The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias

Abstract

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R) and 20 older children (MLL-R cases) with leukemia. Our data demonstrated infant MLL-R ALL to have one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite the paucity of mutations, activating mutations in kinase/PI3K/RAS signaling pathways were detected in 47%. Surprisingly, however, these mutations were often sub-clonal and frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (a mean of 6.5/case versus 1.3/case, P=7.15×10−5) and contained frequent mutations (45%) in epigenetic regulators, a category of genes that with the exception of MLL was rarely mutated in infant MLL-R ALL.

The landscape of genomic alterations across childhood cancers

“…External data were downloaded from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) using the accession numbers EGAD00001000085, EGAD00001000135, EGAD00001000159, EGAD00001000160, EGAD00001000161, EGAD00001000162, EGAD00001000163, EGAD00001000164, EGAD00001000165, EGAD00001000259, EGAD00001000260, EGAD00001000261, EGAD00001000268, and EGAD00001000269 [49][50][51][52][53][54][55][56][57][58][59][60][61][62] ; internal datasets are related to previous PMIDs 27748748, 27479119, 26923874, 25670083, 25253770, 24972766, 24553142, 25135868, 26632267, 26179511, 24651015, 28726821, 23817572, 25962120, 26294725 17,19,44,63-74 (Supplementary Note 1).…”

“…Ninety-five per cent of the patients were under 18 years of age (or age unspecified but confirmed age group paediatric), but available data were included for patients up to 25 years, as these were considered relevant for cancer types that typically peak at a young age. All centres have approved data access and informed consent had been obtained from all patients.External data were downloaded from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) using the accession numbers EGAD00001000085, EGAD00001000135, EGAD00001000159, EGAD00001000160, EGAD00001000161, EGAD00001000162, EGAD00001000163, EGAD00001000164, EGAD00001000165, EGAD00001000259, EGAD00001000260, EGAD00001000261, EGAD00001000268, and EGAD00001000269 [49][50][51][52][53][54][55][56][57][58][59][60][61][62] ; internal datasets are related to previous PMIDs 27748748, 27479119, 26923874, 25670083, 25253770, 24972766, 24553142, 25135868, 26632267, 26179511, 24651015, 28726821, 23817572, 25962120, 26294725 17,19,44,63-74 (Supplementary Note 1).The final cohort included 914 individual patients of no more than 25 years of age including primary tumours for 879 patients with 47 matched relapsed tumours, and an additional 35 independent relapsed tumours ( Supplementary Tables 1, 2). Deep-sequencing (~ 30× ) whole-genome data (WGS) were available for 547 samples with matched control, whole-exome sequencing (WES) for 414, and low-coverage whole-genome sequencing (lcWGS) for an additional 54 germline and 186 tumour samples.…”

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

“…Approximately two‐thirds of NMC cases harbor a BRD4–NUTM1 fusion gene, which has been functionally validated as an oncogenic event 39, 40. In the other one‐third of cases, several fusion partners of NUTM1 have been reported in the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman) and recent papers, such as ACIN1, 41, 42, 43 BCOR1, 44 BRD3, 40 BRD9, 41 BPTF, 45 CIC, 46 CUX1, 42 IKZF1, 42, 47 MXD1, 44 NSD3, 48 SLC12A6, 42 ZNF532, 49 and ZNF618. 42 Although MXD1–NUTM1 fusion has been reported in gastric sarcoma, MXD4 has not been previously reported as a fusion partner of NUTM1.…”

Comprehensive evaluation and validation of targeted next-generation sequencing performance in two clinical laboratories

“…Currently, the power of NGS technology has allowed large scale DNA sequencing projects to be completed in record time, releasing huge amounts of invaluable genetic information. The Cancer Genome Atlas (TCGA) is an international consortium that has sequenced the exome from more than 17,200 tumor patient samples including lung (1)(2)(3)(4), colon and rectal (5), breast (6), prostate (7), bladder (8), melanoma (9), gastric adenocarcinoma (10), and numerous other cancer types (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). NGS has helped to identify actionable somatic mutations in cancer.…”