Study Of Pediatric Tumors Research Articles

Abstract 5081: Systematic identification of germline mutations in rhabdomyosarcoma and neuroblastoma using massively paralleled sequencing

Abstract Despite improvement of survival using multimodal chemo- and immunotherapy, high mortality and morbidity is still substantial for pediatric patients with metastatic cancers. Recent large-scale sequencing studies of pediatric tumors including rhabdomyosarcoma (RMS) and neuroblastoma (NB) have been focusing on somatic mutations, and revealed a low somatic mutation rate and surprisingly few recurrently somatic mutated genes in these childhood tumors. Currently, only a small portion of pediatric cancer cases can be explained by somatic driver events; whereas the cause for the majority of these diseases remains unknown. Because both these two types of tumors are uncommon, here we hypothesize that infrequent germline mutations (frequency<0.05 in control populations) may play a role in the initiation of sporadically occurring tumor. To test this hypothesis, we utilized sequencing data from two cancer patient cohorts consisting of RMS (n=133) and NB (n=222) patients, of which latter is a part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative for pediatric cancers. First, high-quality protein-coding changing single nucleotide variants (SNVs) were called in both paired germline and tumor genomic DNAs. Then we excluded common variants with frequency >5% in a normal human population using the 1000 Genomes data. Due to our interest in the enriched variants, we further required the frequencies of variants in our rhabdomyosarcoma and neuroblastoma patient cohorts are higher than those in the ESP dataset, a non-cancer control population comprising 6503 individuals. There are 63247 SNVs fulfilled these selection criteria. Among them, 1589 have been reported in these pediatric cancers or in other malignancies in the Cancer Genome Atlas (TCGA) project; and 1178 variants are present in the Human Gene Mutation Database (HGMD). Of these HGMD variants, 49 have been reported in human diseases and 34 of them are known disease-causing mutations for human cancers and genetic disorders including TP53, ALK, CHEK2, and PINK1. Interestingly, the most frequent germline mutations in these pediatric tumors were rarely found in the TCGA project which mostly consists of adult cancers. This observation suggests a very different genetic background of pediatric cancer patients from that of the adult cancers, and warrants a careful examination of germline mutations in these cancers. Furthermore, previous studies have highlighted the importance of expression of variant genes (including tumor suppressor genes) for identification of driver mutations in cancers. Therefore we will use 178 transcriptome sequencing experiments available for these tumors (RMS=84; NB=93) to identify expressed variants in tumor. Statistical and pathway analyses are currently underway to determine potential pathological or casual germline mutations associated with neuroblastoma and rhabdomyosarcoma. Citation Format: Jun S. Wei, Rajesh Patidar, John Shern, Shile Zhang, Trevor Pugh, Sharon J. Diskin, Sivasish Sindiri, Young K. Song, Hongling Liao, Xinyu Wen, Jianjun Wang, Stephen X. Skapek, James R. Anderson, Frederic G. Barr, Robert C. Seeger, John M. Maris, Douglas S. Hawkins, Javed Khan. Systematic identification of germline mutations in rhabdomyosarcoma and neuroblastoma using massively paralleled sequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5081. doi:10.1158/1538-7445.AM2014-5081

On Equipoise and Emerging Technologies

TO THEEDITOR: Recently, Goitein and Cox 1 published an editorial in this journal questioning the ethics of conducting randomized controlled trials in the face of what they consider to be overwhelmingly convincing surrogate evidence that proton therapy is superior to conventional x-ray therapy in terms of dose and volume of normal tissue irradiated. They consider blind the insistence on level I evidence by many in the radiation and broader oncology community, asserting that it is not possible to view the two modalities with equipoise. I would suggest one main response to this argument. The traditional use of the term “equipoise” in suggesting a clinical trial has been from the standpoint of the treating physician, for whom it is uncertain which trial arm will prove to be superior. I believe, in general, that this term should be redefined from the perspective of the ultimate autonomous being in charge of patient care: the patient himself. However, because a cancer diagnosis puts the patient under duress for his life, the next most interested party is composed of those involved by virtue of paying the bill. Today, the patient in particular and the public at large clearly believe that financial concerns cloud the judgment of the physician and hospital, both of whom certainly stand to benefit from increased use of new and expensive technologies. Recently, there have been several articles in the mainstream media attesting to this fact. Although the physician may observe that patients will knock down the door to obtain access to the latest technology, he does not as immediately hear the grumbling distrust of the taxpayers and policyholders who actually pay the costs and who do not directly live under the duress of the cancer diagnosis. Most radiation oncologists agree that certain pediatric cancers, for example, represent an area where little expense should be spared, and where the patients stand to benefit greatly from proton therapy over x-rays. However, the broad availability of protons will inevitably lead to their use in less clear circumstances, such as in prostate cancer, where another relatively recent addition to our arsenal has already significantly reduced bladder and rectal toxicity. Powering studies in pediatric tumors to prove the decreased clinical incidence of adverse effects will surely not present a challenge, once one accepts the assertion that public perception finds neither physician nor patient disinterested enough to even consider equipoise. Conversely, powering the prostate study to prove that the added expense of protons will result in a statistically significant decrease in clinically relevant late adverse reactions will be appropriately difficult. It is incumbent upon all of us to insist on level I evidence to justify changes in patient care. We must have the courage to generate highquality, disinterested, and unbiased data. This is especially true in the current era, when changes in practice result in higher reimbursement rates, and when the United States taxpayer is increasingly held hostage to spiraling medical costs. We must broaden our perspective to realize that we are not the only ones whom we must convince with evidence. As long as they entrust us with their lives and with their pocketbooks, the public has a right to hold us to our own highest standards. Only in this way do we hope to retain the trust and respect of the patient, the public, and each other.

Molecular genetics in the diagnosis and prognosis of solid pediatric tumors.

The field of molecular genetics continues to see an ever increasing number of applications to pediatric tumor analysis. Studies in pediatric tumors have identified novel genes and other genetic changes, a large number of which reflect one of the following mechanisms: (1) activation of proto-oncogenes; (2) loss of tumor suppressor genes; or (3) creation of novel fusion proteins. At least one of these mechanisms is operational in each of the following pediatric tumors: neuroblastoma, Ewing sarcoma and peripheral primitive neuroectodermal tumor (pPNET), intra-abdominal desmoplastic small-cell tumor, rhabdomyosarcoma, synovial sarcoma, and Wilms tumor. Out of this research has come not only an increased understanding of oncogenesis but also, for each of the tumors listed above, diagnostic and/or prognostic markers that can be used by the pathologist and oncologist to improve overall patient management.