Performance comparison of two commercial human whole-exome capture systems on formalin-fixed paraffin-embedded lung adenocarcinoma samples

Abstract

Background

Next Generation Sequencing (NGS) has become a valuable tool for molecular landscape characterization of cancer genomes, leading to a better understanding of tumor onset and progression, and opening new avenues in translational oncology. Formalin-fixed paraffin-embedded (FFPE) tissue is the method of choice for storage of clinical samples, however low quality of FFPE genomic DNA (gDNA) can limit its use for downstream applications.

Methods

To investigate the FFPE specimen suitability for NGS analysis and to establish the performance of two solution-based exome capture technologies, we compared the whole-exome sequencing (WES) data of gDNA extracted from 5 fresh frozen (FF) and 5 matched FFPE lung adenocarcinoma tissues using: SeqCap EZ Human Exome v.3.0 (Roche NimbleGen) and SureSelect XT Human All Exon v.5 (Agilent Technologies).

Results

Sequencing metrics on Illumina HiSeq were optimal for both exome systems and comparable among FFPE and FF samples, with a slight increase of PCR duplicates in FFPE, mainly in Roche NimbleGen libraries. Comparison of single nucleotide variants (SNVs) between FFPE-FF pairs reached overlapping values >90 % in both systems. Both WES showed high concordance with target re-sequencing data by Ion PGM™ in 22 lung-cancer genes, regardless the source of samples. Exon coverage of 623 cancer-related genes revealed high coverage efficiency of both kits, proposing WES as a valid alternative to target re-sequencing.

Conclusions

High-quality and reliable data can be successfully obtained from WES of FFPE samples starting from a relatively low amount of input gDNA, suggesting the inclusion of NGS-based tests into clinical contest. In conclusion, our analysis suggests that the WES approach could be extended to a translational research context as well as to the clinic (e.g. to study rare malignancies), where the simultaneous analysis of the whole coding region of the genome may help in the detection of cancer-linked variants.

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Decreased expression of stomatin predicts poor prognosis in HER2-positive breast cancer

Abstract

Background

Human epidermal growth factor receptor-2 (HER2) is a transmembrane tyrosine kinase receptor that is overexpressed in 25 to 30 % of human breast cancers and is preferentially localized in lipid rafts. Stomatin is a membrane protein that is absent from the erythrocyte plasma membrane in patients with congenital stomatocytosis and is the major component of the lipid raft.

Results

In a total of 68 clinical cases of HER2-positive breast cancer, the absence of stomatin expression was associated with a decreased 5-year survival (65 % vs. 93 %, p = 0.005) by survival analysis. For stage I-III HER2-positive breast cancer, the absence of stomatin expression was associated with a decreased 5-year disease-free survival (57 % vs. 81 %, p = 0.016) and was an independent prognostic factor by multivariate analysis. Negative stomatin expression predicts distant metastases in a hazard ratio of 4.0 (95 % confidence interval from 1.3 to 12.5).

Conclusions

These results may suggest that stomatin is a new prognostic indicator for HER2-positive breast cancer.

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Advanced MRI manifestations of trigeminal ganglioneuroma: a case report and literature review

Abstract

Background

Ganglioneuroma is a rare benign tumor originating from the sympathetic nerves, and its origination from the trigeminal nerves is even rarer. Only 4 cases of ganglioneuroma originating from the trigeminal nerve have previously been reported, and these studies only reported conventional MRI manifestations. To our knowledge, the advanced MRI features of trigeminal ganglioneuroma have not been reported thus far.

Case presentation

This study reports a case of trigeminal ganglioneuroma in the left cerebellopontine angle. Advanced MRI showed the following tumor characteristics: significantly increased perfusion on perfusion imaging; isointense on diffusion-weighted imaging, whorled appearance within the tumor and no significant signs of damage to the white matter fiber tracts in the fractional anisotropy color map, and compare to the adjacent brain tissue, Choline didn't show markedly elevation, and N-acetylaspartate peak showed slightly reduction on magnetic resonance spectroscopy. The tumor was completely resected, and the diagnosis of ganglioneuroma was confirmed by postoperative pathological examination.

