Stuart Ralston and colleagues report results of a genome-wide association study for Paget's disease of bone. Their work identifies common variants at three loci associated with risk of this disease. Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by focal increases in bone turnover, which in some cases is caused by mutations in SQSTM1. To identify additional susceptibility genes, we performed a genome-wide association study in 750 individuals with PDB (cases) without SQSTM1 mutations and 1,002 controls and identified three candidate disease loci, which were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene (P = 5.38 × 10−24). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 × 10−13) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 × 10−13). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

A common chromosomal abnormality in childhood T-cell acute leukemia is a translocation, t(10;14) (q24;q11), that together with the variant t(7;10)(q35;q24) is present in up to 7% of this tumor type. The gene adjacent to the 10q24 region is transcriptionally activated after translocation to either TCRD (14q11) or TCRB (7q35). It encodes a homeobox gene closely related to the developmentally regulated homeotic genes of flies and mammals. The coding capacity of this activated gene, designated HOX11, is undisturbed in a T-cell line carrying the translocation t(7;10)(q35;q24). Therefore, the HOX11 homeobox gene seems to be involved in T-cell tumorigenesis.

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and its incidence continues to rise. Although CSCC usually display a benign clinical behavior, it can be both locally invasive and metastatic. The signaling pathways involved in CSCC development have given rise to targetable molecules in recent decades. In addition, the high mutational burden and increased risk of CSCC in patients under immunosuppression were part of the rationale for developing the immunotherapy for CSCC that has changed the therapeutic landscape. This review focuses on the molecular basis of CSCC and the current biology-based approaches of targeted therapies and immune checkpoint inhibitors. Another purpose of this review is to explore the landscape of drugs that may induce or contribute to the development of CSCC. Beginning with the pathogenetic basis of these drug-induced CSCCs, we move on to consider potential therapeutic opportunities for overcoming this adverse effect.

We screened index cases from 410 Spanish breast/ovarian cancer families and 214 patients (19 of them males) with breast cancer for germ‐line mutations in the BRCA1 and BRCA2 genes, using SSCP, PTT, CSGE, DGGE, and direct sequencing. We identified 60 mutations in BRCA1 and 53 in BRCA2. Of the 53 distinct mutations observed, 11 are novel and 12 have been reported only in Spanish families (41.5%). The prevalence of mutations in this set of families was 26.3%, but the percentage was higher in the families with breast and ovarian cancer (52.1%). The lowest proportion of mutations was found in the site‐specific female breast cancer families (15.4%). Of the families with male breast cancer cases, 59.1% presented mutations in the BRCA2 gene. We found a higher frequency of ovarian cancer associated with mutations localized in the 5′ end of the BRCA1 gene, but there was no association between the prevalence of this type of cancer and mutations situated in the ovarian cancer cluster region (OCCR) region of exon 11 of the BRCA2 gene. The mutations 187underscore;188delAG, 330A>G, 5236G>A, 5242C>A, and 589underscore;590del (numbered after GenBank U14680) account for 46.6% of BRCA1 detected mutations whereas 3036underscore;3039del, 6857underscore;6858del, 9254underscore;9258del, and 9538underscore;9539del (numbered after GenBank U43746) account for 56.6% of the BRCA2 mutations. The BRCA1 330A>G has a Galician origin (northwest Spain), and BRCA2 6857underscore;6858del and 9254underscore;9258del probably originated in Catalonia (northeast Spain). Knowledge of the spectrum of mutations and their geographical distribution in Spain will allow a more effective detection strategy in countries with large Spanish populations. Hum Mutat 22:301–312, 2003.