Discovering functional modules by identifying recurrent and mutually exclusive mutational patterns in tumors

<p>Abstract</p> <p>Background</p> <p>Assays of multiple tumor samples frequently reveal recurrent genomic aberrations, including point mutations and copy-number alterations, that affect individual genes. Analyses that extend beyond single genes are often restricted to examining pathways, interactions and functional modules that are already known.</p> <p>Methods</p> <p>We present a method that identifies functional modules without any information other than patterns of recurrent and mutually exclusive aberrations (RME patterns) that arise due to positive selection for key cancer phenotypes. Our algorithm efficiently constructs and searches networks of potential interactions and identifies significant modules (RME modules) by using the algorithmic significance test.</p> <p>Results</p> <p>We apply the method to the TCGA collection of 145 glioblastoma samples, resulting in extension of known pathways and discovery of new functional modules. The method predicts a role for <it>EP300 </it>that was previously unknown in glioblastoma. We demonstrate the clinical relevance of these results by validating that expression of <it>EP300 </it>is prognostic, predicting survival independent of age at diagnosis and tumor grade.</p> <p>Conclusions</p> <p>We have developed a sensitive, simple, and fast method for automatically detecting functional modules in tumors based solely on patterns of recurrent genomic aberration. Due to its ability to analyze very large amounts of diverse data, we expect it to be increasingly useful when applied to the many tumor panels scheduled to be assayed in the near future.</p

The dosimetric effects of limited elective nodal irradiation in volumetric modulated arc therapy treatment planning for locally advanced non-small cell lung cancer

Objective—Contemporary radiotherapy guidelines for locally advanced non-small cell lung carcinoma (LA-NSCLC) recommend omitting elective nodal irradiation, despite the fact that evidence supporting this came primarily from older reports assessing comprehensive nodal coverage using 3D conformal techniques. Herein, we evaluated the dosimetric implications of the addition of limited elective nodal irradiation (LENI) to standard involved field irradiation (IFI) using volumetric modulated arc therapy (VMAT) planning. Method—Target volumes and organs-at-risk (OARs) were delineated on CT simulation images of 20 patients with LA-NSCLC. Two VMAT plans (IFI and LENI) were generated for each patient. Involved sites were treated to 60 Gy in 30 fractions for both IFI and LENI plans. Adjacent uninvolved nodal regions, considered high risk based on the primary tumor site and extent of nodal involvement, were treated to 51 Gy in 30 fractions in LENI plans using a simultaneous integrated boost approach. Results—All planning objectives for PTVs and OARs were achieved for both IFI and LENI plans. LENI resulted in significantly higher esophagus Dmean (15.3 vs. 22.5 Gy, p \u3c 0.01), spinal cord Dmax (34.9 vs. 42.4 Gy, p = 0.02) and lung Dmean (13.5 vs. 15.9 Gy, p = 0.02), V20 (23.0 vs. 27.9%, p = 0.03), and V5 (52.6 vs. 59.4%, p = 0.02). No differences were observed in heart parameters. On average, only 32.2% of the high-risk nodal volume received an incidental dose of 51 Gy when untargeted in IFI plans. Conclusion—The addition of LENI to VMAT plans for LA-NSCLC is feasible, with only modestly increased doses to OARs and marginal expected increase in associated toxicity

Implications of a RAD54L polymorphism (2290C/T) in human meningiomas as a risk factor and/or a genetic marker

BACKGROUND: RAD54L (OMIM 603615, Locus Link 8438) has been proposed as a candidate oncosupressor in tumours bearing a non-random deletion of 1p32, such as breast or colon carcinomas, lymphomas and meningiomas. In a search for RAD54L mutations in 29 menigiomas with allelic deletions in 1p, the only genetic change observed was a silent C/T transition at nucleotide 2290 in exon 18. In this communication the possible association of the 2290C/T polymorphism with the risk of meningiomas was examined. In addition, the usefulness of this polymorphism as a genetic marker within the meningioma consensus deletion region in 1p32 was also verified. The present study comprises 287 blood control samples and 70 meningiomas from Spain and Ecuador. Matched blood samples were only available from Spanish patients. RESULTS: The frequency of the rare allele-T and heterozygotes for the 2290C/T polymorphism in the blood of Spanish meningioma patients and in the Ecuadorian meningioma tumours was higher than in the control population (P < 0.05). Four other rare variants (2290C/G, 2299C/G, 2313G/A, 2344A/G) were found within 50 bp at the 3' end of RAD54L. Frequent loss of heterozygosity for the 2290C/T SNP in meningiomas allowed to further narrow the 1p32 consensus region of deletion in meningiomas to either 2.08 Mbp – within D1S2713 (44.35 Mbp) and RAD54L (46.43 Mbp) – or to 1.47 Mbp – within RAD54L and D1S2134 (47.90 Mbp) – according to recent gene mapping results. CONCLUSION: The statistical analysis of genotypes at the 2290C/T polymorphism suggest an association between the rare T allele and the development of meningeal tumours. This polymorphism can be used as a genetic marker inside the consensus deletion region at 1p32 in meningiomas

EPHB2 germline variants in patients with colorectal cancer or hyperplastic polyposis

