Unexpected frequency of genomic alterations in histologically normal colonic tissue from colon cancer patients

Abstract

As shown by genomic studies, colorectal cancer (CRC) is a highly heterogeneous disease, where copy number alterations (CNAs) may greatly vary among different patients. To explore whether CNAs may be present also in histologically normal tissues from patients affected by CRC, we performed CGH + SNP Microarray on 15 paired tumoral and normal samples. Here, we report for the first time the occurrence of CNAs as a common feature of the histologically normal tissue from CRC patients, particularly CNAs affecting different oncogenes and tumor-suppressor genes, including some not previously reported in CRC and others known as being involved in tumor progression. Moreover, from the comparison of normal vs paired tumoral tissue, we were able to identify three groups: samples with an increased number of CNAs in tumoral vs normal tissue, samples with a similar number of CNAs in both tissues, and samples with a decrease of CNAs in tumoral vs normal tissue, which may be likely due to a selection of the cell population within the tumor. In conclusion, our approach allowed us to uncover for the first time an unexpected frequency of genetic alteration in normal tissue, suggesting that tumorigenic genetic lesions are already present in histologically normal colonic tissue and that the use in array comparative genomic hybridization (CGH) studies of normal samples as reference for the paired tumors can lead to misrepresented genomic data, which may be incomplete or limited, especially if used for the research of target molecules for personalized therapy and for the possible correlation with clinical outcome.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-016-5181-0) contains supplementary material, which is available to authorized users.

Identification of different mutational profiles in cancers arising in specific colon segments by next generation sequencing

“…APC, KRAS, TP53) (data not shown). This result is in agreement with a recent manuscript showing the occurrence of CNAs as a common feature of the histologically normal tissue from CRC patients [ 23 ]. For this reason, the filtering of germline variants, for the identification of true somatic mutations, was performed by pooling the variants detected in the 13 PBL samples, generating a “virtual pool” of germline variants as previously described [ 24 – 27 ].…”

Genomic approaches to accelerate cancer interception

“…Cancer is thought to proceed through a multi-step process where accumulating alterations in driver genes allow cells to clonally expand and invade surrounding tissues 34 . A limited number of RNA and DNA sequencing studies interrogating a range of precancerous tissues from the breast 35–39 , colon 40–44 , lung 45,46 , head and neck 47 , skin 48,49 , and esophagus 50–55 have indicated that the path to cancer development is context-specific and involves diverse processes. Thesey studies suggest that early lesions are polyclonal and driver mutations present in late-stage disease, and that tumor development occurs via large-scale genomic rearrangements and copy number changes.…”

Hypothesis about Transdifferentiation As Backbone of Malignancy

“…A clear proof of that, concerning for instance the trophoblastic program, is the reproductive cloning through somatic cell nuclear transfer, which leads to all the intra- and extra-embryonic structures, and in particular the placenta. The probability of completion of malignant transdifferentiation is supposed to be infinitely small as compared to the rate of potentially oncogenic mutations ( 10 – 13 ). This matches the fact that the cancer rate in the population would otherwise be disproportionate to the observed one.…”