Isochromosome 7p, i(7)(p10): A rare AML, myelodysplasia-related entity.

We describe genomic findings in an AML case with isochromosome 7p, i(7)(p10), in which SNP array analysis uncovered an additional 7.07-Mb 20q deletion not detected by karyotyping. Several AML cases with i(7)(p10) as an isolated cytogenetic finding have been previously reported. Based on consequent loss of 7q, we propose that AML with i(7)(p10) represents a distinct entity belonging in the WHO group -7/7q-, which represents one of the genetic abnormalities defining AML, myelodysplasia-related. Additionally, the focal del(20q) identified here adds support for a specific common region of deletion in 20q in myeloid malignancies, implicating a small number of candidate genes.

Copy neutral loss of heterozygosity in 20q in chronic lymphocytic leukemia/small lymphocytic lymphoma.

Single nucleotide polymorphism (SNP)-based chromosome microarray analysis was used to uncover copy neutral loss of heterozygosity (LOH) in the long arm of chromosome 20 in blood or bone marrow specimens from three patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). All three patients presented with lymph node enlargement. Whereas one of the patients has had a complicated clinical course, the other two have a more indolent disease. Sequence analysis of the tumor suppressor gene ASXL1, which is located in 20q and is commonly mutated in malignant myeloid diseases and occasionally in CLL/SLL specimens, revealed no mutations in our three patients with copy neutral LOH in 20q. The possible contribution of other imprinted microRNAs and antisense genes residing in 20q to the pathogenesis of a subset of CLL/SLL patients is discussed. These findings illustrate the value of SNP arrays for the detection of novel recurrent genomic alterations that may contribute to CLL/SLL onset or progression.

Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis.

Malignant mesothelioma is a highly aggressive, asbestos-related cancer frequently marked by mutations of both NF2 and CDKN2A. We demonstrate that germline knockout of one allele of each of these genes causes accelerated onset and progression of asbestos-induced malignant mesothelioma compared with asbestos-exposed Nf2(+/-) or wild-type mice. Ascites from some Nf2(+/-);Cdkn2a(+/-) mice exhibited large tumor spheroids, and tail vein injections of malignant mesothelioma cells established from these mice, but not from Nf2(+/-) or wild-type mice, produced numerous tumors in the lung, suggesting increased metastatic potential of tumor cells from Nf2(+/-);Cdkn2a(+/-) mice. Intraperitoneal injections of malignant mesothelioma cells derived from Nf2(+/-);Cdkn2a(+/-) mice into severe combined immunodeficient mice produced tumors that penetrated the diaphragm and pleural cavity and harbored increased cancer stem cells (CSC). Malignant mesothelioma cells from Nf2(+/-);Cdkn2a(+/-) mice stained positively for CSC markers and formed CSC spheroids in vitro more efficiently than counterparts from wild-type mice. Moreover, tumor cells from Nf2(+/-);Cdkn2a(+/-) mice showed elevated c-Met expression/activation, which was partly dependent on p53-mediated regulation of miR-34a and required for tumor migration/invasiveness and maintenance of the CSC population. Collectively, these studies demonstrate in vivo that inactivation of Nf2 and Cdkn2a cooperate to drive the development of highly aggressive malignant mesotheliomas characterized by enhanced tumor spreading capability and the presence of a CSC population associated with p53/miR-34a-dependent activation of c-Met. These findings suggest that cooperativity between losses of Nf2 and Cdkn2a plays a fundamental role in driving the highly aggressive tumorigenic phenotype considered to be a hallmark of malignant mesothelioma.

Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis.

The CDKN2A/ARF locus encompasses overlapping tumor suppressor genes p16(INK4A) and p14(ARF), which are frequently co-deleted in human malignant mesothelioma (MM). The importance of p16(INK4A) loss in human cancer is well established, but the relative significance of p14(ARF) loss has been debated. The tumor predisposition of mice singly deficient for either Ink4a or Arf, due to targeting of exons 1α or 1ß, respectively, supports the idea that both play significant and nonredundant roles in suppressing spontaneous tumors. To further test this notion, we exposed Ink4a(+/-) and Arf(+/-) mice to asbestos, the major cause of MM. Asbestos-treated Ink4a(+/-) and Arf(+/-) mice showed increased incidence and shorter latency of MM relative to wild-type littermates. MMs from Ink4a(+/-) mice exhibited biallelic inactivation of Ink4a, loss of Arf or p53 expression and frequent loss of p15(Ink4b). In contrast, MMs from Arf(+/-) mice exhibited loss of Arf expression, but did not require loss of Ink4a or Ink4b. Mice doubly deficient for Ink4a and Arf, due to deletion of Cdkn2a/Arf exon 2, showed accelerated asbestos-induced MM formation relative to mice deficient for Ink4a or Arf alone, and MMs exhibited biallelic loss of both tumor suppressor genes. The tumor suppressor function of Arf in MM was p53-independent, since MMs with loss of Arf retained functional p53. Collectively, these in vivo data indicate that both CDKN2A/ARF gene products suppress asbestos carcinogenicity. Furthermore, while inactivation of Arf appears to be crucial for MM pathogenesis, the inactivation of both p16(Ink4a) and p19(Arf) cooperate to accelerate asbestos-induced tumorigenesis.