Acute Lymphoblastic Leukemia

The TARGET ALL Pilot project has produced comprehensive genomic profiles of nearly 200 high-risk, clinically annotated, B-cell ALL patient cases from Children’s Oncology Group (COG) for molecular alterations. Each fully characterized TARGET ALL case includes data from:

• Primary tumor sample collected at diagnosis
• Case-matched tissue sample extracted at the time of remission

Additional cases with partial molecular characterization and/or sequencing data are available to the research community.

Case Selection Criteria

Tissues and clinical data used for the TARGET ALL Pilot project was obtained from patients enrolled on biology studies and clinical trials managed through the COG, POG 9906 (clinical trial for patients with newly diagnosed ALL between March 2000 and April 2003 that were defined as high-risk for relapse). Patient samples for full characterization were chosen based on the following criteria:

• The disease onset at >9 years of age
• Did not have white blood cell count > 50,000/µL
• Did not express BCR/ABL fusion gene
• Were not known to be hypodiploid (DNA index > 0.95)
• Achieved remission (fewer than 5% blasts) following the standard two rounds of induction therapy

Molecular Characterization

The TARGET ALL project team relied on a variety of platforms to obtain a fully characterized dataset of ~190 relapse-enriched cases. The COG ALL Statistics and Data Center provided clinical annotations and outcome data for all cases. Visit the TARGET Project Experimental Methods page for detailed information and protocols.

In addition to the fully characterized cases outlined above, there are also ALL patient cases with partial datasets available. All data from the Pilot cohort are available as specified in the Using TARGET Data and TARGET Publication Guidelines pages. The TARGET Data Matrix provides an overview of the data generated and described above.

In the expansion effort, TARGET investigators analyzed tumors from pediatric patients, most who experienced an early bone marrow relapse (within 4 years of initial diagnosis), to identify new therapeutic approaches and/or biomarkers that correlate with poor clinical outcome to treat childhood pre-cursor B-cell ALL. The tissues used in this study were collected from patients enrolled in Children's Oncology Group (COG) biology studies and clinical trials.

The ALL project team members (like other TARGET researchers) have generated data in two phases: Discovery and Validation. Visit the TARGET Research page to learn more.

Discovery Dataset

The TARGET ALL Phase II project has produced comprehensive genomic profiles of nearly 200 relapse-enriched, clinically annotated patient cases in the discovery dataset. This cohort includes more than 100 patients with adequate relapse specimens to study as trios (see three sample types below). Each fully-characterized TARGET ALL case includes data from nucleic acid samples extracted from peripheral blood or bone marrow tissues as follows:

• Primary tumor sample collected at diagnosis
• Case-matched tissue sample collected at remission (FACS purified, <5% blasts detected following standard induction therapy)
• Relapsed tumor sample (case-matched) when available; >50% cases have 3^rd sample (those cases are considered a “trio”)

Additional cases with partial molecular characterization and/or sequencing data are available to the research community.

Case Selection Criteria

Tissues and clinical data used for the TARGET ALL Phase II project were obtained from patients enrolled on biology studies and clinical trials managed through the Children’s Oncology Group (COG). Patient samples with full characterization were chosen based on the following criteria:

• Experienced early bone marrow relapse (< 4 years from time of diagnosis)
• Adequate amount of high-quality nucleic acids for comprehensive genomic profiling

Molecular Characterization

The TARGET ALL project team relied on a variety of platforms to obtain a fully characterized dataset of ~200 relapse-enriched cases.  The COG ALL Statistics and Data Center provided clinical annotations and outcome data for all cases. Visit the TARGET Project Experimental Methods page for detailed information and protocols.

Verification of Discovery Variants

The TARGET ALL project team utilized a variety of sequencing approaches to confirm candidate variants identified in the discovery sample cohort as somatic. For example, mRNA-seq results are being used to determine variants which were expressed and originally identified through whole genome or exome sequencing. These verified variants will be made available as open-access data.

Validation Strategy

To validate sequence mutations identified in the relapse-enriched discovery cohort, along with some previously published variants in adult ALL, an additional 750 cases were further analyzed. The TARGET ALL project team employed whole exome sequencing to look at the frequency of these changes across a broader spectrum of ALL subtypes in an unbiased cohort of 500 precursor B-cell ALL and 250 T-cell lineage ALL cases. Patients were enrolled on a single COG protocol and selected for inclusion in the validation effort if DNA were available.

All data from the discovery cohort and this validation effort are made available as specified in the Using TARGET Data and TARGET Publication Guidelines pages. The TARGET Data Matrix provides an overview of the data generated and described above.

Leukemia is a cancer of blood cells and can arise within distinct lineages, either lymphoid or myeloid. On occasion, patients present with an acute leukemia for which a specific lineage cannot be clearly determined. These cases are classified as acute leukemias of ambiguous lineage (ALAL), and they account for less than 4% of all acute leukemias across age groups.

TARGET investigators at St. Jude Children’s Research Hospital led an effort to better understand acute leukemias of ambiguous lineage (ALAL), and the TARGET initiative contributed to this key study by generating whole genomic sequencing (WGS) and some transcriptome (mRNA-seq and miRNA-seq) profiles of ~50 ALAL cases as a “TARGET ALL Phase III” subproject. Each TARGET ALAL case includes WGS, mRNA-seq and miRNA-seq data from nucleic acid samples extracted from peripheral blood or bone marrow tissues as follows:

• Primary tumor sample collected at diagnosis
• Case-matched tissue sample collected at remission (<5% blasts detected following standard induction therapy)

This high-risk subtype of leukemia has both myeloid and lymphoid features. In certain cases, fluorescence-activated cell sorting of tumor and normal tissue samples was employed to separate cell populations based on immunity markers expressed. TARGET analyses were published as part of a collaborative study by the NCI TARGET initiative, Children's Oncology Group (COG), and St. Jude Children’s Research Hospital. Altogether, the collaborative team analyzed 115 children (ages 0-18) diagnosed with ALAL across 13 cooperative groups and Institutions. DNA extracted from tumor and remission samples was subjected to whole genome and/or exome sequencing and single-nucleotide polymorphism (SNP) microarray genotyping, and tumor RNA was subjected to transcriptome sequencing (RNA-seq and miRNA-seq).

Molecular Characterization

While TARGET led the whole genome analyses of the ALAL dataset, whole exome analyses were performed through St. Jude Children’s Research Hospital, along with SNP genotyping; transcriptome analyses were done as a joint effort between all groups. The COG Statistics and Data Center for ALL and St. Jude Researchers (collaborating with multiple cooperative groups and Institutions internationally) provided clinical annotations and outcome data for all cases.

All data from the characterizations efforts for the TARGET ALL (Phase III) project are made available as specified in the Using TARGET Data and TARGET Publication Guidelines pages. The TARGET Data Matrix provides an overview of the data generated and described above.

The TARGET ALL Project team consists of COG investigators at various institutions that work together with scientists, analysts, project managers and technicians from the COG (Biorepository, Data and Statistics Core) and NCI offices (Office of Cancer Genomics, Clinical Therapy Evaluation Program, Center for Cancer Research and Center for Bioinformatics and Information Technology). This collaborative network is led by the following:

Principal Investigator

• Stephen P. Hunger, M.D.
  • The Children's Hospital of Philadelphia

Lead Scientific Investigators

• Mignon Loh, M.D.
  • University of California San Francisco Benioff Children's Hospital
• Charles G. Mullighan, M.D., M.Sc.
  • St. Jude Children's Research Hospital
• Cheryl Willman, M.D.
  • University of New Mexico Cancer Center

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