The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4-CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery-an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.

Individuals with melanocortin 1 receptor (MC1R) gene variants have been shown to carry an increased risk for the development of melanoma. In this study, we investigated the relationship of MC1R gene variants and the risk of melanoma in 123 melanoma patients and 155 control subjects from Greece. The entire MC1R gene was sequenced for polymorphisms and the results were correlated with host factors and pigmentary characteristics. MC1R polymorphisms were present in 59.4% of melanoma patients compared to 37.5% of controls, yielding an odds ratio (OR) of 2.43 (95% confidence interval (CI) = 1.50-3.96, P < 0.001) for melanoma among MC1R carriers. The risk of melanoma was enhanced in individuals carrying multiple variant alleles (OR = 6.97; 95% CI = 1.86-26.12, P = 0.004). Only the Val60Leu, Arg142His, and Arg151Cys variants were significantly associated with melanoma risk. In stratified analysis, the risk of melanoma among MC1R carriers was not influenced by skin phototype, skin color, or hair color. No association was found between MC1R genotype and the age of onset of melanoma, the tumor location, or the tumor thickness. In conclusion, MC1R polymorphisms are a predisposing factor of melanoma in a southern European population with a relatively low incidence of the disease.

BackgroundCarriers of apparently balanced translocations are usually phenotypically normal; however in about 6% of de novo cases, an abnormal phenotype is present. In the current study we investigated 12 patients, six de novo and six familial, with apparently balanced translocations and mental retardation and/or congenital malformations by applying 1 Mb resolution array-CGH. In all de novo cases, only the patient was a carrier of the translocation and had abnormal phenotype. In five out of the six familial cases, the phenotype of the patient was abnormal, although the karyotype appeared identical to other phenotypically normal carriers of the family. In the sixth familial case, all carriers of the translocations had an abnormal phenotype.ResultsChromosomal and FISH analyses suggested that the rearrangements were "truly balanced" in all patients. However, array-CGH, revealed cryptic imbalances in three cases (3/12, 25%), two de novo (2/12, 33.3%) and one familial (1/12, 16.6%). The nature and type of abnormalities differed among the cases. In the first case, what was identified as a de novo t(9;15)(q31;q26.1), a complex rearrangement was revealed involving a ~6.1 Mb duplication on the long arm of chromosome 9, an ~10 Mb deletion and an inversion both on the long arm of chromosome 15. These imbalances were located near the translocation breakpoints. In the second case of a de novo t(4;9)(q25;q21.2), an ~6.6 Mb deletion was identified on the short arm of chromosome 7 which is unrelated to the translocation. In the third case, of a familial, t(4;7)(q13.3;p15.3), two deletions of ~4.3 Mb and ~2.3 Mb were found, each at one of the two translocation breakpoints. In the remaining cases the translocations appeared balanced at 1 Mb resolution.ConclusionThis study investigated both de novo and familial apparently balanced translocations unlike other relatively large studies which are mainly focused on de novo cases. This study provides additional evidence that cryptic genomic imbalances are common in patients with abnormal phenotype and "apparently balanced" translocations not only in de novo but can also occur in familial cases. The use of microarrays with higher resolution such as oligo-arrays may reveal that the frequency of cryptic genomic imbalances among these patients is higher.

Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes.

Genome‐wide studies in tumor cells have indicated that chromatin‐modifying proteins are commonly mutated in human cancers. The lysine‐specific methyltransferase 2C ( KMT 2C/ MLL 3) is a putative tumor suppressor in several epithelia and in myeloid cells. Here, we show that downregulation of KMT 2C in bladder cancer cells leads to extensive changes in the epigenetic status and the expression of DNA damage response and DNA repair genes. More specifically, cells with low KMT 2C activity are deficient in homologous recombination‐mediated double‐strand break DNA repair. Consequently, these cells suffer from substantially higher endogenous DNA damage and genomic instability. Finally, these cells seem to rely heavily on PARP 1/2 for DNA repair, and treatment with the PARP 1/2 inhibitor olaparib leads to synthetic lethality, suggesting that cancer cells with low KMT 2C expression are attractive targets for therapies with PARP 1/2 inhibitors.

Osteoarthritis is the most common form of arthritis with still unknown pathogenic etiology and considerable contribution of genetic factors. One of the mechanisms of cartilage degradation in osteoarthritis is enzymatic proteolysis of the extracellular matrix by metalloproteinases. MMP-1, produced by chondrocytes and synovial cells, is a major proteinase of the MMPs family. The present study aims at evaluating the association of MMP1 gene -1607 1G/2G (rs1799750) polymorphism with primary knee osteoarthritis in the Greek population. One hundred fifty five patients with primary symptomatic knee osteoarthritis participated in the study along with 139 controls. Genotypes were determined using PCR-RLFP technique. Allelic and genotypic frequencies were compared between both study groups. There was no significant association between MMP1 -1607 1G/2G polymorphism and knee osteoarthritis, in crude analysis; however, after multiple logistic regression analysis, 1G/2G was associated with reduced odds of knee osteoarthritis by 75% in males, compared to genotypes 1G/1G þ 2G/2G, adjusting for age and BMI (adjusted OR: 0.25, 95% CI: 0.069, 0.910, p ¼ 0.035). The present study shows that MMP1 -1607 1G/2G (rs1799750) polymorphism might be a risk factor for knee osteoarthritis susceptibility in the Greek population. Further investigations are needed to confirm this association in the pathogenesis of osteoarthritis. ß

Summary Diabetic neuropathy (DN) is a common long‐term complication of type 1 (T1D) and type 2 (T2D) diabetes mellitus, with significant morbidity and mortality. DN is defined as impaired function of the autonomic and/or peripheral nervous system, often subclinical, particularly in children and adolescents with T1D. Nerve conduction studies (NCS) and skin biopsies are considered gold‐standard methods in the assessment of DN. Multiple environmental and genetic factors are involved in the pathogenesis of DN. Specifically, the role of metabolic control and glycemic variability is of paramount importance. A number of recently identified genes, including the AKR1B1, VEGF, MTHFR, APOE, and ACE genes, contribute significantly in the pathogenesis of DN. These genes may serve as biomarkers to predict future DN development or treatment response. In addition, they may serve as the basis for the development of new medications or gene therapy. In this review, the diagnostic evaluation, pathogenesis, and associated genetic markers of DN in children and adolescents with T1D are presented and discussed.

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