucleotide value.

35. The method of claim 33, further comprising 2, 3, 4 or all of the following: (i) responsive to said first value, second value or both values, assigning a nucleotide value from reads for a first preselected nucleotide position for which a coverage greater than 500.times. sequencing depth is required to enable a high level of sensitivity for a mutation that appears at a frequency of 5% or less in cells in the sample; (ii) responsive to said first value, second value or both values, assigning a nucleotide value from reads for a second preselected nucleotide position for which greater than 200.times. sequencing depth is required to enable a high level of sensitivity for a mutation that appears at a frequency of greater than 5% and up to 10, 15 or 20% in cells in the sample; (iii) responsive to said first value, second value or both values, assigning a nucleotide value from reads for a third preselected nucleotide position for which coverage less than that in (i) or (ii) above is required to enable a high level of sensitivity for heterozygous alleles, wherein said third preselected nucleotide position is chosen from (1) a pharmacogenomic SNP associated with the ability of a patient to respond to or metabolize a drug; (2) a plurality of genomic SNPs that are used to uniquely identify (fingerprint) a patient; or (3) a genomic SNP or locus that is used to assess copy number gains or losses of genomic DNA and LOH; (iv) responsive to said first value, second value or both values, assigning a nucleotide value from reads for a fourth preselected nucleotide position chosen from a structural breakpoint, a rearrangement, a translocation or an indel; and (v) responsive to said first value, second value or both values, assigning a nucleotide value from reads for a fifth preselected nucleotide position for which the coverage is less than in one of (i), (ii) (iii) or (iv) to ensure high detection reliability.

36. The method of claim 19, further comprising acquiring a threshold value for each of a number of preselected subgenomic intervals, wherein said threshold value is customized based on one or more of: the type of cancer in a sample, the gene in which the subgenomic interval to be sequenced is located, or the variant to be sequenced.

37. The method of claim 19, wherein the calling method comprises: acquiring, for each of said X subgenomic intervals, a threshold value, wherein each of said acquired X threshold values is unique as compared with the other X-1 threshold values, thereby providing X unique threshold values; for each of said X subgenomic intervals, comparing an observed value which is a function of the number of reads having a preselected nucleotide value at a preselected nucleotide position with its unique threshold value, thereby applying to each of said X subgenomic intervals, its unique threshold value; and responsive to the result of said comparison, assigning a nucleotide value to a preselected nucleotide position, wherein X is equal to or greater than 2.

38. The method of claim 37, wherein a unique threshold value is applied to subgenomic intervals in each of at least 10 different genes.

39. The method of claim 38, wherein a unique threshold value is applied to a subgenomic interval in each of at least 10% of said genes analyzed.

40. The method of claim 37, wherein a nucleotide position in at least 20 genes from Table 1 or 1A is assigned a nucleotide value; and a unique threshold value is applied to a subgenomic interval in each of at least 10% of said genes analyzed.

41. The method of claim 37, wherein a nucleotide position in at least 10 genes from Table 1 or 1A having the priority 1 annotation is assigned a nucleotide value; and a unique threshold value is applied to a subgenomic interval in each of at least 10% of said genes analyzed.

42. The method of claim 37, wherein a nucleotide position for at least 20 variants or codons from Table 1, 1A, 2, or 3, is assigned a nucleotide value; and a unique threshold value is applied to a subgenomic interval in each of at least 10% of said genes analyzed.

43. The method of claim 37, wherein a nucleotide position for at least 10 variants from the bottom half or bottom third of Table 9 is assigned a nucleotide value; and a unique threshold value is applied to a subgenomic interval in each of at least 10% of said genes analyzed.

44. The method of claim 1, wherein: a read from each of X unique subgenomic intervals is aligned with a unique alignment method and X is at least 2, wherein unique subgenomic interval means different from the other X-1 subgenomic intervals, and wherein unique alignment method means different from the other X-1 alignment methods.

45. The method of claim 44, wherein subgenomic intervals from at least X genes from Table 1 or 1A having the priority 1 annotation, are aligned with unique alignment methods, and X is equal to 10.

46. The method of claim 44, comprising: a) applying a first unique alignment method to a first genomic interval, a variant of which is associated with a tumor phenotype, wherein the variant is a point mutation from Table 6; b) applying a second unique alignment method to a second genomic interval, a variant of which is associated with a tumor phenotype, wherein the variant is a rearrangement chosen from a deletion, insertion, or translocation on Table 5; and c) applying a third unique alignment method to a third genomic interval comprising a genomic interval in which variants are not associated with a tumor phenotype or with a tumor of the type in said sample.

