Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; John A. Thorson, MD, PhD, associate professor of pathology, director of the Clinical Genomics Laboratory, Center for Advanced Laboratory Medicine, UCSD; Sarah S. Murray, PhD, professor, Department of Pathology, and director of genomic technologies, Center for Advanced Laboratory Medicine, UCSD; and James Solomon, MD, PhD, resident, Department of Pathology, UCSD.
Molecular profiling in MDS to predict clinical outcomes after transplantation
In recent years, several insights have been gleaned regarding the role of molecular markers for prognosis in myeloproliferative disease. This study expanded the use of molecular markers for prognosis in myelodysplastic syndrome (MDS) to predicting clinical outcomes after allogeneic hematopoietic stem-cell transplants. The study enrolled 1,514 people who had 20 percent or more blasts in the bone marrow or blood or had received a diagnosis of chronic myelomonocytic leukemia or overlap myelodysplastic-myeloproliferative neoplasms. DNA specimens derived from blood or bone marrow were sequenced in a set of 129 genes involved in the pathogenesis of myeloid cancers or inherited or acquired bone marrow failure syndromes. The study identified at least one mutation in 79 percent of the patients, with mutations associated with higher-risk MDS being most prevalent, in particular mutations in TP53 and DNMT3A. Lower-risk MDS genes, such as SF3B1, were less prevalent. Focusing on the 32 genes that were mutated in at least 20 patients, the authors found that TP53 and PPM1D were associated with shorter overall survival when compared to the group without the respective mutations. In multivariable analyses, mutations in TP53 were associated with shorter survival and shorter time to relapse. Mutations in RAS pathway genes were also associated with shorter time to relapse, while JAK2 V617F mutations were associated with a higher rate of death without relapse. When the authors looked at the integration of clinical and genetic variables, the presence of TP53 mutations was the most prognostic variable, identifying patients with poor survival and high risk of relapse. Other patterns emerged when the authors looked at subsets of patients within their cohort. TP53 mutations occurred more frequently in patients with therapy-related MDS (n=311) than in patients with primary MDS (n=1,203), and the presence of TP53 mutations was associated with shorter overall survival. Mutations in PPM1D were also found more frequently in the therapy-related MDS group, often concurrently with TP53. The genes GATA2, PIGA, and SBDS were more commonly mutated in patients younger than 40 years (n=241) than in patients older than 40 years. Inherited variants in GATA2 and PIGA have been associated with germline bone marrow failure syndromes that predispose patients to develop myeloid cancers. The authors concluded that molecular profiling can be used in lieu of reduced-intensity approaches to help guide the use of myeloablative conditioning, in particular for patients with TP53-mutated MDS. Patients with RAS pathway-mutated MDS may benefit from myeloablative conditioning when the patient safety profile is acceptable. Older patients with JAK2 mutations may benefit from treatment strategies that focus on minimizing toxic effects. This study sheds light on extending the prognostic value of molecular markers for treatment options, in particular for patients with MDS who are considering allogeneic hematopoietic stem-cell transplants.
Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376(6):536–547.
Correspondence: Dr. B. L. Ebert at bebert@partners.org
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Use of haploinsufficiency network analysis to guide ovarian cancer therapy
Molecular profiling for mutations in tumor-suppressor genes and oncogenes in tumors is increasingly helping to determine the most efficacious therapy for cancer patients. The authors conducted a study in which they evaluated the role of somatic copy number alterations (SCNA) as a driver for the development of high-grade serous ovarian cancer. In particular, they looked at copy number data generated by The Cancer Genome Atlas using Affymetrix 6.0 DNA microarrays for 9,740 specimens from 21 tumor types, including 579 high-grade serous ovarian tumor specimens. The authors found that ovarian cancers had the lowest single-nucleotide and short insertion-deletion mutation rate among all cancer types tested. Forty-eight percent had no mutations in oncogenes or tumor-suppressor genes other than TP53. They also found that ovarian tumors had the highest percentage of genes altered by copy number, encompassing an average of two-thirds of the genome. To study the role of SCNAs in key pathway disruption in ovarian tumors, the authors developed a computational tool that incorporated two key features to characterize the genetic disruption of key pathways: protein-protein interactions and haploinsufficiency. Their tool, called Haploinsufficient/Triplosensitive Gene (HAPTRIG), was used to generate network scores using KEGG pathways and gene-based copy number in each ovarian tumor with the goal of identifying significant driver pathways among the vast background of passenger SCNAs. The authors found that the ovarian tumors were enriched for loss of genes in the autophagy pathway, and these tumors were the most disrupted for proteostasis among the 21 tumor types (from The Cancer Genome Atlas) tested. For the autophagy pathway, the two highest impact genes were MAP1LC3B (LC3) and BECN1. These genes had single copy losses in 94 percent of the ovarian tumor specimens. The SCNA network alterations appeared to have functional consequence as the ovarian tumors in The Cancer Genome Atlas exhibited decreased mRNA expression of core autophagy genes with single copy losses and often contained several core autophagy gene deletions. Finally, the study provided evidence that the HAPTRIG-informed choice of therapies could alter disease in preclinical models of ovarian tumors by showing that cisplatin and docetaxel did not alter the growth of a patient-derived mouse xenograft model derived from a recurrent chemotherapy-resistant patient, while the proteostasis-targeted cocktail resulted in complete ablation of tumor growth. The authors concluded that the results of their study support a model implicating haploinsufficiency, for LC3 and BECN1 at a minimum, in the sensitivity of high-grade serous ovarian tumors to therapies targeting autophagy. The study illustrates that assaying single nucleotide and short insertion-deletion variants may not be informative in all tumor types and that other types of variation, such as single copy losses, may be the key to determining the best treatment option for patients.
Delaney JR, Patel CB, Willis KM, et al. Haploinsufficiency networks identify targetable patterns of allelic deficiency in low mutation ovarian cancer. Nat Commun. 2017;8:14423. doi:10.1038/ncomms14423.
Correspondence: Joe Ryan Delaney at j1delaney@ucsd.edu or Dwayne G. Stupack at dstupack@ucsd.edu