Reveal® is a registered service mark of Laboratory Corporation of America® Holdings. ©2015 Laboratory Corporation of America® Holdings. All rights reserved.

onc-537-v4-0915L14730-0915-4

www.integratedoncology.com

Hematologic MalignanciesREVEALING ANSWERS

SNP Microarray

®

Reveal® Detects Abnormalities Unidentified by Classic Cytogenetic Studies

Approximately 70% of MM patients have a normal karyotype and only 80% of MM patients have genetic alteration detected by FISH.

Reveal has been shown to detect abnormalities in 50% of cases with normal cytogenetics and/or FISH.

Reveal has also been shown to detect additional abnormalities in 87% of cases with abnormal cytogenetics and/or FISH. Each case either had additional abnormalities detected or the abnormalities were better-defined.*

The detection of additional abnormalities in multiple myeloma may provide supporting prognostic information when determining frequency of patient surveillance, aggressive treatment regimens, or explanations for contradictory patient outcomes.

Utilization of Reveal will allow for the detection of two diseases by the analysis of both the CD138 enriched fraction and the CD138 negative fraction.

Frequently Detected Genetic Abnormalities in Multiple Myeloma

MULTIPLE MYELOMA (MM)

Abnormality Description % MM Cases Detected by SNP Array

Clinical Association

Acquired Copy- Neutral Loss of Heterozygosity

Copy-neutral loss of heterozygosity; suggests homozygous mutation of tumor suppressor gene

22%* Yes Unfavorable risk (for some genes)10-12

Chromothripsis Massive genomic rearrangements 14.6%* Yes Unfavorable risk13

IgH Translocations† t(11;14) 15% No Standard risk10,14,15

t(14:16) 5-7% No Unfavorable risk10,14,15

t(4;14) 15% No Unfavorable risk10,14,15

Homozygous Deletions of Tumor Suppressor Genes

Homozygous loss of specific tumor suppressor genes

7%* Yes Unfavorable risk (for some genes)10-12

Hyperdiploidy Typically involves gains of 3, 5, 7, 9, 11, 15, 18, 19 and/or 21IGH translocation seen 10% of time in hyperdiploid cases

50-60% Yes Standard risk14, 15

Higher incidence of bone disease14

Hypodiploid, pseudodiploid and structural aberrations

Could involve gain or loss of sub-chromosomal materialAmplification of 1q, 6pLoss of 1p, 6q, 8p, 12p, 14q, 16p, 16q, and/or 20p

50% Yes Unfavorable risk16

Secondary Events (individual abnormalities)

Monosomy 13 50% Yes Unfavorable risk when paired with t(4;14)14

Deletion 17p 10% Yes Unfavorable risk14,15

1p loss and 1q gain 40% new70% relapse

Yes Unfavorable risk14,15

12p deletions 12% Yes Unfavorable risk14

16q deletions 20% Yes Unfavorable risk10

MYC amplification 45% of patients with advanced MM

Yes Unfavorable risk14

*Data sourced from studies performed at LabCorp’s Center for Molecular Biology and Pathology†FISH required to detect translocation

SPECIMEN REQUIREMENTS FOR MDS, CLL, ALL, AML, OTHERSSpecimen: Whole blood or bone marrow

Volume: 4 mL whole blood or 2 mL bone marrow

Minimum Volume: 2 mL whole blood or 1 mL bone marrow for array only (Note: This volume does not allow for repeat testing.)

Container: Green-top (heparin) tube (preferred); yellow-top (ACD) tube, or lavender-top (EDTA) tube

SPECIMEN REQUIREMENTS FOR MM* Specimen: Bone marrow

Volume: 2 mL

Minimum Volume: 1 mL (Note: This volume does not allow for repeat testing.)

Container: Green-top (heparin) tube (preferred); yellow-top (ACD) tube, or lavender-top (EDTA) tube

If MM FISH is also requested, please provide 1-3 mL bone marrow in green-top (heparin) tube.

*Multiple myeloma specimens will be CD-138 plasma cell enriched.

Turnaround Time: 10-14 days

References 1. Lehmann S, Ogawa S, Raynaud SD, et al. Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia. Cancer 2008 Mar 15; 112(6):1296-1305. 2. O’Keefe C, McDevitt MA, Maciejewski JP. Copy neutral loss of heterozygosity: A novel chromosomal lesion in myeloid malignancies. Blood 2010 Apr 8; 115(14):2731-2739. 3. Heinrichs S, Kulkarni RV, Bueso-Ramos CE, et al. Accurate detection of uniparental disomy and microdeletions by SNP array analysis in myelodysplastic syndromes

with normal cytogenetics. Leukemia 2009 Sep; 23(9):1605-1613. 4. Parkin B, Erba H, Ouillette P, et al., Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood 2010 Dec 2; 116(23):4958-67. 5. Tiu RV, Condek LP, O’Keefe CL, et al., Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 2011;