47. The method of claim 44, wherein a subgenomic interval being analyzed comprises a nucleotide position with a genomic rearrangement, and the method comprises using an alignment method that includes: selecting a rearrangement reference sequence for alignment with a read, wherein said rearrangement reference sequence is preselected to align with a preselected rearrangement, wherein the preselected rearrangement reference sequence is not identical to the preselected rearrangement; comparing a read with said preselected rearrangement reference sequence; and determining if said read meets a predetermined alignment criterion, wherein the predetermined alignment criterion is an alignment to said preselected rearrangement reference sequence with less than a preselected level of mismatch or gaps; thereby analyzing a read.

48. The method of claim 1, wherein the method comprises 2, 3, 4 or 5 of: a) sequencing a first subgenomic interval to provide for about 500.times. or higher sequencing depth, thereby detecting a mutation present in no more than 5% of the cells from the tumor sample; b) sequencing a second subgenomic interval to provide for about 200.times.-500.times. sequencing depth, thereby detecting a mutation present in no more than 10% of the cells from the tumor sample; c) sequencing a third subgenomic interval to provide for about 200.times.-500.times. sequencing depth, thereby detecting a subgenomic interval chosen from one or more of: 1) a pharmacogenomic (PGx) single nucleotide polymorphism (SNP) that distinguishes the ability of a patient to metabolize different drugs, or 2) a plurality of genomic SNPs that uniquely identifies a patient; d) sequencing a fourth subgenomic interval to provide for about 5.times.-50.times. sequencing depth, thereby detecting a structural breakpoint; or e) sequencing a fifth subgenomic interval to provide for about 100.times.-300.times. sequencing depth, thereby detecting a copy number change.

49. The method of claim 48, wherein the detection of the copy number change comprises detection of a genomic SNP or locus that is used to assess copy number gains or losses of genomic DNA or loss-of-heterozygosity (LOH).

50. The method of claim 1, wherein said contacting step (b) is performed in solution.

51. The method of claim 1, wherein the method comprises contacting the library with at least three, four, or five bait sets.

52. The method of claim 8, wherein the bait set is chosen from five, six, seven, eight, nine, ten, eleven, twelve or all of A-M.

53. The method of claim 8, wherein the bait set is chosen from ten, eleven, twelve or all of A-M.

54. The method of claim 24, wherein the unique calling methods differ by relying on different Bayesian prior values chosen from a first calling method applied to a first nucleotide position that is a function of a first Bayesian prior and a second calling method applied to a second nucleotide position that is a function of a second Bayesian prior.

55. The method of claim 44, wherein the aligning step comprises two or more of the following: (i) a first alignment method that is selected responsive to, or is optimized for, a high level target comprising a gene, an exon, or a base that appears at a frequency of 5% or less, in cells in the tumor sample, the nucleic acid molecules of the library, or the nucleic acid molecules of the library catch; (ii) a second alignment method that is selected responsive to, or is optimized for, a mid-level target comprising a gene, an exon, or a base that appears at a frequency of greater than 5% and up to 10, 15 or 20%, in cells in the tumor sample, the nucleic acid molecules of the library, or the nucleic acid molecules of the library catch; (iii) a third alignment method that is selected responsive to, or is optimized for, a low-level target comprising a gene, exon, or base, chosen from one or more of: (1) a pharmacogenomic SNP that is associated with the ability of patient to respond to or metabolize a drug; (2) a plurality of genomic SNPs that uniquely identify (fingerprint) a patient; or (3) a genomic SNP or locus that is used to assess copy number gains or losses of genomic DNA and LOH; (iv) a fourth alignment method that is selected responsive to, or is optimized for, a structural breakpoint; and (v) a fifth alignment method that is selected responsive to, or is optimized for, a target comprising an intron for which sparse coverage can improve the ability to detect copy number changes.

56. The method of claim 55, wherein the structural breakpoint is in a rearrangement, a translocation or an indel.

57. The method of claim 47, wherein the preselected rearrangement is a preselected indel.

58. The method of claim 47, wherein: (i) the preselected rearrangement reference sequence comprises a sequence or its complement corresponding to said preselected rearrangement; (ii) the preselected rearrangement reference sequence comprises a simulated sequence that is other than the sequence of the preselected rearrangement or its complement selected to align with a read of said preselected rearrangement; or (iii) the preselected rearrangement reference sequence is not identical to the preselected rearrangement.

