The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Psycho-educational group intervention for family caregivers of hospitalized palliative care patients: Pilot study

Background: Family caregivers of patients requiring palliative care commonly experience physical, social, and psychological burdens. Although family caregivers are acknowledged as valid service recipients of palliative care, many have unmet needs, and systematic reviews have shown there are limited evidence-based supportive interventions. Objectives: This study aimed to develop and pilot test a psycho-educational group education program delivered in the inpatient specialist palliative care setting and designed to prepare primary family caregivers for the role of supporting a relative receiving hospital-based palliative care. Methods: (1) Development of education session and delivery protocol by the research team and expert panel; (2) pilot the intervention in three clinical sites (five sessions in total); (3) evaluate its accessibility and acceptability; and (4) preliminary testing of outcome measures used to access the intervention’s effectiveness. Results and conclusion: The results revealed that the intervention was appropriate and acceptable to caregivers. The intervention needs to be tested in a larger sample to determine the potential benefits for caregivers’ sense of preparedness and competence, and testing needs to ascertain if the intervention is accessible

Psycho-educational group intervention for family caregivers of hospitalized palliative care patients:pilot study

Background: Family caregivers of patients requiring palliative care commonly experience physical, social, and psychological burdens. Although family caregivers are acknowledged as valid service recipients of palliative care, many have unmet needs, and systematic reviews have shown there are limited evidence-based supportive interventions. Objectives: This study aimed to develop and pilot test a psycho-educational group education program delivered in the inpatient specialist palliative care setting and designed to prepare primary family caregivers for the role of supporting a relative receiving hospital-based palliative care. Methods: (1) Development of education session and delivery protocol by the research team and expert panel; (2) pilot the intervention in three clinical sites (five sessions in total); (3) evaluate its accessibility and acceptability; and (4) preliminary testing of outcome measures used to access the intervention\u27s effectiveness. Results and conclusion: The results revealed that the intervention was appropriate and acceptable to caregivers. The intervention needs to be tested in a larger sample to determine the potential benefits for caregivers\u27 sense of preparedness and competence, and testing needs to ascertain if the intervention is accessible

Discovery of 1‑(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)­pyrido[2,3‑<i>d</i>]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against <i>BRAF</i> or <i>RAS</i> Mutant Tumor Cells

The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with <i>RAS</i> mutations in preclinical models and are contraindicated for treatment of cancer patients with <i>BRAF</i> WT background, including patients with <i>KRAS</i> or <i>NRAS</i> mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with <i>RAS</i> mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound <b>13</b> was selected for further development and is currently being evaluated in phase I clinical studies