117:4552–4560. 6. Hagenkord JM, Monzon FA, Kash SF, Lilleberg S, Xie Q, Kant JA. Array-Based Karyotyping for Prognostic Assessment in Chronic Lymphocytic Leukemia: Performance

Comparison of Affymetrix 10K2.0, 250K Nsp, and SNP6.0 Arrays. J Mol Diagn 2010 Mar; 12(2):184-196. 7. Haase D, Germing U, Schanz J, et al., New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core

dataset of 2124 patients. Blood. 2007 110:4385-4395. 8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes V.2.2011. http://www.nccn.org. Published

November 15, 2010. Accessed June 10, 2011. 9. Ouillette P, Collins R, Shakhan S, et al. The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia. Clinical Cancer Research

2011 Nov 1; 17(21):6778-90. 10. Aldaz CM, Ferguson BW, Abba MC. WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies. Biochim Biophys Acta

2014 Jun 14; 1846(1):188-200. 11. Dickens NJ, Walker BA, Leone PE, et al., Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to

pathogenesis and outcome. Clin Cancer Res 2010 Mar 15; 16(6):1856-64. 12. Leone PE, Walker BA, Jenner MW, et al., Deletions of CDKN2C in multiple myeloma: biological and clinical implications. Clin Cancer Res. 2008 Oct 1; 14(19):6033-41. 13. Magrangeas F, Avet-Loiseau H, Munshi NC, Minvielle S. Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients.

Blood 2011 Jul 21; 118(3):675-8. 14. Fonseca R, Bergsagel PL, Drach J, et al., International Myeloma Working Group. International Myeloma Working Group molecular classification of multiple

myeloma: spotlight review. Leukemia 2009 Dec; 23(12):2210-21. 15. Sawyer JR. The prognostic significance of cytogenetics and molecular profiling in multiple myeloma. Cancer Genet 2011 Jan; 204(1):3-12. 16. Trcic RL, Skelin IK, Sustercic D, et al., Cytogenetics of multiple myeloma. Coll Antropol 2010 Mar; 34(1):41-4.’ ’

Reveal SNP Microarray Identifies Abnormalities in CLL

Comparative studies of >450 cases tested by both FISH and Reveal SNP Microarray performed at LabCorp’s Center for Molecular Biology and Pathology showed that Reveal SNP Microarray increased detection of chromosomal abnormalities compared to FISH.*

Approximately 30% of FISH-normal CLL patients had an abnormality detected by Reveal SNP Microarray.*

Approximately 45% of patients with a 13q deletion had a deletion of the Rb1 tumor-suppressor gene.* Deletions of the Rb1 gene may be associated with a more adverse prognosis.9

51% of CLL patients with an abnormality by FISH had additional abnormalities detected by the Reveal SNP Microarray.*

Reveal SNP Microarray is a Useful Prognostic Tool for Evaluating CLL

Studies have investigated the significance of acquired copy number changes (aCN) in both untreated and relapsed patients.

Two or more aCN were shown to be present in 39% of all cases (34% untreated, 56% relapsed).4

The detection of ≥2 aCN showed to be predictive of shortened time to first treatment (TTFT) and overall survival (OS).4

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND ACUTE LYMPHOCYTIC LEUKEMIA (ALL)

Reveal SNP Microarray Can Aid in the Diagnosis of MDS

Chromosomal abnormalities are shown to be detected by cytogenetics in ~50% of MDS.7

In a study of 430 patients, the SNP array in combination with cytogenetics was shown to detect abnormalities in 74% of cases, as compared to 44% by cytogenetics alone.5

Reveal SNP Microarray has been shown to provide additional diagnostic and prognostic information for MDS patients with normal chromosomes.5 According to LabCorp’s internal data:

If morphological studies were positive for dysplasia or MDS/MPN (n=342), the array analysis detected abnormalities in 62.5% of the patients.

If morphological diagnosis was negative or equivocal for dysplasia (n=347), the array analysis detected abnormalities in 38.0% of patients.

Identification of Additional Chromosomal Alterations has Prognostic Impact in MDS

Results of metaphase cytogenetic analysis are an important component of the International Prognostic Scoring System (IPSS).8

A recent study has shown that additional information provided from assays like Reveal SNP Microarray can impact prognostic classification of MDS patients.5

Prognostic Groups Based on MC and SNP

Prognostic Group

Points MC New Lesions by

SNP-A?

n Median OS, mo

Median EFS, mo

Favorable 0 Good No 129 47 30.4

Intermediate-1 1 Good Intermediate

Yes No

166 18.6 15.2

Intermediate-2 2 Intermediate Poor

Yes No

55 11.7 10

Unfavorable 3 Poor Yes 46 4.2 3.4

This research was originally published in Blood. Tiu, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 2011; 117:4552–4560.

