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

Socioeconomic Determinants of Health: Towards a National Research Program and a Policy and Intervention Agenda

This report has four primary objectives: 1. To review Australian research pertaining to socioeconomic health inequalities; 2. To provide a descriptive profile of Australia’s research capacity vis-à-vis socioeconomic health inequalities; 3. To critically examine the policies and interventions that have been suggested to reduce socioeconomic health inequalities; 4. To make a number of preliminary recommendations about the development of a national health inequalities research program and a policy and intervention agenda. This report utilises a conceptual framework that identifies the multi-level and diverse determinants of socioeconomic health inequalities. The structure and content of the framework, and the identified relationships between each of its major components, are based on the existing scientific evidence. Its conceptualisation has also been informed by a broader understanding of the determinants of health. The framework consists of three discrete yet closely interrelated stages or levels, namely, upstream, midstream, and downstream. The upstream (or macro-level) factors include international influences, government policies, and the fundamental determinants of health (i.e. social, physical, economic and environmental). The midstream (or intermediate-level) factors include psychosocial factors, health-related behaviours and the role played by the health care system. The downstream (or micro-level) factors include changes to physiological systems and biological functioning brought about as a consequence of the influence of factors operating at the midstream and upstream levels. Taken as a whole, the evidence on SES and health in Australia is unequivocal: those who occupy positions at lower levels of the socioeconomic hierarchy fare significantly worse in terms of their health. Specifically, persons variously classified as ‘low’ SES have higher mortality rates for most major causes of death, their morbidity profile indicates that they experience more ill-health (both physiological and psychosocial), and their use of health care services suggests that they are less likely to act to prevent disease or detect it at an asymptomatic stage. Moreover, socioeconomic differences in health are evident for both females and males at every stage of the life-course (birth, infancy, childhood and adolescence, and adulthood) and the relationship exists irrespective of how SES and health are measured. The report considers some of the important and relevant components of the country’s existing research capacity and infrastructure vis-à-vis SES and health, and it examines the Australian performance in terms of its contribution to the international evidence base. By all accounts, the Australian research performance in this area, although hard to quantify precisely, has been significant both nationally and internationally. However, there are a relatively small number of universities and research centres that have made a very significant contribution. Considering the lack of critical research mass and the complexity of this area of research, the performance has been very impressive by any standards

Social determinants of smoking among parents with infants

Objectives: To estimate the smoking prevalence among parents of infants and examine these parents' socio-demographic characteristics. Method: The sample of all parents of infants (669 mother-father pairs, 90 single parents) was derived from the 1995 Australian Health Survey. Data were collected by face-to-face interview in the respondent's home. Socio-demographic measures include parent's age, family structure, age-left-school, highest post-school qualification, occupation, and family income. Results: The overall rate of smoking among parents was 28.9% (mothers 24.7%, fathers 33.7%). The lowest rate was observed among mothers with a post-school tertiary qualification (7.6%) and the highest among fathers aged 18-24 (49.0%). In 15.4% of two-parent families both parents smoked, but this rate differed markedly by family income (9.9% vs. 29.7% for high and low-income families respectively). Multiple logistic regression showed that parents who smoked were more likely to be young, minimally educated, employed in blue-collar occupations, and resident in low-income families. Conclusions and implications: Infants in this sample who were exposed to parental smoking were likely to be at increased risk of experiencing higher mortality and morbidity for childhood conditions related to passive smoking; more likely to experience adverse health consequences in adulthood; and may themselves take up smoking in later life. The study results pose serious challenges to our tobacco control efforts and health interventions more generally. No single policy or strategy can adequately address the problem of parental smoking. We need macro/upstream approaches that deal with the degree of social and economic inequality in society, as well as more intermediate approaches that intervene at the level of communities, families and individuals

Pharmaceutical sales of pseudoephedrine: the impact of electronic tracking systems on methamphetamine crime incidents

Background and aims: Electronic tracking systems (ETS) are used extensively in pharmacies across the United States and Australia to control suspicious sales of pseudoephedrine. This study measures the impact of one ETS–Project STOP—on the capacity of police to reduce production, supply and possession of methamphetamine. Design: Using official police data of incidents of production, supply and possession from January 1996 to December 2011 (n\ua0=\ua0192 data points/months over 16\ua0years), we used a quasi-experimental, time–series approach. Setting: The State of Queensland, Australia. Participants: No individual participants are included in the study. The unit of analysis is reported police incidents. Measurements: The study examines the impact of the ETS on production (n\ua0=\ua05938 incidents), drug supply and trafficking (n\ua0=\ua020 094 incidents) and drug possession or use (n\ua0=\ua0118 926) of methamphetamine. Findings: Introduction of the ETS in November 2005 was associated with an insignificant decrease (P\ua0=\ua00.15) in the production of methamphetamine. The intervention was associated with a statistically significant increase in supply incidents (P\ua0=\ua00.0001). There was no statistically significant effect on the incidence of possession (P\ua0=\ua00.59). Conclusions: Electronic tracking systems can reduce the capacity of people to produce methamphetamine domestically, but seem unlikely to affect other aspects of the methamphetamine problem such as possession, distribution and importation

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

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PAM, 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 pArg1931* 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