Next-Generation Sequencing of Matched Primary and Metastatic Rectal Adenocarcinomas Demonstrates Minimal Mutation Gain and Concordance to Colonic Adenocarcinomas

Abstract

-The somatic mutations identified in our rectal adenocarcinoma cohort showed a strong correlation to those previously characterized in colonic adenocarcinoma. In addition, most rectal adenocarcinomas harbored identical somatic mutations in both the primary tumor and metastasis. These findings demonstrate evidence that rectal adenocarcinoma follows a similar molecular pathogenesis as colonic adenocarcinoma and that sampling either the primary or metastatic lesion is valid for initial evaluation of somatic mutations and selection of possible targeted therapy.

Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing

“…Hence, the present data validates mutations in genes (e.g. APC, KRAS, NRAS, TP53 ) known to be involved in (sporadic) CRC development and throughout progression [ 13 , 16 , 17 , 27 ] with close reference to the clinico-pathological features. In fact, these key mutations, here referring to the exact sequence variant, were not directly associated with the primary tumour location (left or right colon, rectum) and histology, tumour stage, grading or molecular sub-type (Microsatellite-(in)stability; CpG-Island methylator phenotype) in this small cohort.…”

“…For example, a large study of initially 2000 CRC patients, then selected 468 cases for NGS and of these only 19 cases had matched metastases, with 12/19 cases presenting distant metastases [ 19 ]. In other studies, 13 cases with mainly liver metastases [ 13 ]; 24 cases with either one ( n = 7), two ( n = 11) or three ( n = 6) local or distant metastatic lesions (lymph node, liver, lung, brain) [ 17 ]; 16 rectal carcinomas with lymph node ( n = 13/16), liver ( n = 1/16) or lung ( n = 2/16) [ 16 ] were included. All of these studies were performed by semi-conductor NGS technology as compared to the present study using a sequencing-by-synthesis tNGS approach.…”

“…Indeed, there are increasing numbers of reports on the general reliability and applicability of tNGS for mutation analyses of formalin-fixed and paraffin-embedded (FFPE) tissue specimens and/or the generation of tumour-entity specific tNGS gene panels, using different platforms and library preparation approaches [ 7 – 12 ]. In addition, several investigators compared primary colon and/or rectal tumours and metastases by NGS approaches in cohorts of 13 cases [ 13 ], 15 cases [ 14 ], 18 cases [ 15 ], 20 cases [ 16 ], 24 cases [ 17 ], 34 cases [ 18 ] or >400 cases [ 19 ]. These studies were based on fresh-frozen tissue specimens [ 15 ] or assessment of FFPE tissue specimens by amplicon-based semi-conductor NGS technology [ 13 , 16 , 17 , 19 ], or evaluation of fresh-frozen tissue specimens with >70 % tumour cell content by whole exome sequencing [ 14 , 18 ].…”

Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

“…Most common mutations were in the APC, TP53, and KRAS genes, which is similar but not identical to the mutations most commonly observed by others. 20 The differences could suggest alternative genetic or environmental mechanisms in our cohort of patients from New Mexico. Figure 1B shows a plot of the observed VAF for each of the COSMIC mutations shown in Figure 1A.…”

A Crispr Knockout Screen Identifies Foxf1 as a Suppressor of Colorectal Cancer Metastasis that Acts through Reduced mTOR Signalling

“…Genomic studies searching for metastasis-specific driver mutations have had limited success in humans (8,9). Unravelling the complexity of metastasis may therefore require alternative strategies that complement human cohort-based approaches.…”