MYELODYSPLASTIC SYNDROMES (MDS) AND ACUTE MYELOID LEUKEMIA (AML)

MC = Metaphase Cytogenetics, EFS = Event-Free Survival, OS = Overall Survival

P* < .0001P* < .0001

REVEAL® SNP MICROARRAY

Reveal® SNP Microarray is a genome-wide array that utilizes single nucleotide polymorphism (SNP) and non-polymorphic probes for high-resolution analysis in the detection of chromosomal copy-number variations (CNV) and copy-neutral loss of heterozygosity (CN-LOH).

Myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML), and acute lymphocytic leukemia (ALL) are especially suitable for Reveal SNP Microarray analysis because of the high incidence of dosage-related clonal changes that have been demonstrated to have an impact on patient outcomes.

Comparison of Chromosomal Abnormality Detection Technologies

Detection of Copy Neutral Loss of Heterozygosity (CN-LOH)

Classic Cytogenetics

Fluorescence In Situ Hybridization (FISH)

Whole Genome SNP Microarray

Normal Karyotype

+ Whole-genome perspective- Low resolution limits detection

of alterations- Requires mitotic activity to

detect clonal abnormalities- Does not detect CN-LOH

11q23 (MLL)

+ Can be used to detect disease-specific translocations

- Only detects targeted genes or regions

- Does not detect CN-LOH

SNP Microarray Virtual Karyotype

+ Whole-genome perspective+ High resolution; can detect small

changes+ Can detect CN-LOH+ Does not require dividing cells- Does not detect balanced

translocations

*

A D

Mitosis LOH: Mitoticrecombination leading touniparentaldisomy (UPD)

**

B

C

* * *

**

** **

** **

If cell homozygous for mutantallele has growth advantage, this leads to clonal expansion and clonal dominance

Mariluz P. Mojica-Henshaw, MD, PhD, and Josef T. Prchal, MD. Uniparental Disomy in Polycythemia Vera and Other Malignancies. The Hematologist, January 1, 2007

CN-LOH is the loss of heterozygosity without the loss of copy number.

CN-LOH has been reported in MDS, CLL, MM, AML, and ALL, involving a variety of chromosomes, including chromosomes 4, 7, 9, 11, 13, 14, and 17.1-5

CN-LOH is detected by Reveal SNP Microarray but is not detectable by standard cytogenetics karyotypes or array comparative genomic hybridization (aCGH).5,6

This research was originally published in Blood. Ouillette P, et al. Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood 2011; 118:3051-3061.

*Data sourced from studies performed at LabCorp’s Center for Molecular Biology and Pathology

Reveal SNP Array May Add Additional Prognostic Information in AML

Detects abnormalities in 62% of patients with normal cytogenetics and detects additional abnormalities in 70% of patients with abnormal cytogenetics*

Detects numerous small deletions and some cryptic rearrangements (CUX1, NF1, ETV6) not detected by standard cytogenetics

*Data sourced from studies performed at LabCorp’s Center for Molecular Biology and Pathology

Reveal SNP Array May Add Additional Prognostic Information in ALL

Detects abnormalities in 83% of patients with normal cytogenetics and detects additional abnormalities in patients with abnormal cytogenetics*

Detects RUNX1 amplification, IKZF deletions, hypodiploid doubling, and some cryptic rearrangements

Reveal SNP Microarray Identifies Abnormalities in CLL

Comparative studies of >450 cases tested by both FISH and Reveal SNP Microarray performed at LabCorp’s Center for Molecular Biology and Pathology showed that Reveal SNP Microarray increased detection of chromosomal abnormalities compared to FISH.*

Approximately 30% of FISH-normal CLL patients had an abnormality detected by Reveal SNP Microarray.*

Approximately 45% of patients with a 13q deletion had a deletion of the Rb1 tumor-suppressor gene.* Deletions of the Rb1 gene may be associated with a more adverse prognosis.9

51% of CLL patients with an abnormality by FISH had additional abnormalities detected by the Reveal SNP Microarray.*

Reveal SNP Microarray is a Useful Prognostic Tool for Evaluating CLL

Studies have investigated the significance of acquired copy number changes (aCN) in both untreated and relapsed patients.

Two or more aCN were shown to be present in 39% of all cases (34% untreated, 56% relapsed).4

The detection of ≥2 aCN showed to be predictive of shortened time to first treatment (TTFT) and overall survival (OS).4

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND ACUTE LYMPHOCYTIC LEUKEMIA (ALL)

Reveal SNP Microarray Can Aid in the Diagnosis of MDS

Chromosomal abnormalities are shown to be detected by cytogenetics in ~50% of MDS.7

In a study of 430 patients, the SNP array in combination with cytogenetics was shown to detect abnormalities in 74% of cases, as compared to 44% by cytogenetics alone.5

Reveal SNP Microarray has been shown to provide additional diagnostic and prognostic information for MDS patients with normal chromosomes.5 According to LabCorp’s internal data:

If morphological studies were positive for dysplasia or MDS/MPN (n=342), the array analysis detected abnormalities in 62.5% of the patients.