59. The method of claim 1, wherein the sequenced somatic mutation in step (c) is from said library catch.

60. The method of claim 2, wherein the different types of oligonucleotide baits are chosen from one or more of: non-naturally occurring DNA oligonucleotides, or one or more non-naturally occurring RNA oligonucleotides, or a combination thereof.

61. The method of claim 60, wherein the non-naturally occurring DNA or RNA oligonucleotides are chosen from one or more of: a locked nucleic acid (LNA); a peptide nucleic acid (PNA); a DNA or RNA oligonucleotide modified to capture low GC regions; a bicyclic nucleic acid (BNA); a crosslinked oligonucleotide; a modified 5-methyl deoxycytidine; or 2,6-diaminopurine.

62. The method of claim 1, wherein the tumor member comprises a sequence from a subject and a sequence not derived from the subject.

63. The method of claim 62, wherein the tumor member comprises an adapter sequence, a primer sequence, or other sequences that allow for identification.

64. The method of claim 63, wherein the tumor member comprises a barcode sequence.

65. A method of analyzing a tumor sample for a somatic mutation, comprising: (a) acquiring a library comprising a plurality of tumor members from the tumor sample; (b) contacting the library with at least two bait sets to provide selected tumor members, wherein said bait sets hybridize with the tumor members, thereby providing a library catch; (c) sequencing by a next generation sequencing method a subgenomic interval comprising the somatic mutation from a tumor member from said library catch, thereby acquiring a read for the subgenomic interval; thereby analyzing said tumor sample for the somatic mutation, wherein the at least two bait sets of step (b) are chosen from two of the following bait sets: (i) a first bait set that selects a high-level target chosen from one or more tumor nucleic acid molecules that comprise a subgenomic interval comprising a somatic mutation that appears at a frequency of about 5% or less of the cells from the tumor sample; (ii) a second bait set that selects a mid-level target chosen from one or more tumor nucleic acid molecules that comprise a subgenomic interval comprising a somatic mutation that appears at a frequency of about 10% or higher of the cells from the tumor sample; (iii) a third bait set that selects a low-level target chosen from one or more nucleic acid molecules that comprise a subgenomic interval chosen from one or more of: a) a pharmacogenomic (PGx) single nucleotide polymorphism (SNP) that distinguishes the ability of a patient to metabolize different drugs, b) a plurality of genomic SNPs that uniquely identify (fingerprint) a patient, or c) a genomic SNP or locus that is used to assess copy number gains or losses of genomic DNA and loss-of-heterozygosity (LOH); (iv) a fourth bait set that selects a nucleic acid molecule that comprises an intron sequence that detects a structural breakpoint; or (v) a fifth bait set that selects a one-copy deletion of several terminal exons, wherein each bait set of said plurality has a unique preselected efficiency for selection for its target as compared with the other bait sets in the plurality.

66. The method of claim 65, wherein the efficiency for selection in step (b) is modified by one or more of: (i) differential representation of different bait sets; (ii) differential overlap of bait subsets; (iii) differential bait parameters; (iv) mixing of different bait sets at different molar ratios to enhance or reduce relative target coverage depths; or (v) using different types of oligonucleotide baits.

67. The method of claim 66, wherein the different types of oligonucleotide baits are chosen from one or more of: (a) one or more chemically (non-enzymatically) individually synthesized baits, (b) one or more baits synthesized in an array, (c) one or more in vitro transcribed baits; (d) any combination of (a), (b) or (c), (e) one or more naturally or non-naturally occurring DNA oligonucleotides, (f) one or more naturally or non-naturally occurring RNA oligonucleotides, (g) a combination of (e) and (f), or (h) a combination of any of the above.

68. The method of claim 67, wherein the different types of oligonucleotide baits are mixed at a ratio chosen from 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:20, 1:50; 1:100, or 1:1000.

69. The method of claim 68, wherein the ratio of the chemically individually synthesized baits to the baits synthesized in an array is chosen from 1:5, 1:10, or 1:20.

70. The method of claim 67, wherein the non-naturally occurring DNA or RNA oligonucleotides are chosen from one or more of: a locked nucleic acid (LNA); a peptide nucleic acid (PNA); a DNA or RNA oligonucleotide modified to capture low GC regions; a bicyclic nucleic acid (BNA); a crosslinked oligonucleotide; a modified 5-methyl deoxycytidine; or 2,6-diaminopurine.