Conclusion

This case demonstrates the conventional as well as advanced MRI manifestations of this rare extra-axial tumor, which have never been previously reported. In addition, we reviewed the literature to demonstrate the advanced MRI features of trigeminal ganglioneuroma, in order to aid preoperative diagnosis and differentiation.

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Validation of the flemish CARES, a quality of life and needs assessment tool for cancer care

Abstract

Background

The Cancer Rehabilitation Evaluation System (CARES) is a quality of life (QOL) and needs assessment instrument of US origin that was developed in the 90's. Since November 2012 the copyright and user fee were abolished and the instrument became publicly available the present study aims to reinvestigate the psychometric properties of the CARES for the Flemish population in Belgium.

Methods

The CARES was translated into Flemish following a translation-back translation process. A sample of 192 cancer patients completed the CARES, concurrent measures, and questions on socio-demographic and medical data. Participants were asked to complete the CARES a second time 1 week later, followed by some questions on their experiences with the instrument. Internal consistency, test-retest reliability, content validity, construct validity, concurrent validity and feasibility of the CARES were subsequently assessed.

Results

The Flemish CARES version demonstrated excellent reliability with high internal consistency (range .87–.96) and test-retest ratings (range .70–.91) for all summary scales. Factor analysis replicated the original factor solution of five higher order factors with factor loadings of .325–.851. Correlations with other instruments ranging from |.43|–|.75| confirmed concurrent validity. Feasibility was indicated by the low number of missing items (mean 2.3; SD 5.0) and positive feedback of participants on the instrument.

Conclusions

The Flemish CARES has strong psychometric properties and can as such be a valid tool to assess cancer patients' QOL and needs in research, for example in international comparisons. The positive feedback of participants on the CARES support the usefulness of this tool for systematic assessment of cancer patients' well-being and care needs in clinical practice.

Trial registration

ClinicalTrials.gov: NCT02282696 (July 16, 2014).

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MET and PTEN gene copy numbers and Ki-67 protein expression associate with pathologic complete response in ERBB2-positive breast carcinoma patients treated with neoadjuvant trastuzumab-based therapy

Abstract

Background

Pathologic complete response (pCR) after neoadjuvant chemotherapy for breast cancer is associated with improved prognosis in aggressive tumor subtypes, including ERBB2- positive tumors. Recent adoption of pCR as a surrogate endpoint for clinical trials in early stage breast cancer in the neoadjuvant setting highlights the need for biomarkers that, alone or in combination, help predict the likelihood of response to treatment.

Methods

Biopsy specimens from 29 patients with invasive ductal carcinoma treated with trastuzumab-based therapy prior to definitive resection and pathologic staging were evaluated by dual color bright field in situ hybridization (dual ISH) using probes for MET, TOP2A, PTEN, and PIK3CA genes, each paired with centromeric probes to their respective chromosomes (chromosomes 7, 17, 10, and 3). Ki-67 expression was assessed by immunohistochemistry (IHC). Various parameters describing copy number alterations were evaluated for each gene and centromere probe to identify the optimal parameters for clinical relevance. Combinations of ISH parameters and IHC expression for Ki-67 were also evaluated.

Results

Of the four genes and their respective chromosomes evaluated by ISH, two gene copy number parameters provided statistically significant associations with pCR: MET gain or loss relative to chromosome 7 (AUC = 0.791, sensitivity = 92 % and specificity = 67 % at optimal cutoff, p = 0.0032) and gain of PTEN (AUC = 0.674, sensitivity = 38 % and specificity = 100 % at optimal cutoff, p = 0.039). Ki-67 expression was also found to associate significantly with pCR (AUC = 0.726, sensitivity = 100 % and specificity = 42 % at optimal cutoff, p = 0.0098). Combining gain or loss of MET relative to chromosome 7 with Ki-67 expression further improved the association with pCR (AUC = 0.847, sensitivity = 92 % and specificity = 83 % at optimal cutoffs, p = 0.0006).

