Genetic Basis of High-risk Childhood Cancer Points to Possible New Drug Treatment Strategy


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Research led by scientists at St. Jude Children’s Research Hospital, Memphis, Tennessee, has identified a possible lead in treatment of two childhood leukemia subtypes known for their dramatic loss of chromosomes and poor treatment outcomes. The findings also provide the first evidence of the genetic basis for this high-risk leukemia, hypodiploid acute lymphoblastic leukemia (ALL). The research appears online in Nature Genetics.1

The study, the largest ever focused on hypodiploid ALL, confirmed that this tumor has distinct subtypes distinguished by the number of chromosomes lost and the submicroscopic genetic alterations they harbor. Researchers found evidence suggesting more than one-third of patients with a subtype known as low hypodiploid ALL have Li-Fraumeni syndrome. Families with Li-Fraumeni syndrome harbor inherited mutations in the TP53 tumor-suppressor gene and have a high risk of a range of cancers. Hypodiploid ALL had not previously been recognized as a common manifestation of Li-Fraumeni syndrome.

Drug Sensitivity

Researchers reported that the major hypodiploid subtypes are both sensitive to a family of compounds that block the proliferation of cancer cells. The compounds include drugs already used to treat other cancers. The subtypes are low hypodiploid ALL, characterized by 32 to 39 chromosomes, and near haploid ALL, which has 24 to 31 chromosomes.

“This study is a good example of the important insights that can be gained by studying the largest possible number of patients in as much detail as possible. This approach led us to key insights about these leukemia subtypes that we would otherwise have missed,” said the study’s senior and corresponding author, Charles Mullighan, MBBS(Hons), MSc, MD, an Associate Member of the St. Jude Pathology Department.

Researchers used a variety of laboratory techniques to look for genetic abnormalities in cancer cells from 124 pediatric patients missing at least one chromosome. The patients included 68 with near haploid ALL and 34 with low hypodiploid ALL. Investigators also checked white blood cells collected when 89 of the 124 patients were in remission. The study included whole-genome sequencing of the entire cancer and normal genomes of 20 patients with near haploid or low hypodiploid subtypes. For another 20 patients, investigators deciphered just DNA involved in protein production. Researchers also screened cancer cells from 117 adult ALL patients, including 11 with the low hypodiploid subtype.

Key Findings

Near haploid ALL was characterized by alterations in six genes and increased activity in key pathways that help regulate cell division and development. Disruption of these pathways, known as Ras and PI3K, has been linked to other cancers. The changes were found in 71% of near haploid ALL patients and included deletion of the NF1 gene. The gene had not previously been linked to high-risk leukemia. Other alterations involved the genes NRAS, KRAS,MAPK1, FLT3, and PTPN11.

Low hypodiploid ALL in both adults and children was linked to mutations in the TP53 tumor-suppressor gene. The gene was altered in 91% of pediatric patients with the low hypodiploid ALL subtype and in 10 of the 11 adults with low hypodiploid ALL included in the study. Other common alterations involved RB1, another tumor-suppressor gene.

About 38% of children with low hypodiploid ALL also carried TP53 abnormalities in noncancerous blood cells. The mutations included many previously linked to Li-Fraumeni syndrome, which is characterized by changes in TP53. ■

Disclosure: The study authors reported no potential conflicts of interest.

Reference

1. Holmfeldt L, Wei L, Diaz-Flores E, et al: The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. January 20, 2013 (early release online).



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