71. The method of claim 65, wherein one or more of the following bait parameters are modified: (i) increasing or decreasing bait representation or overlap to enhance or reduce coverage of tumor members, which are under- or over-covered relative to other targets in the same category; (ii) for low coverage, hard to capture target sequences comprising high GC content sequences, targeting with the bait sets covering adjacent sequences; (iii) modifying a bait sequence to reduce secondary structure of the bait and enhance its efficiency for selection; (iv) modifying a bait length to equalize melting hybridization kinetics of different baits within the same category; (v) modifying baits of different orientation for the same target region, forward and reverse strand, to have different binding efficiencies; (vi) modifying the amount of a binding entity present on each bait that affects the bait's binding efficiency; (vii) modifying the type of nucleotide used for different baits to affect binding affinity to the target, and enhance or reduce the relative target coverage; or (viii) using modified oligonucleotide baits having more stable base pairing to equalize melting hybridization kinetics between areas of low or normal GC content relative to high GC content.

72. The method of claim 65, wherein the bait sets are chosen from two or more of: A. a bait set that selects an exon sequence that comprises a single nucleotide alteration associated with a cancerous phenotype; B. a bait set that selects an in-frame deletion of 1 or more codons from a reference nucleotide sequence; C. a bait set that selects an intragenic deletion; D. a bait set that selects an intragenic insertion; E. a bait set that selects a deletion of a full gene; F. a bait set that selects an inversion; G. a bait set that selects an interchromosal translocation; H. a bait set that selects a tandem duplication; I. a bait set that selects a nucleotide sequence of interest flanked by adjacent non-repetitive sequences; J. a bait set that selects one or more subgenomic intervals corresponding to a fusion sequence; K. a bait set that selects a subgenomic interval adjacent to a nucleotide sequence that includes an undesirable feature chosen from a nucleotide sequence of high GC content, or a nucleotide sequence comprising repeated elements, inverted repeats, or both; L. a bait set that selects a genomic rearrangement that comprises an intron sequence; or M. a bait set that selects a subgenomic interval that comprises an exon adjacent to a cancer associated gene fusion.

73. The method of claim 65, wherein the subgenomic interval comprises or consists of one or more of: a single nucleotide position; an intragenic region or an intergenic region; an exon or an intron, or a fragment thereof; a coding region or a non-coding region; a promoter, an enhancer, a 5' untranslated region (5' UTR), or a 3' untranslated region (3' UTR), or a fragment thereof; a cDNA or a fragment thereof; an SNP; a somatic mutation, a germ line mutation or both; a point or a single mutation; a deletion mutation; an in-frame deletion, an intragenic deletion; a full gene deletion; an insertion mutation; an intragenic insertion; an inversion mutation; an intra-chromosomal inversion; a linking mutation; a linked insertion mutation; an inverted duplication mutation; a tandem duplication; an intrachromosomal tandem duplication; a translocation; a chromosomal translocation, a non-reciprocal translocation; a rearrangement; a genomic rearrangement; a rearrangement of one or more introns, or a fragment thereof; a rearranged intron; a 5'- or a 3'- UTR, or a combination thereof.

74. The method of claim 65, wherein the subgenomic interval comprises an altered nucleotide sequence, encodes an altered amino acid sequence, a chromosomal translocation, an intra-chromosomal inversion, a change in copy number, a change in expression level, a change in protein level, a change in protein activity, or a change in methylation status, in a cancer tissue or cancer cell, as compared to a normal, healthy tissue or cell.

75. The method of claim 65, wherein the tumor sample comprises: one or more premalignant or malignant cells; cells from a solid tumor, a soft tissue tumor or a metastatic lesion; tissue or cells from a surgical margin; a histologically normal tissue; one or more circulating tumor cells (CTCs); a normal adjacent tissue (NAT); a blood sample from a subject having or at risk of having the tumor; or an FFPE-sample.

76. The method of claim 75, wherein the tumor sample comprises the FFPE-sample.

77. The method of claim 75, wherein the tumor sample comprises one or more CTCs.

78. The method of claim 65, wherein the different types of oligonucleotide baits are chosen from one or more non-naturally occurring DNA oligonucleotides, or one or more non-naturally occurring RNA oligonucleotides, or a combination thereof.

79. The method of claim 65, wherein the non-naturally occurring DNA or RNA oligonucleotides are chosen from one or more of: a locked nucleic acid (LNA); a peptide nucleic acid (PNA); a DNA or RNA oligonucleotide modified to capture low GC regions; a bicyclic nucleic acid (BNA); a crosslinked oligonucleotide; a modified 5-methyl deoxycytidine; or 2,6-diaminopurine.

