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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.

Colorectal carcinomas are characterized by frequent recurrent gains and losses of chromosomal material, especially gains of chromosome arms 20q and 13q, and losses of chromosome arms 18q and 4q. These may be important in the development and progression of colorectal carcinomas. Chromosomal aberrations detected by comparative genomic hybridization in 67 sporadic colorectal carcinomas were examined for their possible associations with patient survival. Dukes' stage, tumor DNA ploidy status, and TP53 genotype/phenotype were also examined for the same. Patients with losses of chromosomal arms 1p, 4q, 8p, 14q, or 18q or gain of chromosomal arm 20q had significantly shorter survival times than those without these aberrations (univariate relative risk 3.45, 2.71, 3.32, 3.26, 3.32, 3.91, respectively), as did patients with more than six chromosomal aberrations per tumor than those with fewer than six aberrations (univariate relative risk 3.26, P = 0.013). DNA aneuploidy and Dukes' stage C + D resulted in poor patient survival (univariate relative risk 3.58, 3.39, respectively). Dukes' stage C + D, 1p loss and 8p loss emerged as the only independent prognostic parameters (relative risk 3.22, 2.53, 2.45, respectively) when entered into multivariate survival analysis together with other significant parameters from univariate survival analysis. Loss of chromosome arm 1p, 4q, 8p, 14q, or 18q or gain of chromosome arm 20q thus results in shortened survival times in colorectal cancer patients. 1p loss and 8p loss were shown to be independent predictors of poor prognosis.

Background:  Keratoacanthomas are benign, clinically distinct skin tumors that may infiltrate and show cellular atypia. A viral etiology has been suggested, and the aim was to search for human papillomavirus (HPV) in keratoacanthomas. Methods:  From 21 immunosuppressed organ transplant recipients and 11 non‐immunosuppressed patients, 72 fresh biopsies with diagnosis of keratoacanthomas were analyzed. For detection of cutaneous and genital HPV DNA, single‐tube nested ‘hanging droplet’ polymerase chain reaction (PCR) and another PCR (GP5+ and 6+) were used, respectively. Results:  Among 21 immunosuppressed patients, 71% (15/21) harbored HPV DNA at least in one sample. Of the keratoacanthoma lesions, 55% (33/60) were HPV DNA positive. Fourteen samples from eight immunosuppressed patients contained HPV types 5, 9, 10, 14, 19, 20, 21, 38, 49, 80, putative HPV types as HPVvs20‐4, HPVvs75, and HPVvs92 and FA16.1, FA23.2, FA37, FA75, and FA81. Among 11 non‐immunosuppressed patients, 36% (4/11) harbored HPV DNA at least in one sample, and 33% (4/12) of their keratoacanthomas were HPV DNA positive. In total, HPV DNA was detected in 51% (37/72) of the keratoacanthomas. Conclusions:  By the use of PCR, cutaneous HPV DNA was detected in 51% (37/72) of the keratoacanthomas. No predominating HPV type or genital HPV type was identified. The role of HPV in keratoacanthomas remains thus elusive.

No abstract

Keratoacanthomas are commonly occurring benign skin lesions localized to sun-exposed areas. They typically develop rapidly and may show cellular atypia and infiltration like cutaneous squamous cell carcinomas, but they finally regress spontaneously. This benign lesion shows a high degree of genetic instability as assessed by comparative genomic hybridization, with 35.7% (25 of 70) of the analyzed lesions harboring chromosomal aberrations. The same frequency of genetic imbalance was found in lesions from immunosuppressed organ transplant recipients (36.4%, 20 of 55) and in patients with keratoacanthomas without immunosuppression (33.3%, five of 15), indicating a common pathway in both situations. Recurrent aberrations, given as a fraction of lesions with aberrations, were gains on 8q (20.0%), 1p and 9q (each 16.0%), and deletions on 3p (20.0%), 9p (20.0%), 19p (20.0%), and 19q (16.0%). Many of the most frequently appearing aberrations in keratoacanthomas were not detected in any of the 10 squamous cell carcinomas analyzed, whereas some aberrations were shared by both types of lesions. Aberrations were found in early and late stages of keratoacanthoma development, indicating a role for genetic instability in the progression as well as involution of keratoacanthomas. There were no significant correlations between cytologic atypia and genetic imbalance, or between degree of infiltration and genetic aberrations, although there was a trend for keratoacanthomas with severe atypia to have aberrations. Thus malignant phenotypic development does not appear to be driven by the detected genetic aberrations. More detailed studies of chromosomal areas with recurrent aberrations are needed for the localization of putative genes that determine the biologic behavior of keratoacanthomas, and that may distinguish them from squamous cell carcinomas.

