Chromosomal fragility in the cancer-prone disease xeroderma pigmentosum preferentially involves bands relevant for cutaneous carcinogenesis

Abstract

Spontaneous and folate‐induced chromosomal fragility was analyzed in peripheral blood lymphocytes from 6 patients affected by the cancer‐prone disease xeroderma pigmentosum (XP), from the parents of 4 of the patients, and from 12 normal subjects. All XP patients were defective in nucleotide‐excision repair; 4 belonged to group C and 1 each to groups A and D. A tendency toward increased spontaneous chromosomal fragility was observed in the XP family members, and lesions indicating substantial chromosomal damage, which were not observed in any healthy donors, were frequently found. The spontaneous lesion sites in lymphocytes from homozygous and heterozygous carriers of XP defects appeared to be significantly associated with those observed in normal skin fibroblasts from the same subjects. These XP spontaneous fragility sites showed a statistically significant association with the rearrangement breakpoints reported in skin pre‐tumoral and tumoral lesions from normal and unrelated XP donors. Under conditions of folate deprivation, the chromosomal fragility level, the pattern and the frequency of expression of fragile sites in XP patients and in their parents were similar to normal. However, XP patients generally showed a higher susceptibility to breakage at sites described as mutagen and carcinogen targets. Int. J. Cancer 74:654–663, 1997.© 1997 Wiley‐Liss, Inc.

DNA Repair and Transcriptional Deficiencies Caused by Mutations in the Drosophila p52 Subunit of TFIIH Generate Developmental Defects and Chromosome Fragility

“…The most frequent abnormalities were the presence of chromosome breaks and partial chromatid condensation at different mitotic stages. In mammals, chromosomal fragility is common in solid tumors (25), and chromosome instability has been reported in fibroblasts derived from XP individuals, as well as uncontrolled DNA breakage in UV-irradiated XPD from cells of patients (3,5,28). However, there are few studies of global genome integrity in patients with deficiencies in TFIIH (17).…”

4-Nitroquinoline-1-Oxide-Induced Mutagen Sensitivity and Risk of Nonmelanoma Skin Cancer: A Case–Control Analysis

“…Although mutagen sensitivity was measured in cultured peripheral lymphocytes, high susceptibility to carcinogeninduced chromatid breaks has a clear genetic basis (Cloos et al, 1999;Tedeschi et al, 2004), and either spontaneous or in vitro-induced chromosomal aberrations by mutagens or carcinogens are relevant to cutaneous carcinogenesis in the target organ (Wei et al, 1996a;Lanza et al, 1997). The feasibility of procuring peripheral blood samples, the ease of using this in vitro 4-NQO mutagen sensitivity assay, and the small amount (2 ml) of blood needed for this assay make it a promising biomarker for assessing individual susceptibility to cancer.…”

Aneuploidy and Cancer: From Correlation to Causation

“…According to the chromosomal theory these mutations are genetic equivalents of carcinogens that induce aneuploidy at high rates. This view is supported by the presence of aneuploidy in such patients prior to carcinogenesis, as for example in mosaic variegated aneuploidy patients [183,184], Bloom patients [182] and xeroderma patients [185], and by the presence of aneuploidy in the cancers of patients with retinoblastoma [186][187][188][189], mosaic variegated aneuploidy [183,184], xeroderma [185,190] and Bloom patients [182].…”