80. The method of claim 65, wherein the tumor member comprises a sequence from a subject and a sequence not derived from the subject.

81. The method of claim 80, wherein the tumor member comprises an adapter sequence, a primer sequence, or other sequences that allow for identification.

82. The method of claim 81, wherein the tumor member comprises a barcode sequence.

83. The method of claim 65, wherein the method comprises sequencing a subgenomic interval chosen from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or all of the following: A) at least five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty or more subgenomic intervals from a mutated or wild-type gene or gene product chosen from at least five or more of: ABL1, AKT1, AKT2, AKT3, ALK, APC, AR, BRAF, CCND1, CDK4, CDKN2A, CEBPA, CTNNB1, EGFR, ERBB2, ESR1, FGFR1, FGFR2, FGFR3, FLT3, HRAS, JAK2, KIT, KRAS, MAP2K1, MAP2K2, MET, MLL, MYC, NF1, NOTCH1, NPM1, NRAS, NTRK3, PDGFRA, PIK3CA, PIK3CG, PIK3R1, PTCH1, PTCH2, PTEN, RB1, RET, SMO, STK11, SUFU, or TP53; B) at least five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty, thirty-five, forty, forty-five, fifty, fifty-five, sixty, sixty-five, seventy, seventy-five, eighty, eighty-five, ninety, ninety-five, one hundred, one hundred and five, one hundred and ten, one hundred and fifteen, one hundred and twenty or more of subgenomic intervals from a mutated or wild type gene or gene product chosen from at least five or more of: ABL2, ARAF, ARFRP1, ARID1A, ATM, ATR, AURKA, AURKB, BAP1, BCL2, BCL2A1, BCL2L1, BCL2L2, BCL6, BRCA1, BRCA2, CBL, CARD11, CBL, CCND2, CCND3, CCNE1, CD79A, CD79B, CDH1, CDH2, CDH20, CDHS, CDK6, CDK8, CDKN2B, CDKN2C, CHEK1, CHEK2, CRKL, CRLF2, DNMT3A, DOT1L, EPHA3, EPHAS, EPHA6, EPHA7, EPHB1, EPHB4, EPHB6, ERBB3, ERBB4, ERG, ETV1, ETV4, ETV5, ETV6, EWSR1, EZH2, FANCA, FBXW7, FGFR4, FLT1, FLT4, FOXP4, GATA1, GNA11, GNAQ, GNAS, GPR124, GUCY1A2, HOXA3,HSP90AA1, IDH1, IDH2, IGF1R, IGF2R, IKBKE, IKZF1, INHBA, IRS2, JAK1, JAK3, JUN, KDM6A, KDR, LRP1B, LRP6, LTK, MAP2K4, MCL1, MDM2, MDM4, MEN1, MITF, MLH1, MPL, MRE11A, MSH2, MSH6, MTOR, MUTYH, MYCL1, MYCN, NF2, NKX2-1, NTRK1, NTRK2, PAK3, PAX5, PDGFRB, PKHD1, PLCG1, PRKDC, PTPN11, PTPRD, RAF1, RARA, RICTOR, RPTOR, RUNX1, SMAD2, SMAD3, SMAD4, SMARCA4, SMARCB1, SOX10, SOX2, SRC, TBX22, TET2, TGFBR2, TMPRSS2, TNFAIP3, TNK, TNKS2, TOP1, TSC1, TSC2, USP9X, VHL, or WT1; C) at least five, six, seven, eight, nine, ten, fifteen, twenty, or more subgenomic intervals from a gene or gene product according to Table 1, 1A, 2, 3, or 4; D) at least five, six, seven, eight, nine, ten, fifteen, twenty, or more subgenomic intervals from a gene or gene product chosen from one or more of: ABL1, AKT1, ALK, AR, BRAF, BRCA1, BRCA2, CEBPA, EGFR, ERBB2, FLT3, JAK2, KIT, KRAS, MET, NPM1, PDGFRA, PIK3CA, RARA, AKT2, AKT3, MAP2K4, NOTCH1, and TP53; E) at least five, six, seven, eight, nine, ten, or more subgenomic intervals including a mutated or a wild type codon chosen from one or more of: codon 315 of the ABL1 gene; codon 1114, 1338, 1450 or 1556 of APC; codon 600 of BRAF; codon 32, 33, 34, 37, 41 or 45 of CTNNB1; codon 719, 746-750, 768, 790, 858 or 861 of EGFR; codon 835 of FLT3; codon 12, 13, or 61 of HRAS; codon 617 of JAK2; codon 816 of KIT; codon 12, 13, or 61 of KRAS; codon 88, 542, 545, 546, 1047, or 1049 of PIK3CA; codon 130, 173, 233, or 267 of PTEN; codon 918 of RET; or codon 175, 245, 248, 273, or 306 of TP53; F) at least five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty, or more of subgenomic intervals from a mutated or wild type gene or gene product chosen from: ABCB1, BCC2, ABCC4, ABCG2, C1orf144, CYP1B1, CYP2C19, CYP2C8, CYP2D6, CYP3A4, CYP3A5, DPYD, ERCC2, ESR2, FCGR3A, GSTP1, ITPA, LRP2, MAN1B1, MTHFR, NQO1, NRP2, SLC19A1, SLC22A2, SLCO1B3, SOD2, SULT1A1, TPMT, TYMS, UGT1A1, or UMPS; G) at least five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty, or more of subgenomic intervals from a mutated or wild type PGx gene or gene product associated with one or more of: (i) better survival of a cancer patient treated with a drug; (ii) paclitaxel metabolism; (iii) toxicity to a drug; or (iv) a side effect to a drug; H) a translocation alteration of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 110 or more genes or gene products according to Table 3; I) a translocation alteration of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 110 or more genes or gene products according to Table 3 in a solid tumor sample from the cancer types specified therein; J) a translocation alteration of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200 or more genes or gene products according to Table 4; K) a translocation alteration of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200 or more genes or gene products according to Table 4 in a heme tumor sample from the cancer types specified therein; L) at least five genes or gene products selected from the genes in any of Table 1, 1A, 2, 3, or 4, wherein an allelic variation is associated with a preselected type of tumor and wherein said allelic variation is present in less than 5% of the cells in said tumor type; M) at least five genes or gene products selected from the genes in any of Table 1, 1A, 2, 3, or 4, which are embedded in a GC-rich region; or N) at least five genes or gene products indicative of a genetic factor for developing cancer chosen from one or more of BRCA1, BRCA2, EGFR, HRAS, KIT, MPL, ALK, PTEN, RET, APC, CDKN2A, MLH1, MSH2, MSH6, NF1, NF2, RB1, TP53, VHL, or WT1.

