Loss of distal 11q is associated with DNA repair deficiency and reduced sensitivity to ionizing radiation in head and neck squamous cell carcinoma

Abstract

About 45% of head and neck squamous cell carcinomas (HNSCC) are characterized by amplification of chromosomal band 11q13. This amplification occurs by a breakage-fusion-bridge (BFB) cycle mechanism. The first step in the BFB cycle involves breakage and loss of distal 11q, from FRA11F (11q14.2) to 11qter. Consequently, numerous genes, including three critical genes involved in the DNA damage response pathway, MRE11A, ATM, and H2AFX are lost in the step preceding 11q13 amplification. We hypothesized that this partial loss of genes on distal 11q may lead to a diminished DNA damage response in HNSCC. Characterization of HNSCC using fluorescence in situ hybridization (FISH) revealed concurrent partial loss of MRE11A, ATM, and H2AFX in all four cell lines with 11q13 amplification and in four of seven cell lines without 11q13 amplification. Quantitative microsatellite analysis and loss of heterozygosity studies confirmed the distal 11q loss. FISH evaluation of a small series of HNSCC, ovarian, and breast cancers confirmed the presence of 11q loss in at least 60% of these tumors. All cell lines with distal 11q loss exhibited a diminished DNA damage response, as measured by a decrease in the size and number of gamma-H2AX foci and increased chromosomal instability following treatment with ionizing radiation. In conclusion, loss of distal 11q results in a defective DNA damage response in HNSCC. Distal 11q loss was also unexpectedly associated with reduced sensitivity to ionizing radiation. Although the literature attributes the poor prognosis in HNSCC to 11q13 gene amplification, our results suggest that distal 11q deletions may be an equally significant factor.

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma

“…Co-amplification between 11q13.3 and 11q22 has recently been confirmed in NGS data (Cancer Genome Atlas Network, 2015), proposed to stem from a selective pressure for amplification and over-expression of both FADD (11q13.3) and BIRC2 (11q22) in HNSCC, with likely anti-apoptotic effect. In other studies, 11q13.3 amplification has been associated with deletions of regions distal to 11q14 (Bockmuhl et al, 2002;Parikh et al, 2007), and deletions of 3p regions, each likely to involve loss of tumour suppressor genes which may contribute to disease progression and clinical outcome.…”

γH2AX as a molecular marker of aging and disease

“…38,39 This is consistent with the fact that numerous other DDR genes are located at the distal q arm including, ATM and meiotic recombination 11 (MRE11). 40 Therefore, loss of the region severely compromises the DDR, resulting in chromosomal instability and carcinogenesis. 40,41 For example, the findings from an interesting study indicated that genetic variability in the H2AFX enhances the risk of non-Hodgkin lymphoma (NHL).…”

“…40 Therefore, loss of the region severely compromises the DDR, resulting in chromosomal instability and carcinogenesis. 40,41 For example, the findings from an interesting study indicated that genetic variability in the H2AFX enhances the risk of non-Hodgkin lymphoma (NHL). 34 In this particular γH2AX as a molecular marker of aging and disease at Ser-139 to form γH2AX is an early cellular response to DNA double-strand breaks.…”

In Vitro Biological Characterization of DCUN1D5 in DNA Damage Response

“…Wei Guo 1 , Guo-Jun Li 4 , Hong-Bo Xu 1 , Jie-Shi Xie 2 , Tai-Ping Shi 2 , Sheng-Zhong Zhang 3 , Xiao-Hong Chen 1 *, Zhi-Gang Huang 1 * advanced tumor progression and an aggressive phenotype (Zhou et al, 2005;Parikh et al, 2007). DCUN1D5 cDNA encoded a protein of 237 amino acids, which contained two domains associated with DNA repair and cell cycle regulation (Kurz et al, 2005;Yang et al, 2007).…”