If morphological diagnosis was negative or equivocal for dysplasia (n=347), the array analysis detected abnormalities in 38.0% of patients.

Identification of Additional Chromosomal Alterations has Prognostic Impact in MDS

Results of metaphase cytogenetic analysis are an important component of the International Prognostic Scoring System (IPSS).8

A recent study has shown that additional information provided from assays like Reveal SNP Microarray can impact prognostic classification of MDS patients.5

Prognostic Groups Based on MC and SNP

Prognostic Group

Points MC New Lesions by

SNP-A?

n Median OS, mo

Median EFS, mo

Favorable 0 Good No 129 47 30.4

Intermediate-1 1 Good Intermediate

Yes No

166 18.6 15.2

Intermediate-2 2 Intermediate Poor

Yes No

55 11.7 10

Unfavorable 3 Poor Yes 46 4.2 3.4

This research was originally published in Blood. Tiu, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 2011; 117:4552–4560.

MYELODYSPLASTIC SYNDROMES (MDS) AND ACUTE MYELOID LEUKEMIA (AML)

MC = Metaphase Cytogenetics, EFS = Event-Free Survival, OS = Overall Survival

P* < .0001P* < .0001

REVEAL® SNP MICROARRAY

Reveal® SNP Microarray is a genome-wide array that utilizes single nucleotide polymorphism (SNP) and non-polymorphic probes for high-resolution analysis in the detection of chromosomal copy-number variations (CNV) and copy-neutral loss of heterozygosity (CN-LOH).

Myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML), and acute lymphocytic leukemia (ALL) are especially suitable for Reveal SNP Microarray analysis because of the high incidence of dosage-related clonal changes that have been demonstrated to have an impact on patient outcomes.

Comparison of Chromosomal Abnormality Detection Technologies

Detection of Copy Neutral Loss of Heterozygosity (CN-LOH)

Classic Cytogenetics

Fluorescence In Situ Hybridization (FISH)

Whole Genome SNP Microarray

Normal Karyotype

+ Whole-genome perspective- Low resolution limits detection

of alterations- Requires mitotic activity to

detect clonal abnormalities- Does not detect CN-LOH

11q23 (MLL)

+ Can be used to detect disease-specific translocations

- Only detects targeted genes or regions

- Does not detect CN-LOH

SNP Microarray Virtual Karyotype

+ Whole-genome perspective+ High resolution; can detect small

changes+ Can detect CN-LOH+ Does not require dividing cells- Does not detect balanced

translocations

*

A D

Mitosis LOH: Mitoticrecombination leading touniparentaldisomy (UPD)

**

B

C

* * *

**

** **

** **

If cell homozygous for mutantallele has growth advantage, this leads to clonal expansion and clonal dominance

Mariluz P. Mojica-Henshaw, MD, PhD, and Josef T. Prchal, MD. Uniparental Disomy in Polycythemia Vera and Other Malignancies. The Hematologist, January 1, 2007

CN-LOH is the loss of heterozygosity without the loss of copy number.

CN-LOH has been reported in MDS, CLL, MM, AML, and ALL, involving a variety of chromosomes, including chromosomes 4, 7, 9, 11, 13, 14, and 17.1-5

CN-LOH is detected by Reveal SNP Microarray but is not detectable by standard cytogenetics karyotypes or array comparative genomic hybridization (aCGH).5,6

This research was originally published in Blood. Ouillette P, et al. Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood 2011; 118:3051-3061.

*Data sourced from studies performed at LabCorp’s Center for Molecular Biology and Pathology

Reveal SNP Array May Add Additional Prognostic Information in AML

Detects abnormalities in 62% of patients with normal cytogenetics and detects additional abnormalities in 70% of patients with abnormal cytogenetics*

Detects numerous small deletions and some cryptic rearrangements (CUX1, NF1, ETV6) not detected by standard cytogenetics

*Data sourced from studies performed at LabCorp’s Center for Molecular Biology and Pathology

Reveal SNP Array May Add Additional Prognostic Information in ALL

Detects abnormalities in 83% of patients with normal cytogenetics and detects additional abnormalities in patients with abnormal cytogenetics*

Detects RUNX1 amplification, IKZF deletions, hypodiploid doubling, and some cryptic rearrangements

Reveal SNP Microarray Identifies Abnormalities in CLL

Comparative studies of >450 cases tested by both FISH and Reveal SNP Microarray performed at LabCorp’s Center for Molecular Biology and Pathology showed that Reveal SNP Microarray increased detection of chromosomal abnormalities compared to FISH.*

Approximately 30% of FISH-normal CLL patients had an abnormality detected by Reveal SNP Microarray.*

Approximately 45% of patients with a 13q deletion had a deletion of the Rb1 tumor-suppressor gene.* Deletions of the Rb1 gene may be associated with a more adverse prognosis.9

51% of CLL patients with an abnormality by FISH had additional abnormalities detected by the Reveal SNP Microarray.*

Reveal SNP Microarray is a Useful Prognostic Tool for Evaluating CLL

Studies have investigated the significance of acquired copy number changes (aCN) in both untreated and relapsed patients.