Conclusions

An immunogenotypic signature of low complexity comprising MET relative copy number and Ki-67 expression generated by dual ISH and IHC may help predict pCR in ERBB2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab. These findings require validation in additional patient cohorts.

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Induction Chemotherapy Followed by Radiotherapy versus Concurrent Chemoradiotherapy in elderly patients with nasopharyngeal carcinoma: finding from a propensity-matched analysis

Abstract

Background

To date, no guideline is proposed for elderly nasopharyngeal carcinoma (NPC) due to lack of prospective clinical trials. The present study comparing the survivals and toxicities in elderly NPC patients received either induction chemotherapy followed by radiotherapy(IC + RT) or concurrent chemoradiotherapy (CCRT) was therefore undertaken to provide a more accurate basis for future clinical practice.

Methods

The eligible elderly NPC patients were retrospectively enrolled. Propensity score matching generated a matched cohort (1:2) composed from CCRT and IC + RT groups. The survivals and treatment-induced toxicities were compared between two groups. Multivariable analysis was carried to identify significant prognostic factors.

Results

The 5-year overall survival, cancer-specific survival, locoregional failure-free survival, distant failure-free survival for all patients were 58.3 %, 62.7 %, 88.7 %, 83.0 %, respectively. No significant survival differences were found between CCRT and IC + RT groups in the propensity-matched cohort. In comparison with the patients who received IC + RT, patients who underwent CCRT were associated with more severe acute toxicities including leucopenia (30 % vs. 6.8 %, P = 0.005), anemia (20 % vs. 4.1 %, P = 0.027), mucositis (63.3 % vs. 34.2 %, P = 0.007), weight loss (23.4 % vs. 4.1 %, P = 0.009). Basicranial bone involvement was an independent prognostic factor that predicted all-cause death (HR = 0.553, 95 % CI 0.329–0.929; P = 0.025) and cancer specific death (HR = 0.558, 95 % CI 0.321–0.969; P = 0.038) in elderly patients.

Conclusions

In the context of no guideline for elderly NPC, the present study suggested IC + RT should be a preferable modality compared with CCRT, with similar treatment outcomes but less acute toxicities.

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Racial differences in six major subtypes of melanoma: descriptive epidemiology

Abstract

Background

Melanoma accounts for the majority of skin cancer deaths. It has over thirty different subtypes. Different races have been observed to differ in multiple aspects of melanoma.

Methods

SEER (Surveillance, Epidemiology, and End Results) data on six major subtypes, namely melanoma in situ (MIS), superficial spreading melanoma (SSM), nodular melanoma (NM), lentigo maligna melanoma (LMM), acral lentiginous melanoma malignant (ALM), and malignant melanoma NOS (NOS), were analyzed. The racial groups studied included NHW (non-Hispanic white), HW (Hispanic white), Black, and Asian/PI (Pacific Islanders). Univariate and multivariate analysis was conducted to quantify racial differences in patients' characteristics, incidence, treatment, and survival.

Results

Significant racial differences are observed in patients' characteristics. For all subtypes except for ALM, NHWs have the highest incidence rates, followed by HWs, while Blacks have the lowest. For ALM, HWs have the highest rate, followed by NHWs. In stratified analysis, interaction between gender and race is observed. For the first five subtypes and localized and regional NOS, the dominating majority of patients had surgery, while for distant NOS, the distribution of treatment is more scattered. Significant racial differences are observed for distant ALM and NOS. For MIS, SSM, NM, LMM, and ALM, there is no significant racial difference in survival. For NOS, significant racial differences in survival are observed for the localized and regional stages, with NHWs having the best and Blacks having the worst five-year survival rates.

Conclusions

Racial differences exist for the six major melanoma subtypes in the U.S. More data collection and analysis are needed to fully describe and interpret the differences across racial groups and across subtypes.

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