Abstract
Frequency and spectrum of clinically significant molecular alterations detected by tumor gene panel testing for pediatric cancer patients in the Texas KidsCanSeq study.
Author
person
Frank Y. Lin
Texas Children's Cancer and Hematology Center, Baylor College of Medicine, Houston, TX
info_outline
Frank Y. Lin, Jacquelyn Reuther, Samara L Potter, Ross Mangum, Carrie A Mohila, John Hicks, Donna M. Muzny, Juan Carlos Bernini, Jonathan Benjamin Gill, Timothy Cameron Griffin, Gail Elizabeth Tomlinson, Kelly L. Vallance, Jennifer Foster, Carl E. Allen, Murali M. Chintagumpala, Dolores H. López-Terrada, Kevin Fisher, Angshumoy Roy, Sharon E. Plon, Donald Williams Parsons
Full text
Authors
person
Frank Y. Lin
Texas Children's Cancer and Hematology Center, Baylor College of Medicine, Houston, TX
info_outline
Frank Y. Lin, Jacquelyn Reuther, Samara L Potter, Ross Mangum, Carrie A Mohila, John Hicks, Donna M. Muzny, Juan Carlos Bernini, Jonathan Benjamin Gill, Timothy Cameron Griffin, Gail Elizabeth Tomlinson, Kelly L. Vallance, Jennifer Foster, Carl E. Allen, Murali M. Chintagumpala, Dolores H. López-Terrada, Kevin Fisher, Angshumoy Roy, Sharon E. Plon, Donald Williams Parsons
Organizations
Texas Children's Cancer and Hematology Center, Baylor College of Medicine, Houston, TX, Invitae, San Francisco, CA, Nationwide Children’s Hospital, Columbus, OH, Phoenix Children's Hospital, Phoenix, AZ, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, Baylor College of Medicine, Houston, TX, Vannie E. Cook Children's Cancer and Hematology Clinic, Baylor College of Medicine, Mcallen, TL, Mexico, University of Texas MD Anderson Cancer Center, Houston, TX, Children's Hospital of San Antonio, Baylor College of Medicine, San Antonio, TX, UT Health San Antonio, San Antonio, TX, Cook Children's Medical Center, Fort Worth, TX
Abstract Disclosures
Research Funding
U.S. National Institutes of Health
U.S. National Institutes of Health
Background:
Tumor sequencing has the potential to inform diagnosis, prognosis, and treatment of childhood cancer patients. Prospective data are needed to evaluate the clinical utility of these tests.
Methods:
Patients less than 18 years of age with extracranial solid tumors (ST), central nervous system tumors (CNS), lymphomas and histiocytic disorders (L/H) were enrolled in the Texas KidsCanSeq clinical genomics study at six Texas institutions. Available tumor samples from a subset of patients designated as high risk (based on poor prognosis at diagnosis or tumor recurrence) were sequenced using pediatric cancer-focused targeted DNA (initially 124 genes; expanded to 169 genes) and RNA (81 genes) panels developed at Texas Children’s Hospital. DNA variants (single nucleotide variants, insertion/deletions, splice site variants, copy number alterations) and fusion genes detected by RNA testing were analyzed. Tumor alterations were classified by molecular pathologists and oncologists as carrying strong (Tier 1) or potential (Tier 2) clinical significance following consensus guidelines from the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists.
Results:
A total of 626 patients were enrolled between 2018 and 2021, of whom 380 were designated as high risk. Tumor samples adequate for molecular testing were available from 342 of the 380 (90%) high risk patients (196 ST [57%], 132 CNS [39%] and 14 L/H [4%]). Clinically significant alterations were identified in 246 of 342 (72%) tumors: 165 (48%) from DNA testing only, 34 (10%) from RNA testing only, and 47 (14%) from both modalities. The frequency of clinically significant alterations was similar across tumor cohorts (74% ST, 68% CNS, 71% L/H). Alterations relevant to therapy-choice were reported in 127 of 342 (37%) tumors (35% ST, 26% CNS, 57% L/H); 87 of these 127 (69%) were not known from prior clinical testing. The most frequently altered therapeutic gene alterations (Table) involved
BRAF
(n=25),
CDKN2A/B
(n=20),
SMARCB1
(n=17),
FGFR1/2/3/4
(n=14),
NF1
(n=13),
PIK3CA
(n=11),
ALK
(n=10),
CDK4
(n=9), and
RET
(n=7). One hypermutated tumor was identified: a high-grade glioma (tumor mutation burden >190 mut/Mb) in a patient with Lynch syndrome due to a germline
MSH6
variant.
Conclusions:
Tumor alterations of clinical significance according to consensus guidelines were reported in a large proportion of children with diverse high risk or recurrent cancer diagnoses, the majority of which were not detected by other standard pathologic analysis. These data further support broader adoption of tumor molecular profiling for these patients.
Therapeutic tier I and II gene alterations.
Gene
SNV/indel
CNV
Fusion
Total
BRAF
16
0
9
25
CDKN2A/B
4
16
0
20
SMARCB1
5
12
0
17
FGFR1/2/3/4
11
1
2
14
NF1
13
0
0
13
PIK3CA
11
0
0
11
ALK
4
1
5
10
CDK4
0
9
0
9
RET
1
0
6
7
11 organizations
9 drugs
13 targets
Organization
Texas Children's Cancer and Hematology CenterOrganization
Baylor College of MedicineOrganization
InvitaeOrganization
Nationwide Children’s HospitalOrganization
Phoenix Children's HospitalOrganization
Texas Children's HospitalOrganization
University of Texas MD Anderson Cancer CenterOrganization
Children's Hospital of San AntonioOrganization
UT Health San Antonio, MD Anderson Cancer CenterOrganization
Cook Children's Medical CenterDrug
BRAFDrug
CDKN2A/BDrug
SMARCB1Drug
FGFR1/2/3/4Drug
NF1Drug
PIK3CADrug
MelphalanDrug
RET TKIsTarget
CDKN2A/BTarget
CDKN2BTarget
BRAFTarget
FGFR2bTarget
FGFR3Target
NF1Target
ALKTarget
RETTarget
SMARCB1Target
PIK3CATarget
CDK4 & 6Target
FGFR4Target
FGFR1