Low-cost and clinically applicable copy number profiling using repeat DNA.

BACKGROUND: Somatic copy number alterations (SCNAs) are an important class of genomic alteration in cancer. They are frequently observed in cancer samples, with studies showing that, on average, SCNAs affect 34% of a cancer cell's genome. Furthermore, SCNAs have been shown to be major drivers of tumour development and have been associated with response to therapy and prognosis. Large-scale cancer genome studies suggest that tumours are driven by somatic copy number alterations (SCNAs) or single-nucleotide variants (SNVs). Despite the frequency of SCNAs and their clinical relevance, the use of genomics assays in the clinic is biased towards targeted gene panels, which identify SNVs but provide limited scope to detect SCNAs throughout the genome. There is a need for a comparably low-cost and simple method for high-resolution SCNA profiling. RESULTS: We present conliga, a fully probabilistic method that infers SCNA profiles from a low-cost, simple, and clinically-relevant assay (FAST-SeqS). When applied to 11 high-purity oesophageal adenocarcinoma samples, we obtain good agreement (Spearman's rank correlation coefficient, rs=0.94) between conliga's inferred SCNA profiles using FAST-SeqS data (approximately £14 per sample) and those inferred by ASCAT using high-coverage WGS (gold-standard). We find that conliga outperforms CNVkit (rs=0.89), also applied to FAST-SeqS data, and is comparable to QDNAseq (rs=0.96) applied to low-coverage WGS, which is approximately four-fold more expensive, more laborious and less clinically-relevant. By performing an in silico dilution series experiment, we find that conliga is particularly suited to detecting SCNAs in low tumour purity samples. At two million reads per sample, conliga is able to detect SCNAs in all nine samples at 3% tumour purity and as low as 0.5% purity in one sample. Crucially, we show that conliga's hidden state information can be used to decide when a sample is abnormal or normal, whereas CNVkit and QDNAseq cannot provide this critical information. CONCLUSIONS: We show that conliga provides high-resolution SCNA profiles using a convenient, low-cost assay. We believe conliga makes FAST-SeqS a more clinically valuable assay as well as a useful research tool, enabling inexpensive and fast copy number profiling of pre-malignant and cancer samples.

Yield of Surveillance Colonoscopies 1 Year After Curative Surgical Colorectal Cancer Resections.

BACKGROUND & AIMS: Endoscopic surveillance after curative colorectal cancer (CRC) resection is routine. However, there is controversy whether the 1-year interval between preoperative and postoperative colonoscopy is justified owing to improved colonoscopy standards. We aimed to assess the yield of surveillance colonoscopies 1 year after CRC surgery. METHODS: We performed a retrospective cohort study of 572 patients (54.9% male; mean age, 66.2 ± 9.9 y), who underwent curative surgical resection of a first CRC from June 2013 through April 2016 in the Northwest region of The Netherlands. Patients were included if a complete clearing colonoscopy was performed before surgery and the interval between the preoperative and postoperative colonoscopy was 12 months (range, 6-20 mo), conforming to Dutch guidelines. The primary outcome of the study was the yield of CRC at the surveillance colonoscopy performed 1 year after curative resection. A secondary outcome was the yield of advanced neoplasia. RESULTS: After a mean surveillance interval of 13.7 months (±2.8 mo), 10 of 572 patients (1.7%; 95% CI, 0.7%-2.8%) received a diagnosis of CRC. Of these, 5 CRCs were apparently metachronous cancers (3 were stage III or IV) and 5 were recurrences at the anastomosis (1 was stage IV). In 11.4% of patients (95% CI, 8.9%-13.8%), advanced neoplasia was detected at the 1-year follow-up colonoscopy. Synchronous advanced neoplasia at baseline colonoscopy was a risk factor for detection of advanced neoplasia at the follow-up colonoscopy (odds ratio, 2.2; 95% CI, 1.3-3.8; P ≤ .01). CONCLUSIONS: Despite high colonoscopy quality, the yield of CRC at surveillance colonoscopy 1 year after CRC resection was 1.7%. These were metachronous CRCs and recurrences, often of advanced stage. The high yield justifies the recommendation of a 1-year surveillance interval after surgical CRC resection.

Molecular stool testing as an alternative for surveillance colonoscopy: a cross-sectional cohort study.

BACKGROUND: As in many other European countries, a nationwide screening program for colorectal cancer (CRC) has recently been introduced in the Netherlands. As a side effect, such a screening program will inherently yield an increase in the demand for surveillance after removal of polyps/adenomas or CRC. Although these patients are at increased risk of metachronous colorectal neoplasia, solid evidence on CRC-related mortality reduction as a result of colonoscopy-based surveillance programs is lacking. Furthermore, colonoscopy-based surveillance leads to high patient burden, high logistic demands and high costs. Therefore, new surveillance strategies are needed. The aim of the present study, named Molecular stool testing for Colorectal CAncer Surveillance (MOCCAS), is to determine the performance characteristics of two established non-invasive tests, i.e., the multitarget stool DNA test Cologuard® and the faecal immunochemical test (FIT) in the detection of CRC and advanced adenomas as an alternative for colonoscopy surveillance. METHODS: In this observational cross-sectional cohort study, subjects aged 50 to 75 years will be approached to collect (whole-) stool samples for molecular testing and a FIT prior to their scheduled surveillance colonoscopy. The results of the tests will allow calculation of test sensitivities and specificities in the context of surveillance. This will provide the required input for the Dutch ASCCA model (Adenoma and Serrated pathway to Colorectal CAncer) to simulate surveillance strategies differing in frequency and duration. The model will allow predictions of lifetime health effects and costs. Multiple centres in the Netherlands will participate in the study that aims to include 4,000 individuals. DISCUSSION: The outcome of this study will inform on the (cost-) effectiveness of stool based molecular testing as an alternative for colonoscopy in the rapidly expanding surveillance population. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT02715141 . Retrospectively registered 17 February 2016.

Colorectal cancer screening by colonoscopy: putting it into perspective.

Implementation of nationwide screening programs aims to decrease the disease burden of colorectal cancer (CRC) in the general population. Globally, most population screening programs for CRC are carried out by either fecal occult blood test, flexible sigmoidoscopy or colonoscopy. For screening programs with colonoscopy as the primary method, only circumstantial evidence from observational studies is available to prove its effectiveness, suggesting that colonoscopy effectively reduces CRC incidence and mortality. Currently, large randomized trials are being conducted to corroborate these findings. Besides the direct effect of a screening program for CRC, its protective effect is further enhanced by enrolment of patients that underwent polypectomy in surveillance programs. However, despite CRC screening and surveillance colonoscopies, interval CRC still occur. Those are predominantly located in the right-sided colon and potential explanations, besides unfavorable tumor characteristics, are preventable operator-dependent factors relating to the quality of the colonoscopy procedure. In an effort to reduce differences in endoscopists' performance and thereby the occurrence of interval CRC, quality indicators of colonoscopy have been introduced. In addition, emerging advanced colonoscopy techniques might contribute to improvement in polyp detection and removal. Meticulous inspection of the colonic mucosa not only results in the detection of advanced and relevant lesions, but also in the removal of many diminutive and small lesions leading to an increasing number of surveillance colonoscopies, known as the 'high-detection paradox'. More data on the cost-effectiveness of high-quality colonoscopy as a primary screening method and surveillance programs with intervals based on optimal risk stratification are eagerly awaited.