Two or more aCN were shown to be present in 39% of all cases (34% untreated, 56% relapsed).4

The detection of ≥2 aCN showed to be predictive of shortened time to first treatment (TTFT) and overall survival (OS).4

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND ACUTE LYMPHOCYTIC LEUKEMIA (ALL)

Reveal SNP Microarray Can Aid in the Diagnosis of MDS

Chromosomal abnormalities are shown to be detected by cytogenetics in ~50% of MDS.7

In a study of 430 patients, the SNP array in combination with cytogenetics was shown to detect abnormalities in 74% of cases, as compared to 44% by cytogenetics alone.5

Reveal SNP Microarray has been shown to provide additional diagnostic and prognostic information for MDS patients with normal chromosomes.5 According to LabCorp’s internal data:

If morphological studies were positive for dysplasia or MDS/MPN (n=342), the array analysis detected abnormalities in 62.5% of the patients.

If morphological diagnosis was negative or equivocal for dysplasia (n=347), the array analysis detected abnormalities in 38.0% of patients.

Identification of Additional Chromosomal Alterations has Prognostic Impact in MDS

Results of metaphase cytogenetic analysis are an important component of the International Prognostic Scoring System (IPSS).8

A recent study has shown that additional information provided from assays like Reveal SNP Microarray can impact prognostic classification of MDS patients.5

Prognostic Groups Based on MC and SNP

Prognostic Group

Points MC New Lesions by

SNP-A?

n Median OS, mo

Median EFS, mo

Favorable 0 Good No 129 47 30.4

Intermediate-1 1 Good Intermediate

Yes No

166 18.6 15.2

Intermediate-2 2 Intermediate Poor

Yes No

55 11.7 10

Unfavorable 3 Poor Yes 46 4.2 3.4

This research was originally published in Blood. Tiu, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 2011; 117:4552–4560.

MYELODYSPLASTIC SYNDROMES (MDS) AND ACUTE MYELOID LEUKEMIA (AML)

MC = Metaphase Cytogenetics, EFS = Event-Free Survival, OS = Overall Survival

P* < .0001P* < .0001

REVEAL® SNP MICROARRAY

Reveal® SNP Microarray is a genome-wide array that utilizes single nucleotide polymorphism (SNP) and non-polymorphic probes for high-resolution analysis in the detection of chromosomal copy-number variations (CNV) and copy-neutral loss of heterozygosity (CN-LOH).

Myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML), and acute lymphocytic leukemia (ALL) are especially suitable for Reveal SNP Microarray analysis because of the high incidence of dosage-related clonal changes that have been demonstrated to have an impact on patient outcomes.

Comparison of Chromosomal Abnormality Detection Technologies

Detection of Copy Neutral Loss of Heterozygosity (CN-LOH)

Classic Cytogenetics

Fluorescence In Situ Hybridization (FISH)

Whole Genome SNP Microarray

Normal Karyotype

+ Whole-genome perspective- Low resolution limits detection

of alterations- Requires mitotic activity to

detect clonal abnormalities- Does not detect CN-LOH

11q23 (MLL)

+ Can be used to detect disease-specific translocations

- Only detects targeted genes or regions

- Does not detect CN-LOH

SNP Microarray Virtual Karyotype

+ Whole-genome perspective+ High resolution; can detect small

changes+ Can detect CN-LOH+ Does not require dividing cells- Does not detect balanced

translocations

*

A D

Mitosis LOH: Mitoticrecombination leading touniparentaldisomy (UPD)

**

B

C

* * *

**

** **

** **

If cell homozygous for mutantallele has growth advantage, this leads to clonal expansion and clonal dominance

Mariluz P. Mojica-Henshaw, MD, PhD, and Josef T. Prchal, MD. Uniparental Disomy in Polycythemia Vera and Other Malignancies. The Hematologist, January 1, 2007

CN-LOH is the loss of heterozygosity without the loss of copy number.

CN-LOH has been reported in MDS, CLL, MM, AML, and ALL, involving a variety of chromosomes, including chromosomes 4, 7, 9, 11, 13, 14, and 17.1-5

CN-LOH is detected by Reveal SNP Microarray but is not detectable by standard cytogenetics karyotypes or array comparative genomic hybridization (aCGH).5,6

This research was originally published in Blood. Ouillette P, et al. Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood 2011; 118:3051-3061.

