High frequency of loss of heterozygosity in actinic keratoses, a usually benign disease

doi:10.1016/S0140-6736(94)92343-4

The Lancet

Volume 344, Issue 8925, 17 September 1994, Pages 788-789

https://doi.org/10.1016/S0140-6736(94)92343-4 Get rights and content

Abstract

Actinic keratoses (AKs) are focal areas of dysplasia with low risk of progression to squamous cell cancer; many regress spontaneously. Using polymerase-chain-reaction micro-satellite analysis, we found that loss of heterozygosity on several chromosome arms, including 17p, 17q, 9p, 9q, and 13q, was common in AKs. More than half the AKs examined showed loss of heterozygosity at four or more loci. The a pparent genetic instability of these lesions contrasts with their benign clinical course.

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Cited by (64)

Subclonal Evolution of Cancer-Related Gene Mutations in p53 Immunopositive Patches in Human Skin
2018, Journal of Investigative Dermatology
Citation Excerpt :
Indeed, the mutation burden within our AKs was similar to that reported in cSCCs, suggesting that minimal additional genetic events may be necessary for some AKs to progress to cSCCs. Similar to the targeted sequencing, WES analysis also demonstrated allelic loss in our AKs, including one AK with extensive loss of heterozygosity (Supplementary Table S1 online), consistent with the previous report of high frequency of allelic losses in AKs (Rehman et al., 1994). However, despite the high mutation load in AKs, previous observational studies have reported that 26–74% of AKs in humans can regress either spontaneously or with the use of sunscreen (Frost et al., 2000; Marks et al., 1986; Thompson et al., 1993).
Normal sun-exposed skin contains numerous epidermal patches that stain positive for p53 protein (p53 immunopositive patches, PIPs), which are considered potential early precursors of skin cancer. Although the TP53 gene is mutated in many PIPs, it is unclear whether PIPs contain any other cancer-related mutations. Here we report that PIPs, predominantly <3,000 p53 immunopositive cells in size, within normal chronically exposed skin contain mutations in multiple genes that are mutated in cutaneous squamous cell cancers. These mutations in the PIPs were not detected within the non-PIP epidermis of corresponding normal chronically exposed skin. Although some of these genetic alterations are clonal in the PIPs, many of the mutations are subclonal within these lesions. Similar mutations are seen in later precancers (actinic keratoses and Bowen’s disease). Our results demonstrate that PIPs in chronically exposed skin contain multiple mutations in cancer-related genes. In addition, the results indicate that the clonal evolution of mutations that are seen within later precancerous lesions and in established malignancy can also occur in PIPs within normal human skin.
Quantitative fluorescence in situ hybridization measurement of telomere length in skin with/without sun exposure or actinic keratosis
2014, Human Pathology
Citation Excerpt :
Actinic keratosis and telomere shortening in the skin can be regarded as a disease associated with sun exposure arising through high sensitivity to sun exposure, specific occupations, or lifestyles. Genetic studies of actinic keratosis have demonstrated that more than 50% of cases show loss of heterozygosity [27] and that 69% of cases show aneuploidy [28]. These reports indicate that most cases of actinic keratosis have prominent chromosomal instability.
Chromosomal and genomic instability due to telomere dysfunction is known to play an important role in carcinogenesis. To study telomere shortening in the epidermis surrounding actinic keratosis, we measured telomere lengths of basal, parabasal, and suprabasal cells in epidermis with actinic keratosis (actinic keratosis group, n = 18) and without actinic keratosis (sun-protected, n = 15, and sun-exposed, n = 13 groups) and in actinic keratosis itself as well as in dermal fibroblasts in the 3 groups, using quantitative fluorescence in situ hybridization. Among the 3 cell types, telomeres of basal cells were not always the longest, suggesting that tissue stem cells are not necessarily located among basal cells. Telomeres of basal cells in the sun-exposed group were shorter than those in the sun-protected group. Telomeres in the background of actinic keratosis and in actinic keratosis itself and those of fibroblasts in actinic keratosis were significantly shorter than those in the controls. Our findings demonstrate that sun exposure induces telomere shortening and that actinic keratosis arises from epidermis with shorter telomeres despite the absence of any histologic atypia.
Donor-derived keratinocytes in actinic keratosis and squamous cell carcinoma in patients with kidney transplant
