Abstract B06: Distinct genomic profiles and targetable alterations revealed by FoundationOne® Heme in hematolymphoid malignancies in adolescents and young adults.
Authors: Wang Kai , Morosini Deborah , Yelensky Roman , Lipson Doron , Chmielecki Juliann , Ali Siraj M. , Ross Jeffrey S. , Stephens Phil , Miller Vincent A. 
Published: August 2015

Background: Hematolymphoid malignancies (HLM) in adolescent and young adult (AYA, age 15-39) patients exhibit distinct clinical and routine pathologic characteristics. Comparative analysis of genomic alterations (GA) of HLM in AYA versus younger and older patient cohorts has not been reported previously.

Methods: DNA was extracted and captured using custom baits targeting all exons of 405 cancer-related genes and select introns of 31 genes commonly rearranged in cancer (n=24), or both DNA and RNA were extracted and captured using custom baits for 405 genes and 265 frequently rearranged genes, respectively (n=49) (FoundationOne® Heme). All captured libraries were sequenced to high uniform depth in a CLIA-certified, CAP-accredited laboratory with an average depth of &gt;500x for DNA and &gt;10M unique pairs for RNA (Illumina HiSeq). Sequence data were assessed for base substitutions, insertions/deletions (indels), copy number alterations, and select gene rearrangements.

Results: The assays identified an average of 3.1 cancer-related GAs per HLM (range 0-22), including 135 base substitutions, 45 indels, 36 gene fusions or rearrangements, 13 gene deletions, and 12 gene amplifications. The most frequently altered genes in this AYA HLM cohort were TP53 (22%), NRAS (12%), KRAS (11%), PTPN11 (10%), MYC (8%), B2M (8%), SOCS1 (7%), FLT3 (7%), and CDKN2A (7%). Clinically relevant GAs (targetable by therapies approved or in clinical trials) were found in 64% of cases, including 60% of lymphoma, 71% of acute myeloid leukemia (AML), and 79% of acute lymphoblastic leukemia (ALL). Clinically relevant GAs identified in this AYA cohort included NRAS and KRAS (23%), targetable by MEK inhibitors, FLT3 (7%), targetable by multiple agents, as well as partial tandem duplication of MLL and rearrangement of IGH/MYC. AML AYA samples contained a high frequency of PTPN11 mutations (41%) which can activate the RAS/MAP/ERK, PI3K, and Src pathways. The enrichment of PTPN11 mutations in 7/17 (41%) AYA AML vs. 0/10 (0%) pediatric AML (age&lt;15) and 1/ 80 (1%) of older adult AML was significant (p=0.0001). A higher frequency of KRAS mutations in AYA AML (29%) vs. older adults (6%) was additionally observed (p=0.01). 2 of 9 AYA diffuse large B-cell lymphoma (DLBCL) cases were found to harbor ALK fusions, a potential enrichment relative to older patients which will be further explored.

Conclusions: FoundationOne Heme can detect all classes of genomic alterations in AYA hematolymphoid malignancies. Significant molecular distinctions identified in this AYA population implicate age-related mechanisms in the development and progression of HLM, and provide novel potential therapeutic approaches to improve clinical outcomes in this distinct patient cohort.

Citation Format: Kai Wang, Deborah Morosini, Roman Yelensky, Doron Lipson, Juliann Chmielecki, Siraj M. Ali, Jeffrey S. Ross, Phil Stephens, Vincent A. Miller. Distinct genomic profiles and targetable alterations revealed by FoundationOne® Heme in hematolymphoid malignancies in adolescents and young adults. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B06.