BACKGROUND: Ephrin receptor B2 (EPHB2) has recently been proposed as a novel tumor suppressor gene in colorectal cancer (CRC). Inactivation of the gene has been shown to correlate with progression of colorectal tumorigenesis, and somatic mutations have been reported in both colorectal and prostate tumors. METHODS: Here we have analyzed the EPHB2 gene for germline alterations in 101 individuals either with 1) CRC and a personal or family history of prostate cancer (PC), or 2) intestinal hyperplastic polyposis (HPP), a condition associated with malignant degeneration such as serrated adenoma and CRC. RESULTS: Four previously unknown missense alterations were observed, which may be associated with the disease phenotype. Two of the changes, I361V and R568W, were identified in Finnish CRC patients, but not in over 300 Finnish familial CRC or PC patients or more than 200 population-matched healthy controls. The third change, D861N, was observed in a UK HPP patient, but not in additional 40 UK HPP patients or in 200 UK healthy controls. The fourth change R80H, originally identified in a Finnish CRC patient, was also found in 1/106 familial CRC patients and in 9/281 healthy controls and is likely to be a neutral polymorphism. CONCLUSION: We detected novel germline EPHB2 alterations in patients with colorectal tumors. The results suggest a limited role for these EPHB2 variants in colon tumor predisposition. Further studies including functional analyses are needed to confirm this

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

BACKGROUND: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. RESULTS: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. CONCLUSIONS: Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity

A review of clinical trials of cetuximab combined with radiotherapy for non-small cell lung cancer

Treatment of non-small cell lung cancer (NSCLC) is challenging in many ways. One of the problems is disappointing local control rates in larger volume disease. Moreover, the likelihood of both nodal and distant spread increases with primary tumour (T-) stage. Many patients are elderly and have considerable comorbidity. Therefore, aggressive combined modality treatment might be contraindicated or poorly tolerated. In many cases with larger tumour volume, sufficiently high radiation doses can not be administered because the tolerance of surrounding normal tissues must be respected. Under such circumstances, simultaneous administration of radiosensitizing agents, which increase tumour cell kill, might improve the therapeutic ratio. If such agents have a favourable toxicity profile, even elderly patients might tolerate concomitant treatment. Based on sound preclinical evidence, several relatively small studies have examined radiotherapy (RT) with cetuximab in stage III NSCLC. Three different strategies were pursued: 1) RT plus cetuximab (2 studies), 2) induction chemotherapy followed by RT plus cetuximab (2 studies) and 3) concomitant RT and chemotherapy plus cetuximab (2 studies). Radiation doses were limited to 60-70 Gy. As a result of study design, in particular lack of randomised comparison between cetuximab and no cetuximab, the efficacy results are difficult to interpret. However, strategy 1) and 3) appear more promising than induction chemotherapy followed by RT and cetuximab. Toxicity and adverse events were more common when concomitant chemotherapy was given. Nevertheless, combined treatment appears feasible. The role of consolidation cetuximab after RT is uncertain. A large randomised phase III study of combined RT, chemotherapy and cetuximab has been initiated

Reirradiation of head and neck cancer focusing on hypofractionated stereotactic body radiation therapy

Reirradiation is a feasible option for patients who do not otherwise have treatment options available. Depending on the location and extent of the tumor, reirradiation may be accomplished with external beam radiotherapy, brachytherapy, radiosurgery, or intensity modulated radiation therapy (IMRT). Although there has been limited experience with hypofractionated stereotactic radiotherapy (hSRT), it may have the potential for curative or palliative treatment due to its advanced precision technology, particularly for limited small lesion. On the other hand, severe late adverse reactions are anticipated with reirradiation than with initial radiation therapy. The risk of severe late complications has been reported to be 20- 40% and is related to prior radiotherapy dose, primary site, retreatment radiotherapy dose, treatment volume, and technique. Early researchers have observed lethal bleeding in such patients up to a rate of 14%. Recently, similar rate of 10-15% was observed for fatal bleeding with use of modern hSRT like in case of carotid blowout syndrome. To determine the feasibility and efficacy of reirradiation using modern technology, we reviewed the pertinent literature. The potentially lethal side effects should be kept in mind when reirradiation by hSRT is considered for treatment, and efforts should be made to minimize the risk in any future investigations

Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival

The distal half of chromosome 1p was analysed with 15 polymorphic microsatellite markers in 683 human solid tumours at different locations. Loss of heterozygosity (LOH) was observed at least at one site in 369 cases or 54% of the tumours. LOHs detected ranged from 30–64%, depending on tumour location. The major results regarding LOH at different tumour locations were as follows: stomach, 20/38 (53%); colon and rectum, 60/109 (55%); lung, 38/63 (60%); breast, 145/238 (61%); endometrium, 18/25 (72%); ovary, 17/31 (55%); testis, 11/30 (37%); kidney, 22/73 (30%); thyroid, 4/14 (29%); and sarcomas, 9/14 (64%). High percentages of LOH were seen in the 1p36.3, 1p36.1, 1p35–p34.3, 1p32 and 1p31 regions, suggesting the presence of tumour-suppressor genes. All these regions on chromosome 1p show high LOH in more than one tumour type. However, distinct patterns of LOH were detected at different tumour locations. There was a significant separation of survival curves, with and without LOH at chromosome 1p, in the breast cancer patients. Multivariate analysis showed that LOH at 1p in breast tumours is a better indicator for prognosis than the other variables tested in our model, including nodal metastasis. © 1999 Cancer Research Campaig