2013, Journal of Investigative Dermatology
Actinic keratosis: Facts and controversies
2010, Clinics in Dermatology
Citation Excerpt :
Clonality provides evidence that one cell has expanded excessively, giving rise to an entire tumor. AKs have been shown to be clonal,14 with high rates of loss of heterozygosity, specifically on chromosome arms 17p, 17q, 9p, 9q, and 13q.15 Mutations in p53 have been documented on the gene level.16
Actinic keratoses are common lesions that are generally clinically diagnosed. Although currently most actinic keratoses are treated, whether this is truly necessary is debated. Treatment of all actinic keratoses is advocated because preliminary evidence indicates that actinic keratoses may progress to squamous cell carcinomas. Some also consider actinic keratoses equivalent to squamous cell carcinoma.
Are keratoacanthomas variants of squamous cell carcinomas? A comparison of chromosomal aberrations by comparative genomic hybridization
2006, Journal of Investigative Dermatology
Citation Excerpt :
The reported frequencies of malignant transformation within actinic keratosis are debated, but recent data indicate a significant frequency of transformation, possibly higher than 10% (Mittelbronn et al., 1998). Genetic studies have demonstrated a high frequency of loss of heterozygosity in actinic keratosis (Rehman et al., 1994). Contrary to SCCs, no such precursor lesion has been recognized for KAs, which undergo complete regression in almost all cases (Weedon, 2003).
Keratoacanthoma (KA) is a benign keratinocytic neoplasm that usually presents as a solitary nodule on sun-exposed areas, develops within 6–8 weeks and spontaneously regresses after 3–6 months. KAs share features such as infiltration and cytological atypia with squamous cell carcinomas (SCCs). Furthermore, there are reports of KAs that have metastasized, invoking the question of whether or not KA is a variant of SCC. To date no reported criteria are sensitive enough to discriminate reliably between KA and SCC, and consequently there is a clinical need for discriminating markers. We screened fresh frozen material from 132 KAs and 37 SCCs for gross chromosomal aberrations by using comparative genomic hybridization (CGH). Forty-nine KAs (37.1%) and 31 SCCs (83.7%) showed genomic aberrations, indicating a higher degree of chromosomal instability in SCCs. Gains of chromosomal material from 1p, 14q, 16q, 20q, and losses from 4p were seen significantly more frequently in SCCs compared with KAs (P-values 0.0033, 0.0198, 0.0301, 0.0017, and 0.0070), whereas loss from 9p was seen significantly more frequently in KAs (P-value 0.0434). The patterns of recurrent aberrations were also different in the two types of neoplasms, pointing to different genetic mechanisms involved in their developments.
Laboratory markers for COPD in "susceptible" smokers
2006, Clinica Chimica Acta
Smoking is the major risk factor for the development of chronic obstructive pulmonary disease. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition. However, only a relatively small proportion of smokers–about 15%–will develop clinically relevant COPD.
Allergy, airway hyper-responsiveness (AHR) to methacholine, and gender differences have been proposed to identify individuals susceptible to the development of COPD. However, variable response to cigarette smoke clearly suggests genetic susceptibility. Among the COPD candidate genes are those (a) that effect the production of proteases and antiproteases, (b) modulate the metabolism of toxic substances in cigarette smoke, (c) are involved with mucocilliary clearance, and (d) that influence inflammatory mediators. Recently, sputum cells from smokers with and without COPD were tested for Microsatellite DNA Instability (MSI) with positive results. This finding suggests that MSI can be a useful marker of genetic susceptibility and thereby indicate destabilization of the genome in the “susceptible” smoker.
Nevertheless, COPD lacks established viable biomarkers to predict and monitor disease progression and outcome variables. Such monitoring tools may be induced sputum, exhaled air condensate, peripheral blood, urine, bronchial biopsies, and bronchoalveolar lavage fluid (BALF). This review summarizes recent research on potential laboratory markers in smokers and subsequent COPD development.

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Short reportsHigh frequency of loss of heterozygosity in actinic keratoses, a usually benign disease

Abstract

Cell

Lancet

J Am Acad Dermatol

J Invest Dermatol

Oncogenes, tumour suppressor genes, and cell transformation: trying to put it all together

Short reports
High frequency of loss of heterozygosity in actinic keratoses, a usually benign disease