Positive and negative well-being and objectively measured sedentary behaviour in older adults: evidence from three cohorts

Background: Sedentary behaviour is related to poorer health independently of time spent in moderate to vigorous physical activity. The aim of this study was to investigate whether wellbeing or symptoms of anxiety or depression predict sedentary behaviour in older adults. Method: Participants were drawn from the Lothian Birth Cohort 1936 (LBC1936) (n = 271), and the West of Scotland Twenty-07 1950s (n = 309) and 1930s (n = 118) cohorts. Sedentary outcomes, sedentary time, and number of sit-to-stand transitions, were measured with a three-dimensional accelerometer (activPAL activity monitor) worn for 7 days. In the Twenty-07 cohorts, symptoms of anxiety and depression were assessed in 2008 and sedentary outcomes were assessed ~ 8 years later in 2015 and 2016. In the LBC1936 cohort, wellbeing and symptoms of anxiety and depression were assessed concurrently with sedentary behaviour in 2015 and 2016. We tested for an association between wellbeing, anxiety or depression and the sedentary outcomes using multivariate regression analysis. Results: We observed no association between wellbeing or symptoms of anxiety and the sedentary outcomes. Symptoms of depression were positively associated with sedentary time in the LBC1936 and Twenty-07 1950s cohort, and negatively associated with number of sit-to-stand transitions in the LBC1936. Meta-analytic estimates of the association between depressive symptoms and sedentary time or number of sit-to-stand transitions, adjusted for age, sex, BMI, long-standing illness, and education, were β = 0.11 (95% CI = 0.03, 0.18) and β = − 0.11 (95% CI = − 0.19, −0.03) respectively. Conclusion: Our findings indicate that depressive symptoms are positively associated with sedentary behavior. Future studies should investigate the causal direction of this association

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD

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

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024Funder: Quebec Breast cancer Foundation Genome QuebecFunder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))Funder: European Union’s Horizon 2020Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972Funder: BCAST - European Union’s Horizon 2020Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913Abstract: Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women

Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) as first line therapy for patients with diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II single arm study

Introduction: R‐CHOP remains the standard of care for DLBCL yet many patients (pts.) either fail to respond or relapse after having achieved an initial remission. Dysregulation of B Cell receptor (BCR) signalling is well recognised in some sub-types of DLBCL. In the phase III PHOENIX study (NCT01855750), the addition of the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib (I) to R‐CHOP (R‐CHOP‐I) did not improve the outcome of the study population with non‐germinal centre like DLBCL. However, R‐CHOP‐I treated pts. who were aged less than 60 years had a significantly improved progression free survival (PFS) and overall survival (OS) compared to those receiving R‐CHOP alone. In pts. aged over 60 years, the addition of I increased toxicity and compromised the delivery of R‐CHOP. Acalabrutinib (A) is a second generation BTKi, with enhanced kinase selectivity and potential for better efficacy and tolerability over first‐generation inhibitors. There is a strong rationale to combine A with R‐CHOP in untreated de novo DLBCL to understand its safety profile and efficacy.Methods: eligible pts. were treatment naive with histologically confirmed DLBCL. All pts. received 6 cycles of R‐CHOP therapy on a standard 21‐day schedule, with the addition of A in cycles 2‐6. A continuation phase of A only, for 2 cycles of 28 days was administered after R-CHOP. The primary objective of the phase Ib was to establish a recommended phase II dose (RP2D) of A in combination with R‐CHOP (modified classical 6+6 design). Phase II assessed the overall response rate (ORR) of the combination and ascertained additional safety information. Secondary endpoints included metabolic complete response rates (mCR), PFS and OS and their relation to the COO, pharmacokinetics and pharmacodynamics. Cell of origin (COO) was determined by HTG EdgeSeq. Recruitment of pts. over the age of 65 was suspended as an urgent safety measure (USM) following the abstract release of data from PHOENIX (Nov 2018). ACCEPT reopened to all ages after a comprehensive safety review by the Independent Data Monitoring Committee (Sep 2019). The trial was endorsed by CRUK (CRUKDE/16/006).Results: from May 2017 to Jan 2020, 38 pts. were enrolled (safety population: Pts. in receipt of any component of therapy). The median age was 64 years (range 24-80, 39% >65 years old); 74% stage III/IV; 66%; raised LDH; 29% B symptoms; 32% bulk; 26% high IPI; 29% high-intermediate IPI; 16% High NCCN-IPI. Seven of the enrolled pts. were found to be ineligible (insufficient material for translational work, 2pts.; taking a proton pump inhibitor during therapy, 2 pts.; follicular histology, 1pt.; abnormal LFTs at baseline, 1pt.; age >65 at time of USM, 1 pts). There were no dose-limiting toxicities and the maximum tolerated dose was not reached. The RP2D was chosen as 100mg bd acalabrutinib. The most common >grade3 adverse events were neutropenia (26% of pts.), febrile neutropenia (13%) and diarrhoea (11%). The most frequently reported serious adverse event was febrile neutropenia (13% of pts.). Age did not compromise the delivery of full dose R-CHOP in combination with A. One patient in the first cohort (A 100mg od) progressed on therapy. Of the 24 eligible patients who received the RP2D (A 100mg bd) in either dose escalation or expansion, 22 responses have been reported (1 awaiting response assessment and 1 not assessed). Four pts. withdrew early from treatment (2 pts. subject withdrawal, 1 pt. investigator withdrawal and 1pt. due to toxicity) and are included in the efficacy analysis. The ORR was 95% with 82% of pts. achieving a mCR (3 pts. partial response (PR), 1pts. stable disease). One pt. with MYC/BCL2/BCL6 rearrangements and one pt. with MYC/BCL2 rearrangement achieved a mCR; neither have progressed. Ten of twelve ABC pts. (83%), 7/8 GCB pts (88%) and 1/2 unclassified pts. (50%) achieved a mCR. With a median follow-up of 15 months, the primary progressive patient from cohort 1 has died. PFS and OS at 12 months for those eligible pts. in receipt of the RP2D is 100%. Two of the RP2D pts. not achieving mCR have however received additional therapy (1 radiotherapy, 1 chemotherapy) prior to progression. R-CHOP did not affect the pharmacokinetics of A. Additional translational data will be presented.Conclusions: Acalabrutinib is well tolerated when given in combination with R-CHOP chemotherapy and may be associated with improved efficacy that should be explored in future randomised trials