Defective Nuclear Lamina in Aneuploidy and Carcinogenesis.

Elizabeth R Smith,Callinice D Capo-Chichi,Xiang-Xi Xu

doi:10.3389/fonc.2018.00529

Abstract

Aneuploidy, loss or gain of whole chromosomes, is a prominent feature of carcinomas, and is generally considered to play an important role in the initiation and progression of cancer. In high-grade serous ovarian cancer, the only common gene aberration is the p53 point mutation, though extensive genomic perturbation is common due to severe aneuploidy, which presents as a deviant karyotype. Several mechanisms for the development of aneuploidy in cancer cells have been recognized, including chromosomal non-disjunction during mitosis, centrosome amplification, and more recently, nuclear envelope rupture at interphase. Many cancer types including ovarian cancer have lost or reduced expression of Lamin A/C, a structural component of the lamina matrix that underlies the nuclear envelope in differentiated cells. Several recent studies suggest that a nuclear lamina defect caused by the loss or reduction of Lamin A/C leads to failure in cytokinesis and formation of tetraploid cells, transient nuclear envelope rupture, and formation of nuclear protrusions and micronuclei during the cell cycle gap phase. Thus, loss and reduction of Lamin A/C underlies the two common features of cancer—aberrations in nuclear morphology and aneuploidy. We discuss here and emphasize the newly recognized mechanism of chromosomal instability due to the rupture of a defective nuclear lamina, which may account for the rapid genomic changes in carcinogenesis.

Highlights

The Cancer Atlas Project [1] determined that TP53 is the only common genetic mutation (96%) found in high-grade serous epithelial ovarian cancer [2, 3], the most common histological subtype of the gynecological malignancy
Based on many of these recent studies and commentaries, as well as our preliminary findings, and we suggest that a nuclear envelope structural defect, such as the loss or reduction of Lamin A/C, a structural protein of the nuclear lamina, may lead to aneuploidy by both mitotic failure and subsequent formation of tetraploid intermediates, and the loss of chromosome(s) through nuclear budding at interphase and the generation and consequent rupture of micronuclei (Figure 2)
We suggest that the loss of the nuclear envelope structural proteins, Lamin A/C, may underlie these two hallmarks of cancer: nuclear envelope defects and chromosomal instability

Summary

Introduction

The Cancer Atlas Project [1] determined that TP53 is the only common genetic mutation (96%) found in high-grade serous epithelial ovarian cancer [2, 3], the most common histological subtype of the gynecological malignancy. Recent observations suggest that a nuclear envelope defect may cause chromosomal numerical instability and aneuploidy in cancer [25,26,27,28], and nuclear budding leading to the loss of chromosomes at the cell cycle interphase may be a major mechanism in the development of aneuploidy in ovarian carcinogenesis [26].

Results

Conclusion