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.

We recently described that the autoimmune, central nervous system disease, multiple sclerosis (MS), is genetically associated with the human endogenous retroviral locus, HERV-Fc1, in Scandinavians. A number of dominant human genes encoding factors that restrict retrovirus replication have been known for a long time. Today human restriction genes for retroviruses include amongst others TRIMs, APOBEC3s, BST2 and TREXs. We have therefore looked for a role of these retroviral restriction genes in MS using genetic epidemiology. We here report that markers in two TRIMs, TRIM5 and TRIM22 and a marker in BST2, associated statistically with the risk of getting MS, while markers in or near APOBEC3s and TREXs showed little or no effect. This indicates that the two TRIMs and BST2 influence the risk of disease and thus supports the hypothesis of a viral involvement.

Objective To investigate the effects of centralizing the acute stroke services in the Central Denmark Region (CDR). Methods The CDR (1.3 million inhabitants) centralized acute stroke care from 6 to 2 designated acute stroke units with 7-day outpatient clinics. We performed a prospective “before-and-after” cohort study comparing all strokes from the CDR with strokes in the rest of Denmark to discover underlying general trends, adopting a difference-in-differences approach. The population comprised 22,141 stroke cases hospitalized from May 2011 to April 2012 and May 2013 to April 2014. Results Centralization was associated with a significant reduction in length of acute hospital stay from a median of 5 to 2 days with a length-of-stay ratio of 0.53 (95% confidence interval 0.38–0.75, data adjusted) with no corresponding change seen in the rest of Denmark. Similarly, centralization led to a significant increase in strokes with same-day admission (mainly outpatients), whereas this remained unchanged in the rest of Denmark. We observed a significant improvement in quality of care captured in 11 process performance measures in both the CDR and the rest of Denmark. Centralization was associated with a nonsignificant increase in thrombolysis rate. We observed a slight increase in readmissions at day 30, but this was not significantly different from the general trend. Mortality at days 30 and 365 remained unchanged, as in the rest of Denmark. Conclusions Centralizing acute stroke care in the CDR significantly reduced the length of acute hospital stay without compromising quality. Readmissions and mortality stayed comparable to the rest of Denmark.

The possibility that retroviruses play a role in multiple sclerosis (MS) has long been considered; accumulating findings suggest this to be most likely in the form of human endogenous retroviruses (HERVs). A genetic test series of fifty endogenous retroviral loci for association with MS in Danes showed SNP markers near a specific endogenous retroviral locus, HERV-Fc1 located on the X-chromosome, to be positive. Bout Onset MS was associated with the HERV-Fc1 locus, while a rarer form, Primary Progressive MS, was not. Moreover, HERV-Fc1 Gag RNA in plasma was increased 4-fold in patients with recent history of attacks, relative to patients in a stable state and to healthy controls. Finally, genetic variations in restriction genes for retroviruses influence the risk of MS, providing further support for a role of retroviral elements in disease. We speculate that endogenous retroviruses may activate the innate immune system in a variety of ways, involving the host proteins, TRIMs, TLRs, TREXs and STING. Observations in HIV-positive patients suggest that antiretroviral drugs can curb MS. Thus, these new findings regarding the etiology and pathogenesis of MS, suggest alternative ways to challenge autoimmune diseases.

Background: Preoperative genetic testing affects the surgical decision-making among women with breast cancer. To avoid breast-conserving surgery and to offer the possibility of mastectomy with immediate reconstruction in high-risk patients, genetic testing for pathogenic variants in BRCA1 or BRCA2 and a pedigree-based familial breast cancer risk assessment was offered to younger women with breast cancer in Denmark. We evaluated the impact of the risk stratification through genetic counseling on the uptake of contralateral prophylactic mastectomy (CPM). Material and methods: The prospective cohort study included all women with unilateral breast cancer before the age of 45 who participated in a genetic counseling program during their primary diagnostics in the Central Denmark Region (2013–2018). Each patient was followed from the time of the genetic test result to the end of follow-up to estimate the long-term uptake of CPM as a competing risk-adjusted cumulative incidence. We compared the uptake of CPM between the various genetic risk categories, ages of onset, and family histories in a multivariable Cox proportional hazards regression model, reporting hazard ratios (HR) with two-sided 95% confidence intervals (CIs). Results: 156 females, aged 21–44, learned their genetic test result within a median of 92 days [interquartile range (IQR): 75–114]. The maximal follow-up was 3.8 years (median 1.8; IQR: 0.49–2.5), after which 33% (95% CI: 24–42%) of the patients had undergone CPM. The uptake of CPM was inversely associated with the age of onset (HR 0.92; 95% CI: 0.86–0.98) and significantly higher among BRCA carriers (HR 2.9; 95% CI: 1.3–6.8) and patients from the high risk of breast cancer families (HR 5.6; 95% CI: 1.9–16) compared to the lower genetic risk categories. Conclusion: The risk stratification obtained through genetic counseling had a considerable impact on the surgical decision-making among younger women with breast cancer at long-term follow-up.