84. The method of claim 65, wherein the method comprises sequencing a subgenomic interval from at least twenty, twenty-five, thirty or more genes or gene products from the sample, wherein the genes or gene products are chosen from: ABL1, AKT1, AKT2, AKT3, ALK, APC, AR, BRAF, CCND1, CDK4, CDKN2A, CEBPA, CTNNB1, EGFR, ERBB2, ESR1, FGFR1, FGFR2, FGFR3, FLT3, HRAS, JAK2, KIT, KRAS, MAP2K1, MAP2K2, MET, MLL, MYC, NF1, NOTCH1, NPM1, NRAS, NTRK3, PDGFRA, PIK3CA, PIK3CG, PIK3R1, PTCH1, PTCH2, PTEN, RB1, RET, SMO, STK11, SUFU, or TP53.

85. The method of claim 65, wherein the method comprises sequencing a subgenomic interval comprising one or more codons chosen from: codon 315 of the ABL1 gene; codon 1114, 1338, 1450 or 1556 of APC; codon 600 of BRAF; codon 32, 33, 34, 37, 41 or 45 of CTNNB1; codon 719, 746-750, 768, 790, 858 or 861 of EGFR; codon 835 of FLT3; codon 12, 13, or 61 of HRAS; codon 617 of JAK2; codon 816 of KIT; codon 12, 13, or 61 of KRAS; codon 88, 542, 545, 546, 1047, or 1049 of PIK3CA; codon 130, 173, 233, or 267 of PTEN; codon 918 of RET; or codon 175, 245, 248, 273, or 306 of TP53.

Details for Patent 9,340,830

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Schering INTRON A interferon alfa-2b VIAL 103132 001 1986-06-04   Start Trial FOUNDATION MEDICINE, INC. (Cambridge, MA) 2030-12-30 RX search
Schering INTRON A interferon alfa-2b VIAL 103132 002 1986-06-04   Start Trial FOUNDATION MEDICINE, INC. (Cambridge, MA) 2030-12-30 RX search
Schering INTRON A interferon alfa-2b VIAL 103132 003 1986-06-04   Start Trial FOUNDATION MEDICINE, INC. (Cambridge, MA) 2030-12-30 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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