Intratumor heterogeneity in chromosomal aberrations is believed to represent a major challenge in the treatment of cancer. The aim of our work was to assess the chromosomal heterogeneity of advanced cervical carcinomas and to distinguish aberrations that had occurred at a late stage of the disease from early events. A total of 55 biopsies, sampled from 2-4 different sites within 20 tumors, were analyzed by use of comparative genomic hybridization. Heterogeneous aberrations were identified as those present in at least 1 of the biopsies and which were not seen, nor seen as a tendency, in the others of the same tumor. The homogeneous aberrations were those seen in all biopsies of the tumor. The most frequent homogeneous aberrations were gain of 3q (65%), 20q (65%) and 5p (50%), indicating that these are early events in the development of the disease. Chromosomal heterogeneity was observed in 11 tumors. The most frequent heterogeneous aberrations were loss of 4p14 -q25 (60% of 10 cases with this aberration), and gain of 2p22-pter (50% of 6 cases), 11qcen-q13 (33% of 9 cases) and 8q (27% of 11 cases), suggesting that these events promote progression at a later stage. Many of the heterogeneous regions contained genes known to influence the prognosis of cervical cancer, such as 7p (EGFR), 8q (c-MYC), 11qcen-q13 (CCND1) and 17q (ERBB2). Three evolution sequences for the subpopulations in the heterogeneous tumors were identified: a serial, a parallel and a mixed sequence. In 2 tumors with a serial sequence, it was indicated that the aberrations ؉8 and ؊X had occurred after the other heterogeneous aberrations and hence were the aberrations most recently formed. Our results suggest pronounced chromosomal instability in advanced cervical carcinomas. Moreover, aggressive and treatment-resistant subpopulations may emerge at a late stage and possibly contribute to a poor prognosis of the advanced stages.

The order of appearance of different genetic aberrations during the shift from diploidy/near-diploidy to aneuploidy in colorectal cancers is not yet clear. We studied genetic alterations in flow cytometrically-sorted DNA diploid and corresponding aneuploid epithelial cell populations from each of 20 colorectal tumors using comparative genomic hybridization, FISH, and PCR. Analysis of the 19 cases in which aberrations were found in the flow-sorted diploid population indicated that large-scale aneuploidization in colorectal cancer was preceded by amplification of oncogene(s) localized to chromosome 20q13.2 and by KRAS mutations, but not by TP53 deletions or losses of large chromosomal regions such as 4q, 8p and 18q. ' 2007 Wiley-Liss, Inc.Key words: DNA aneuploidy; DNA diploidy; flow-sorted colorectal tumors; CGH; chromosomal aberrations; FISH; 20q13 gain Colorectal tumorigenesis is characterized by the sequential accumulation of multiple and extensive genomic changes in normal colonic mucosal cells, 1 which ultimately lead to high-level aneuploidy in the majority of tumors. 2 The order of appearance of different genetic aberrations and the molecular mechanisms underlying the shift from diploidy to aneuploidy are not yet clear. The origin of high-level aneuploidy has been suggested to occur via tetraploidization of near-diploid aberrant colonic mucosal cells followed by chromosome loss. 3 Genes responsible for DNA double-strand break repair, chromosomal stability, chromosomal segregation and chromosome disjunction have also been suggested as likely candidates in the development of aneuploidy. 4,5 TP53 gene alterations may also be permissive for aneuploidy, 6 since the resulting loss of wild-type TP53 function may facilitate the formation and survival of cells with abnormal DNA content. Aneuploid colorectal tumors exhibit considerable chromosomal instability as evidenced by frequent gains of chromosomes 20 and 13 and frequent losses of chromosomes 18 and 4. 7,8 Late-stage colorectal adenomas harbor some of the same chromosomal aberrations as seen in colorectal carcinomas, although their incidence is less frequent. 7,9 The putative oncogenes and tumor suppressor genes localized to these frequently-amplified or -deleted chromosomal regions are still mostly unidentified.The resolution of flow cytometric DNA content measurements is limited to the detection of a variation in DNA content of about 5%. Thus cell populations with gain or loss of only 1 or 2 chromosomes may be measured by flow cytometry as having diploid DNA content, even if such near-diploid populations predominate in a cell sample. Flow cytometric DNA content histograms of aneuploid tumors typically show a cell population with ''diploid'' DNA content (Figure 1a). This DNA diploid cell population consists of infiltrating leucocytes and colonic mucosal cells. Some of these colonic mucosal cells may possibly be late-stage adenoma cells or abnormal cells (with some few chromosomal aberrations) that are at an early stage of tumor progression, and which may stil...