Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological ...relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families.
•Known pathogenic germ line variants in 12 genes can explain nearly 30% of families with inherited predisposition to MDS/AML.•Asymptomatic carriers of germ line RUNX1 mutations develop detectable clonal hematopoiesis with a cumulative risk of >80% by age 50 years.
Estrogen receptor alpha-positive (ERα+) luminal tumors are the most frequent subtype of breast cancer. Stat1−/− mice develop mammary tumors that closely recapitulate the biological characteristics of ...this cancer subtype. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of Stat1−/− primary mammary tumors and matched normal tissues. This investigation identified somatic truncating mutations affecting the prolactin receptor (PRLR) in all tumor and no normal samples. Targeted sequencing confirmed the presence of these mutations in precancerous lesions, indicating that this is an early event in tumorigenesis. Functional evaluation of these heterozygous mutations in Stat1−/− mouse embryonic fibroblasts showed that co-expression of truncated and wild-type PRLR led to aberrant STAT3 and STAT5 activation downstream of the receptor, cellular transformation in vitro, and tumor formation in vivo. In conclusion, truncating mutations of PRLR promote tumor growth in a model of human ERα+ breast cancer and warrant further investigation.
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•Mice lacking Stat1 develop mammary tumors that model human ERα+ breast cancer•DNA sequencing finds a Prlr truncating mutation hotspot in 100% of Stat1−/− tumors•At least 77.8% of DCIS examined also contain PRLR truncating mutations•Co-expression of truncated and full-length PRLR promote tumor growth in MEFs
Griffith et al. report on whole genome sequencing of mammary tumors that spontaneously develop in mice lacking Stat1. They find a 100% recurrent hotspot of mutations resulting in truncation of Prlr. Co-expression of truncated and full-length Prlr in mouse embryonic fibroblasts is shown to promote tumor growth.
More than 25% of patients with AML carry no mutations in genes known to be associated with leukemia. Analyses of genomes, transcriptomes, and methylomes of AML samples implicate mutations in ...cytogenetically normal AML and provide insight into the relationships among causative genes.
The molecular pathogenesis of acute myeloid leukemia (AML) has been studied with the use of cytogenetic analysis for more than three decades. Recurrent chromosomal structural variations are well established as diagnostic and prognostic markers, suggesting that acquired genetic abnormalities (i.e., somatic mutations) have an essential role in pathogenesis.
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However, nearly 50% of AML samples have a normal karyotype, and many of these genomes lack structural abnormalities, even when assessed with high-density comparative genomic hybridization or single-nucleotide polymorphism (SNP) arrays
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(see Glossary). Targeted sequencing has identified recurrent mutations in
FLT3, NPM1, KIT, CEBPA,
and
TET2
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Massively parallel . . .
To investigate the molecular basis underlying aggressive behavior in oral squamous cell carcinoma (OSCC), our laboratory developed a carcinogen-induced mouse oral cancer (MOC) cell line model that ...encompasses the growth and metastasis spectrum of its human counterpart. We performed next-generation sequencing (NGS) and gene expression microarray profiles to explore the genomic and transcriptional backgrounds of the differential MOC line phenotypes, as well as, the cross-species relevance of the model. Here we describe the comparative analysis of NGS (www.ncbi.nlm.nih.gov/biosample?LinkName=bioproject_biosample_all&from_uid=247825) and expression microarray (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE50041) data from the MOC lines and corresponding human data, as described in our recent publication 1.
Abstract
Estrogen receptor alpha positive luminal breast cancers are the most frequent subtype of breast cancer. Previous work has established that Stat1-/- mouse mammary tumor model recapitulates ...signaling, expression and phenotypic alterations observed in this subtype of human breast cancers. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of 22 Stat1-/- primary mammary tumors and cell lines. We discovered a novel hotspot of somatic mutations in 100% of tumors that resulted in a truncated form of the prolactin receptor (Prlr). Targeted sequence analysis identified similar mutations in 77.8% of ductal carcinoma in situ. Co-expression of truncated and full-length Prlr in normal cells led to activation of oncogenic Stat3 and Stat5 as well as cellular transformation. In conclusion, truncating mutations of Prlr drive tumor development in a model of human ERa+ breast cancer and should be considered as novel antitumor targets.
Citation Format: Elaine Mardis, Obi L. Griffith, Ruby Chan Szeman, Malachi Griffith, Kilannin Krysiak, Zachary Skidmore, Jasreet Hundal, Julie A. Allen, Arthur Cora, Alexander P. Miceli, Heather Schmidt, Lee Trani, Krishna-Latha Kanchi, Christopher A. Miller, David E. Larson, Robert S. Fulton, Richard K. Wilson, Robert D. Schreiber. Genomics of a STAT1 knockout mouse model of human ER+ breast cancer. abstract. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA20.
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