The Occurrence of Genetic Alterations during the Progression of Breast Carcinoma

Abstract

The interrelationship among genetic variations between the developing process of carcinoma and the order of occurrence has not been completely understood. Interpreting the mechanisms of copy number variation (CNV) is absolutely necessary for understanding the etiology of genetic disorders. Oncogenetic tree is a special phylogenetic tree inferential pictorial representation of oncogenesis. In our present study, we constructed oncogenetic tree to imitate the occurrence of genetic and cytogenetic alterations in human breast cancer. The oncogenetic tree model was built on CNV of ErbB2, AKT2, KRAS, PIK3CA, PTEN, and CCND1 genes in 963 cases of tumors with sequencing and CNA data of human breast cancer from TCGA. Results from the oncogenetic tree model indicate that ErbB2 copy number variation is the frequent early event of human breast cancer. The oncogenetic tree model based on the phylogenetic tree is a type of mathematical model that may eventually provide a better way to understand the process of oncogenesis.

Figure 1

The CNV frequency of six candidate genes in the breast carcinoma patients. The CNVs of at least one of the six candidate genes occur in 342 (36%) of 963 cases/patients. The CNV frequencies of the six candidate genes are PIK3CA (5%, 51/963), AKT2 (2%, 22/963), KRAS (3%, 25/963), PTEN (6%, 55/963), ErbB2 (13%, 121/963), and CCND1 (16%, 153/963).

Figure 2

The distant-based and branching oncogenetic tree models for copy number alterations in 963 breast tumors. (a) In the distance-based oncogenetic tree, hidden or unknown events are represented as internal nodes. Leaves between the distances depend on the meaning of copy number changes with greater probability of cluster-related copy number variation. The root of the tree close to the left of the last point in the imbalance of genetic evolution occurred early. Interconnection path represents a high correlation between events, forming clusters of genetic balance. (b) In the branching oncogenetic tree, root represents the event with no alterations. The alterations genes include ErbB2, AKT2, KRAS, PIK3CA, PTEN, and CCND. The aberration of ErbB2 is potentially early event as it is close to the root and also the root of a new subtree.

Figure 3

The frequent oncogenetic trees constructed in the 1000-time bootstrap resampling procedure for the primary n = 963 trees. (a) The original tree; (b) the tree based on the most frequent parent; (c) the tree repeatedly appearing 776 times; (d) the tree replicated 48 times; (e) the tree replicated 45 times; (f) the tree replicated 30 times.