Genetic tumor archeology: microdissection and genetic heterogeneity in squamous and basal cell carcinoma

Bäckvall, Helena; Asplund, Anna; Gustafsson, Anna; Sivertsson, Aasa; Lundeberg, Joakim; Pontén, Fredrik

doi:10.1016/j.mrfmmm.2004.10.011

Cited by 48 publications

(48 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, unlike their premalignant precursors, the majority of SCC in situ and invasive SCC were found to be blocked in apoptotic pathways by mechanisms such as upregulation of survivin (Park et al, 2004) or constitutive activation of Akt (Decraene et al, 2004). It therefore appears that, despite the accumulation of p53 mutations both prior to and within AK lesions (Backvall et al, 2005), suppression of apoptosis may be a relatively late event in multistage skin carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

et al. 2006

View full text Add to dashboard Cite

Inhibitor of differentiation/DNA binding (Id) proteins comprise a class of helix-loop-helix transcription factors involved in proliferation, differentiation, apoptosis, and carcinogenesis. We have shown that while Id2 is induced by UVB in primary keratinocytes, Id3 is upregulated only in immortalized cells. We have now determined that the consequences of ectopic expression of Id3 protein are strikingly different between immortalized and primary keratinocytes. Overexpression of Id3 induces a significant increase in apoptotic cells as revealed by Annexin V positivity as well as proteolytic processing of caspase-3 in immortalized, but not in primary keratinocytes. Id3-green fluorescent protein (GFP)-positive cells exhibited a fivefold increase in apoptotic nuclear fragmentation compared to Id3-GFP-negative cells. These apoptotic responses were accompanied by activation of caspase-3, as shown by immunocytochemical staining with antibodies to active caspase-3. Immunostaining with antibodies to the active form of caspase-9 as well as to the active form of Bax further revealed that induction of apoptosis in Id3-overexpressing keratinocytes occurred via a mitochondrial-caspase-9-mediated pathway. Coexpression of dominant-negative caspase-9 with Id3 significantly suppressed apoptotic nuclear fragmentation, indicating that caspase-9 activation is essential for Id3-induced cell death. This response was also markedly attenuated by coexpression with the Bax antagonist antiapoptotic protein Bcl2, confirming a role for Bax activation in this apoptotic response. Id3-induced Bax activation may result from increased expression of Bax protein. Furthermore, reduction of Id3 expression by small interfering RNAs abrogated the UVB-induced proteolytic activation of caspase-3 in these cells. These data together suggest that UVB-induced apoptosis of immortalized keratinocytes is at least in part due to Id3 upregulation in these cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

et al. 2006

View full text Add to dashboard Cite

show abstract

“…To be heritable to offspring, germline mutations must be compatible with gamete functions, conception, early cleavage, implantation, and embryonic and fetal development [Drost and Lee, 1995;Marchetti and Wyrobek, 2005;Crow, 2006]. Regardless of the type of mutation, many DNA sequence alterations ranging from chromosomal aberrations to single base mutations, may occur in somatic cells, but will remain exceedingly rare simply because they do not provide for or enhance cell division and clonal expansion of the new genotype [Hanahan and Weinberg, 2000;Backvall et al, 2005]. However, any mutation in gametes that does not terminally interfere with reproductive and developmental processes is freely propagated and present in every cell of the offspring.…”

Section: Introductionmentioning

confidence: 99%

“…Understanding the risk of disease associated with mutation in humans requires clarification of the occurrence and frequencies of mutations, and knowledge of the mutation spectra in somatic tissues and gametes. Over the last few decades, a significant amount of information associated with somatic diseases has been published on this subject [Hanahan and Weinberg, 2000;Wilson, 2001;Backvall et al, 2005;Tapp et al, 2007]. Unfortunately, information regarding mutation spectra and frequencies in the germline has not received the same degree of attention.…”

Section: Introductionmentioning

confidence: 99%

Human germline and somatic cells have similar TP53 and Kirsten‐RAS gene single base mutation frequencies

Cole

Wilson

2008

Environ and Mol Mutagen

View full text Add to dashboard Cite

Understanding the risk of offspring inheriting rare mutations, and the frequencies at which these mutations are present in germ cells can be explored with direct analysis of human semen samples. The present work utilized the ultrasensitive PCR/RE/LCR mutation assay to detect, identify and determine the prevalence single base substitution mutations in the TP53 and KRAS genes in human sperm. Four disease-associated base sites in the TP53 and KRAS genes, three of which are known to be heritable to live, term offspring, were studied in sperm from eleven human semen specimens. Eight of the specimens (73%) displayed single base substitution mutations, and 30% of all base sites tested were found to harbor mutations ranging in prevalence from 1 x 10(-6) to 1 x 10(-5) wild type sperm. These germ cell single base substitution mutation frequencies are very similar to somatic tissue TP53 and KRAS mutation frequencies. Equivalent single base mutation frequencies in both germ and somatic cells suggest that there is no unusual selection or mutation protective process operating premeiotically in the germline, and that a selection bias at the level of sperm viability, conception, early cleavage, implantation, and/or embryogenesis operates to exclude the majority of these TP53 mutations and all of the activating KRAS mutations.

show abstract

“…In SCC, p53 expression also predominated in the basal layer, particularly at sites of dermal invasion (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/ JCI66721DS1). We therefore performed laser microdissection of p53 + tumor cells from these areas that coexpressed the cytokeratin AE1/AE3 ( Figure 1A), in order to select representative material for genetic analyses (10).…”

Section: Resultsmentioning

confidence: 99%

Human skin carcinoma arising from kidney transplant–derived tumor cells

Verneuil¹,

Varna²,

Ratajczak³

et al. 2013

J. Clin. Invest.

View full text Add to dashboard Cite

Tumor cells with donor genotype have been identified in human skin cancer after allogeneic transplantation; however, the donor contribution to the malignant epithelium has not been established. Kidney transplant recipients have an increased risk of invasive skin squamous cell carcinoma (SCC), which is associated with accumulation of the tumor suppressor p53 and TP53 mutations. In 21 skin SCCs from kidney transplant recipients, we systematically assessed p53 expression and donor/recipient origin in laser-microdissected p53 + tumor cells. In one patient, molecular analyses demonstrated that skin tumor cells had the donor genotype and harbored a TP53 mutation in codon 175. In a kidney graft biopsy performed 7 years before the skin SCC diagnosis, we found p53 + cells in the renal tubules. We identified the same TP53 mutation in these p53 + epithelial cells from the kidney transplant. These findings provide evidence for a donor epithelial cell contribution to the malignant skin epithelium in the recipient in the setting of allogeneic kidney transplantation. This finding has theoretical implications for cancer initiation and progression and clinical implications in the context of prolonged immunosuppression and longer survival of kidney transplant patients.

show abstract

Genetic tumor archeology: microdissection and genetic heterogeneity in squamous and basal cell carcinoma

Cited by 48 publications

References 68 publications

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

Human germline and somatic cells have similar TP53 and Kirsten‐RAS gene single base mutation frequencies

Human skin carcinoma arising from kidney transplant–derived tumor cells

Contact Info

Product

Resources

About