*Data sourced from studies performed at LabCorp’s Center for Molecular Biology and Pathology

Reveal SNP Array May Add Additional Prognostic Information in AML

Detects abnormalities in 62% of patients with normal cytogenetics and detects additional abnormalities in 70% of patients with abnormal cytogenetics*

Detects numerous small deletions and some cryptic rearrangements (CUX1, NF1, ETV6) not detected by standard cytogenetics

*Data sourced from studies performed at LabCorp’s Center for Molecular Biology and Pathology

Reveal SNP Array May Add Additional Prognostic Information in ALL

Detects abnormalities in 83% of patients with normal cytogenetics and detects additional abnormalities in patients with abnormal cytogenetics*

Detects RUNX1 amplification, IKZF deletions, hypodiploid doubling, and some cryptic rearrangements

Reveal® is a registered service mark of Laboratory Corporation of America® Holdings. ©2015 Laboratory Corporation of America® Holdings. All rights reserved.

onc-537-v4-0915L14730-0915-4

www.integratedoncology.com

Hematologic MalignanciesREVEALING ANSWERS

SNP Microarray

®

Reveal® Detects Abnormalities Unidentified by Classic Cytogenetic Studies

Approximately 70% of MM patients have a normal karyotype and only 80% of MM patients have genetic alteration detected by FISH.

Reveal has been shown to detect abnormalities in 50% of cases with normal cytogenetics and/or FISH.

Reveal has also been shown to detect additional abnormalities in 87% of cases with abnormal cytogenetics and/or FISH. Each case either had additional abnormalities detected or the abnormalities were better-defined.*

The detection of additional abnormalities in multiple myeloma may provide supporting prognostic information when determining frequency of patient surveillance, aggressive treatment regimens, or explanations for contradictory patient outcomes.

Utilization of Reveal will allow for the detection of two diseases by the analysis of both the CD138 enriched fraction and the CD138 negative fraction.

Frequently Detected Genetic Abnormalities in Multiple Myeloma

MULTIPLE MYELOMA (MM)

Abnormality Description % MM Cases Detected by SNP Array

Clinical Association

Acquired Copy- Neutral Loss of Heterozygosity

Copy-neutral loss of heterozygosity; suggests homozygous mutation of tumor suppressor gene

22%* Yes Unfavorable risk (for some genes)10-12

Chromothripsis Massive genomic rearrangements 14.6%* Yes Unfavorable risk13

IgH Translocations† t(11;14) 15% No Standard risk10,14,15

t(14:16) 5-7% No Unfavorable risk10,14,15

t(4;14) 15% No Unfavorable risk10,14,15

Homozygous Deletions of Tumor Suppressor Genes

Homozygous loss of specific tumor suppressor genes

7%* Yes Unfavorable risk (for some genes)10-12

Hyperdiploidy Typically involves gains of 3, 5, 7, 9, 11, 15, 18, 19 and/or 21IGH translocation seen 10% of time in hyperdiploid cases

50-60% Yes Standard risk14, 15

Higher incidence of bone disease14

Hypodiploid, pseudodiploid and structural aberrations

Could involve gain or loss of sub-chromosomal materialAmplification of 1q, 6pLoss of 1p, 6q, 8p, 12p, 14q, 16p, 16q, and/or 20p

50% Yes Unfavorable risk16

Secondary Events (individual abnormalities)

Monosomy 13 50% Yes Unfavorable risk when paired with t(4;14)14

Deletion 17p 10% Yes Unfavorable risk14,15

1p loss and 1q gain 40% new70% relapse

Yes Unfavorable risk14,15

12p deletions 12% Yes Unfavorable risk14

16q deletions 20% Yes Unfavorable risk10

MYC amplification 45% of patients with advanced MM

Yes Unfavorable risk14

*Data sourced from studies performed at LabCorp’s Center for Molecular Biology and Pathology†FISH required to detect translocation

SPECIMEN REQUIREMENTS FOR MDS, CLL, ALL, AML, OTHERSSpecimen: Whole blood or bone marrow

Volume: 4 mL whole blood or 2 mL bone marrow

Minimum Volume: 2 mL whole blood or 1 mL bone marrow for array only (Note: This volume does not allow for repeat testing.)

Container: Green-top (heparin) tube (preferred); yellow-top (ACD) tube, or lavender-top (EDTA) tube

SPECIMEN REQUIREMENTS FOR MM* Specimen: Bone marrow

Volume: 2 mL

Minimum Volume: 1 mL (Note: This volume does not allow for repeat testing.)

Container: Green-top (heparin) tube (preferred); yellow-top (ACD) tube, or lavender-top (EDTA) tube

If MM FISH is also requested, please provide 1-3 mL bone marrow in green-top (heparin) tube.

*Multiple myeloma specimens will be CD-138 plasma cell enriched.

