Malignant transformation and genetic alterations are uncoupled in early colorectal cancer progression.

BACKGROUND: Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression. RESULTS: Here, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas. CONCLUSION: Genetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression.

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas and pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine neoplasms (PanNENs) fall into two subclasses: the well-differentiated, low- to high-grade pancreatic neuroendocrine tumors (PanNETs), and the poorly-differentiated, high-grade pancreatic neuroendocrine carcinomas (PanNECs). While recent studies suggest an endocrine descent of PanNETs, the origin of PanNECs remains unknown. METHODS: We performed DNA methylation analysis for 57 PanNEN samples and found that distinct methylation profiles separated PanNENs into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA alterations and immunohistochemistry of cell-type markers PDX1, ARX, and SOX9 were utilized to further characterize PanNECs and their cell of origin in the pancreas. RESULTS: Phylo-epigenetic and cell-type signature features derived from alpha, beta, acinar, and ductal adult cells suggest an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin. CONCLUSIONS: Our study provides a robust and clinically applicable method to clearly distinguish PanNECs from G3 PanNETs, improving patient stratification.

DNA copy number changes define spatial patterns of heterogeneity in colorectal cancer.

Genetic heterogeneity between and within tumours is a major factor determining cancer progression and therapy response. Here we examined DNA sequence and DNA copy-number heterogeneity in colorectal cancer (CRC) by targeted high-depth sequencing of 100 most frequently altered genes. In 97 samples, with primary tumours and matched metastases from 27 patients, we observe inter-tumour concordance for coding mutations; in contrast, gene copy numbers are highly discordant between primary tumours and metastases as validated by fluorescent in situ hybridization. To further investigate intra-tumour heterogeneity, we dissected a single tumour into 68 spatially defined samples and sequenced them separately. We identify evenly distributed coding mutations in APC and TP53 in all tumour areas, yet highly variable gene copy numbers in numerous genes. 3D morpho-molecular reconstruction reveals two clusters with divergent copy number aberrations along the proximal-distal axis indicating that DNA copy number variations are a major source of tumour heterogeneity in CRC.