Copy number alterations and allelic ratio in relation to recurrence of rectal cancer

BACKGROUND: In rectal cancer, total mesorectal excision surgery combined with preoperative (chemo)radiotherapy reduces local recurrence rates but does not improve overall patient survival, a result that may be due to the harmful side effects and/or co-morbidity of preoperative treatment. New biomarkers are needed to facilitate identification of rectal cancer patients at high risk for local recurrent disease. This would allow for preoperative (chemo)radiotherapy to be restricted to high-risk patients, thereby reducing overtreatment and allowing personalized treatment protocols. We analyzed genome-wide DNA copy number (CN) and allelic alterations in 112 tumors from preoperatively untreated rectal cancer patients. Sixty-six patients with local and/or distant recurrent disease were compared to matched controls without recurrence. Results were validated in a second cohort of tumors from 95 matched rectal cancer patients. Additionally, we performed a meta-analysis that included 42 studies reporting on CN alterations in colorectal cancer and compared results to our own data. RESULTS: The genomic profiles in our study were comparable to other rectal cancer studies. Results of the meta-analysis supported the hypothesis that colon cancer and rectal cancer may be distinct disease entities. In our discovery patient study cohort, allelic retention of chromosome 7 was significantly associated with local recurrent disease. Data from the validation cohort were supportive, albeit not statistically significant, of this finding. CONCLUSIONS: We showed that retention of heterozygosity on chromosome 7 may be associated with local recurrence in rectal cancer. Further research is warranted to elucidate the mechanisms and effect of retention of chromosome 7 on the development of local recurrent disease in rectal cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-1550-0) contains supplementary material, which is available to authorized users

Overall frequency of imbalance and LOH per chromosome.

<p>Besides the height of the graph, The colors indicate the frequency of LOH; black: >10%, green: >20%, blue: >0%, red: >40%. The balanced group is not plotted; it is the complement of these 2 groups.</p

Distribution of the DNA index in 81 cervical tumor samples.

<p>There is a bimodal distribution of the DNA index with peaks around 1, and close to 2.</p

Analysis steps for SNP array data with the Illumina Beadstudio and the beadarraySNP package.

<p>The data is preprocessed to obtain quality checked and normalized values for intensity and LAIR. Together with the DNA-index these are interpreted on a discrete and categorical scale. The embedded plot shows normalized intensity as dots in the upper panel, and LAIR in the lower panel as hyphens. The segmentation procedure has divided this region in two segments. The left segment has copy number 1 with LOH. The allelic state is A. The right segment has copy number 2 with balance. The allelic state is AB.</p

Frequency of gains and losses.

<p>Gains are depicted on top of the ideograms, while losses are depicted below. The colors indicate the frequency within the dataset; black: >10%, green: >20%, blue: >30%, red: >40%. Gains and losses were identified when the continuous CN deviated more than 15% from the sample average.</p

Clinical data of 81 SNP analyzed patients.

<p>Clinical data of 81 SNP analyzed patients.</p

Frequency of gains and losses in histological groups.

<p>Gains are depicted on top of the ideograms, while losses are depicted below. Red: squamous tumors, green: adenocarcinoma + mixed type, blue: adenosquamous tumors. Adenocarcinoma and mixed type were combined because of the low numbers of samples in these groups.</p

Everolimus in Patients With Advanced Follicular-Derived Thyroid Cancer: Results of a Phase II Clinical Trial

Background: Mammalian target of rapamycin (mTOR) upregulation has been reported to be involved in the pathogenesis of thyroid tumors, and treatment with the mTOR inhibitor everolimus has shown promising results in endocrine tumors. We conducted a prospective phase II clinical trial to determine the efficacy and safety of everolimus in patients with advanced follicular-derived thyroid cancer. Patients and Methods: Twenty-eight patients with progressive metastatic or locally advanced radioactive refractory differentiated thyroid cancer and 7 patients with anaplastic thyroid cancer were included and received everolimus 10 mg orally once daily. The primary endpoint was disease control rate [complete (CR) + partial response (PR) + stable disease (SD). 24 weeks]. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and mutational and pharmacokinetic-related outcomes. Results: Median follow-up duration was 38 months (2-64). Seventeen patients (65%) showed SD, of which 15 (58%) showed SD>24 weeks. No CR or PR was observed. Median PFS and OS were 9 [95% confidence interval (CI): 4 to 14] and 18 (95% CI: 7 to 29) months, respectively. Survival was negatively influenced by the presence of bone metastases. Toxicity was predominantly grade 1/2 and included anemia (64%), cough (64%), stomatitis (61%), and hyperglycemia (61%). Duration of SD was related to everolimus exposure. The presence of somatic gene variants related to mTOR signaling did not clearly stratify for responses. Conclusion: Everolimus has clinically relevant antitumor activity in patients with advanced differentiated thyroid cancer. Given the observed disease control rate and the relatively low toxicity profile, further investigation of everolimus in sequential or combination therapy in these patients is warranted