Turnaround Time: 10-14 days

References 1. Lehmann S, Ogawa S, Raynaud SD, et al. Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia. Cancer 2008 Mar 15; 112(6):1296-1305. 2. O’Keefe C, McDevitt MA, Maciejewski JP. Copy neutral loss of heterozygosity: A novel chromosomal lesion in myeloid malignancies. Blood 2010 Apr 8; 115(14):2731-2739. 3. Heinrichs S, Kulkarni RV, Bueso-Ramos CE, et al. Accurate detection of uniparental disomy and microdeletions by SNP array analysis in myelodysplastic syndromes

with normal cytogenetics. Leukemia 2009 Sep; 23(9):1605-1613. 4. Parkin B, Erba H, Ouillette P, et al., Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood 2010 Dec 2; 116(23):4958-67. 5. Tiu RV, Condek LP, O’Keefe CL, et al., Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 2011;

117:4552–4560. 6. Hagenkord JM, Monzon FA, Kash SF, Lilleberg S, Xie Q, Kant JA. Array-Based Karyotyping for Prognostic Assessment in Chronic Lymphocytic Leukemia: Performance

Comparison of Affymetrix 10K2.0, 250K Nsp, and SNP6.0 Arrays. J Mol Diagn 2010 Mar; 12(2):184-196. 7. Haase D, Germing U, Schanz J, et al., New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core

dataset of 2124 patients. Blood. 2007 110:4385-4395. 8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes V.2.2011. http://www.nccn.org. Published

November 15, 2010. Accessed June 10, 2011. 9. Ouillette P, Collins R, Shakhan S, et al. The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia. Clinical Cancer Research

2011 Nov 1; 17(21):6778-90. 10. Aldaz CM, Ferguson BW, Abba MC. WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies. Biochim Biophys Acta

2014 Jun 14; 1846(1):188-200. 11. Dickens NJ, Walker BA, Leone PE, et al., Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to

pathogenesis and outcome. Clin Cancer Res 2010 Mar 15; 16(6):1856-64. 12. Leone PE, Walker BA, Jenner MW, et al., Deletions of CDKN2C in multiple myeloma: biological and clinical implications. Clin Cancer Res. 2008 Oct 1; 14(19):6033-41. 13. Magrangeas F, Avet-Loiseau H, Munshi NC, Minvielle S. Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients.

Blood 2011 Jul 21; 118(3):675-8. 14. Fonseca R, Bergsagel PL, Drach J, et al., International Myeloma Working Group. International Myeloma Working Group molecular classification of multiple

myeloma: spotlight review. Leukemia 2009 Dec; 23(12):2210-21. 15. Sawyer JR. The prognostic significance of cytogenetics and molecular profiling in multiple myeloma. Cancer Genet 2011 Jan; 204(1):3-12. 16. Trcic RL, Skelin IK, Sustercic D, et al., Cytogenetics of multiple myeloma. Coll Antropol 2010 Mar; 34(1):41-4.’ ’

Reveal® is a registered service mark of Laboratory Corporation of America® Holdings. ©2015 Laboratory Corporation of America® Holdings. All rights reserved.

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www.integratedoncology.com

Hematologic MalignanciesREVEALING ANSWERS

SNP Microarray

®

Reveal® Detects Abnormalities Unidentified by Classic Cytogenetic Studies

Approximately 70% of MM patients have a normal karyotype and only 80% of MM patients have genetic alteration detected by FISH.

Reveal has been shown to detect abnormalities in 50% of cases with normal cytogenetics and/or FISH.

Reveal has also been shown to detect additional abnormalities in 87% of cases with abnormal cytogenetics and/or FISH. Each case either had additional abnormalities detected or the abnormalities were better-defined.*

The detection of additional abnormalities in multiple myeloma may provide supporting prognostic information when determining frequency of patient surveillance, aggressive treatment regimens, or explanations for contradictory patient outcomes.

Utilization of Reveal will allow for the detection of two diseases by the analysis of both the CD138 enriched fraction and the CD138 negative fraction.

Frequently Detected Genetic Abnormalities in Multiple Myeloma

MULTIPLE MYELOMA (MM)

Abnormality Description % MM Cases Detected by SNP Array

Clinical Association

Acquired Copy- Neutral Loss of Heterozygosity

Copy-neutral loss of heterozygosity; suggests homozygous mutation of tumor suppressor gene

22%* Yes Unfavorable risk (for some genes)10-12

Chromothripsis Massive genomic rearrangements 14.6%* Yes Unfavorable risk13

IgH Translocations† t(11;14) 15% No Standard risk10,14,15

t(14:16) 5-7% No Unfavorable risk10,14,15

t(4;14) 15% No Unfavorable risk10,14,15

Homozygous Deletions of Tumor Suppressor Genes

Homozygous loss of specific tumor suppressor genes

7%* Yes Unfavorable risk (for some genes)10-12

Hyperdiploidy Typically involves gains of 3, 5, 7, 9, 11, 15, 18, 19 and/or 21IGH translocation seen 10% of time in hyperdiploid cases

