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ABSTRACT SLX4/ FANCP is a recently discovered novel disease gene for Fanconi anemia (FA), a rare recessive disorder characterized by chromosomal instability and increased cancer susceptibility. Three of the 15 FA genes are breast cancer susceptibility genes in heterozygous mutation carriers- BRCA2, PALB2, and BRIP1. To investigate if defects in SLX4 also predispose to breast cancer, the gene was sequenced in a cohort of 729 BRCA1/ BRCA2-negative familial breast cancer cases. We identified a single splice site mutation (c.2013+2T>A), which causes a frameshift by skipping of exon 8. We also identified 39 missense variants, four of which were selected for functional testing in a Mitomycin C-induced growth inhibition assay, and appeared indistinguishable from wild type. Although this is the first study that describes a truncating SLX4 mutation in breast cancer patients, our data indicate that germline mutations in SLX4 are very rare and are unlikely to make a significant contribution to familial breast cancer. [ABSTRACT FROM AUTHOR]

PALB2-mutation carriers not only have an increased risk for breast cancer (BC) but also for pancreatic cancer (PC). Thus far, PALB2 mutations have been mainly found in PC patients from families affected by both PC and BC. As it is well known that the prevalence of gene mutations varies between different populations, we studied the prevalence of PALB2 mutations in a Dutch cohort of non-BRCA1/2 familial PC (FPC) families and in non-BRCA1/2 familial BC (FBC) families with at least one PC case. Mutation analysis included direct sequencing and multiplex ligation-dependent probe amplification (MLPA) and was performed in a total of 64 patients from 56 distinct families (28 FPC families, 28 FBC families). In total, 31 patients (48%) originated from FPC families; 24 were FPC patients (77%), 6 had a personal history of BC (19%) and 1 was a suspected carrier (3.2%). The remaining 33 patients (52%) were all female BC patients of whom 31 (94%) had a family history of PC and 2 (6.1%) had a personal history of PC. In none of these 64 patients a PALB2 mutation was found. Therefore, PALB2 does not have a major causal role in familial clustering of PC and BC in non-BRCA1/2 families in the Dutch population. [ABSTRACT FROM AUTHOR]

Porencephaly is a rare neurological disease, typically manifest ininfants, which is characterized by the existence of degenerativecavities in the brain. To investigate the molecular pathogenesis ofporencephaly, we studied a mouse mutant that develops porencephalysecondary to focal disruptions of vascular basement membranes. Half ofthe mutant mice died with cerebral hemorrhage within a day of birth, and~18% of survivors had porencephaly. We show that vascular defects arecaused by a semidominant mutation in the procollagen type IV α 1gene (Col4a1) in mice, which inhibits the secretion of mutant and normaltype IV collagen. We also show that COL4A1 mutations segregate withporencephaly in human families. Because not all mutant mice developporencephaly, we propose that Col4a1 mutations conspire withenvironmental trauma in causing the disease. [ABSTRACT FROM AUTHOR]

Several murine retinoblastoma models have been generated by deleting the genes encoding for retinoblastoma susceptibility protein pRb and one of its family members p107 or p130. In Rb -/- p107 -/- retinoblastomas, somatic copy number alterations (SCNAs) like Mdm2 amplification or Cdkn2a deletion targeting the p53-pathway occur, which is uncommon for human retinoblastoma. In our study, we determined SCNAs in retinoblastomas developing in Rb -/- p130 -/- mice and compared this to murine Rb -/- p107 -/- tumors and human tumors. Chimeric mice were made by injection of 129/Ola-derived Rb -/- p130 -/- embryonic stem cells into wild type C57BL/6 blastocysts. SCNAs of retinoblastoma samples were determined by low-coverage (∼0.5×) whole genome sequencing. In Rb -/- p130 -/- tumors, SCNAs included gain of chromosomes 1 (3/23 tumors), 8 (1/23 tumors), 10 (1/23 tumors), 11 (2/23 tumors), and 12 (4/23 tumors), which could be mapped to frequently altered chromosomes in human retinoblastomas. While the altered chromosomes in Rb -/- p130 -/- tumors were similar to those in Rb -/- p107 -/- tumors, the alteration frequencies were much lower in Rb -/- p130 -/- tumors. Most of the Rb -/- p130 -/- tumors (16/23 tumors, 70%) were devoid of SCNAs, in strong contrast to Rb -/- p107 -/- tumors, which were never (0/15 tumors) SCNA-devoid. Similarly, to human retinoblastoma, increased age at diagnosis significantly correlated with increased SCNA frequencies. Additionally, focal loss of Cdh11 was observed in one Rb -/- p130 -/- tumor, which enforces studies in human retinoblastoma that identified CDH11 as a retinoblastoma suppressor. Moreover, based on a comparison of genes altered in human and murine retinoblastoma, we suggest exploring the role of HMGA1 and SRSF3 in retinoblastoma development. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)