Winnie Lo

BACKGROUND: The natural killer (NK) cells at the site of placentation express killer-cell immunoglobulin-like receptors (KIR) that can bind to human leukocyte antigen (HLA)-C molecules on trophoblast cells. Both these gene systems are polymorphic and an association of particular maternal KIR/fetal HLA-C genotypes has been shown in pre-eclampsia. Pre-eclampsia and recurrent miscarriage (RM) share the pathogenesis of defective placentation and therefore we have now genotyped couples with RM. METHODS AND RESULTS: DNA was obtained from the male (n = 67) and female (n = 95) partners of couples with three or more spontaneous miscarriages and genotyped for HLA-C groups and 11 KIR genes using the PCR-sequence-specific primer method (SSP). The frequency of the HLA-C2 group was increased in both parents (reaching significance only in the male partners, P = 0.018) compared with a parous control population. The KIR gene frequencies of the male partners were similar to controls, but the women had a high frequency of KIR AA haplotypes that lack activating KIR. In particular, the activating KIR for HLA-C2 groups (KIR2DS1) was significantly lower in these women (P = 0.00035, odds ratio 2.63, confidence interval 1.54-4.49). CONCLUSIONS: This is the first report to identify a genetic male factor that confers risk in RM. These findings support the idea that successful placentation depends on the correct balance of NK cell inhibition and activation in response to trophoblast.

Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.

We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.

BACKGROUND: Maternal obesity is associated with menstrual disorders, infertility and sporadic miscarriages. Recurrent miscarriage (RM) affects at least 1% of couples trying to conceive. In over 50% of cases, the cause of the loss of pregnancy remains unexplained. The aim of this study was to determine the relationship between maternal Body Mass Index (BMI) and future outcomes of pregnancy in couples with "unexplained" RM. METHODS AND RESULTS: All couples referred to the specialist recurrent miscarriage clinic at St. Mary's Hospital, London, were investigated for an underlying cause. Those with unexplained RM were eligible. Demographic and clinical data were retrieved from a computerised database and medical records. The World Health Organisation (WHO) classification of BMI was used. Univariate analysis demonstrated that BMI, maternal age, number of previous miscarriages and ethnicity were significantly associated with pregnancy outcome. Logistic regression demonstrated that maternal obesity (BMI ≥ 30 kg/m(2)) significantly increased the risk of miscarriage in couples with unexplained RM (OR 1.73; 95% CI 1.06 - 2.83). Asian women with a BMI similar to Caucasian women had a higher risk of a further miscarriage (OR 2.87, 95% CI, 1.52 - 5.39). CONCLUSIONS: Maternal obesity is an independent factor associated with an increased risk of miscarriage in couples with RM. All women with RM should have their BMI recorded at their first clinic visit. The potential effect of weight loss on the outcome of subsequent pregnancies should be assessed in future studies. The increased risk of miscarriage in Asian women needs to be explored further.