50-60% Yes Standard risk14, 15

Higher incidence of bone disease14

Hypodiploid, pseudodiploid and structural aberrations

Could involve gain or loss of sub-chromosomal materialAmplification of 1q, 6pLoss of 1p, 6q, 8p, 12p, 14q, 16p, 16q, and/or 20p

50% Yes Unfavorable risk16

Secondary Events (individual abnormalities)

Monosomy 13 50% Yes Unfavorable risk when paired with t(4;14)14

Deletion 17p 10% Yes Unfavorable risk14,15

1p loss and 1q gain 40% new70% relapse

Yes Unfavorable risk14,15

12p deletions 12% Yes Unfavorable risk14

16q deletions 20% Yes Unfavorable risk10

MYC amplification 45% of patients with advanced MM

Yes Unfavorable risk14

*Data sourced from studies performed at LabCorp’s Center for Molecular Biology and Pathology†FISH required to detect translocation

SPECIMEN REQUIREMENTS FOR MDS, CLL, ALL, AML, OTHERSSpecimen: Whole blood or bone marrow

Volume: 4 mL whole blood or 2 mL bone marrow

Minimum Volume: 2 mL whole blood or 1 mL bone marrow for array only (Note: This volume does not allow for repeat testing.)

Container: Green-top (heparin) tube (preferred); yellow-top (ACD) tube, or lavender-top (EDTA) tube

SPECIMEN REQUIREMENTS FOR MM* Specimen: Bone marrow

Volume: 2 mL

Minimum Volume: 1 mL (Note: This volume does not allow for repeat testing.)

Container: Green-top (heparin) tube (preferred); yellow-top (ACD) tube, or lavender-top (EDTA) tube

If MM FISH is also requested, please provide 1-3 mL bone marrow in green-top (heparin) tube.

*Multiple myeloma specimens will be CD-138 plasma cell enriched.

Turnaround Time: 10-14 days

References 1. Lehmann S, Ogawa S, Raynaud SD, et al. Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia. Cancer 2008 Mar 15; 112(6):1296-1305. 2. O’Keefe C, McDevitt MA, Maciejewski JP. Copy neutral loss of heterozygosity: A novel chromosomal lesion in myeloid malignancies. Blood 2010 Apr 8; 115(14):2731-2739. 3. Heinrichs S, Kulkarni RV, Bueso-Ramos CE, et al. Accurate detection of uniparental disomy and microdeletions by SNP array analysis in myelodysplastic syndromes

with normal cytogenetics. Leukemia 2009 Sep; 23(9):1605-1613. 4. Parkin B, Erba H, Ouillette P, et al., Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood 2010 Dec 2; 116(23):4958-67. 5. Tiu RV, Condek LP, O’Keefe CL, et al., Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 2011;

117:4552–4560. 6. Hagenkord JM, Monzon FA, Kash SF, Lilleberg S, Xie Q, Kant JA. Array-Based Karyotyping for Prognostic Assessment in Chronic Lymphocytic Leukemia: Performance

Comparison of Affymetrix 10K2.0, 250K Nsp, and SNP6.0 Arrays. J Mol Diagn 2010 Mar; 12(2):184-196. 7. Haase D, Germing U, Schanz J, et al., New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core

dataset of 2124 patients. Blood. 2007 110:4385-4395. 8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes V.2.2011. http://www.nccn.org. Published

November 15, 2010. Accessed June 10, 2011. 9. Ouillette P, Collins R, Shakhan S, et al. The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia. Clinical Cancer Research

2011 Nov 1; 17(21):6778-90. 10. Aldaz CM, Ferguson BW, Abba MC. WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies. Biochim Biophys Acta

2014 Jun 14; 1846(1):188-200. 11. Dickens NJ, Walker BA, Leone PE, et al., Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to

pathogenesis and outcome. Clin Cancer Res 2010 Mar 15; 16(6):1856-64. 12. Leone PE, Walker BA, Jenner MW, et al., Deletions of CDKN2C in multiple myeloma: biological and clinical implications. Clin Cancer Res. 2008 Oct 1; 14(19):6033-41. 13. Magrangeas F, Avet-Loiseau H, Munshi NC, Minvielle S. Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients.

Blood 2011 Jul 21; 118(3):675-8. 14. Fonseca R, Bergsagel PL, Drach J, et al., International Myeloma Working Group. International Myeloma Working Group molecular classification of multiple

myeloma: spotlight review. Leukemia 2009 Dec; 23(12):2210-21. 15. Sawyer JR. The prognostic significance of cytogenetics and molecular profiling in multiple myeloma. Cancer Genet 2011 Jan; 204(1):3-12. 16. Trcic RL, Skelin IK, Sustercic D, et al., Cytogenetics of multiple myeloma. Coll Antropol 2010 Mar; 34(1):41-4.’ ’