Background We investigated the impact of breast cancer molecular subtypes and treatment on survival in a cohort of medically insured women followed for over twenty years. Methods We examined 934 female members of an integrated health care delivery system newly diagnosed with invasive breast cancer between 1988 and 1995 and followed them through 2008. Tumors were classified into four molecular subtypes based on their expression profile: luminal A; luminal B; basal-like; and HER2-enriched. We followed women from the surgery date to death, health plan disenrollment, or study’s end. Hazard rate ratios (HR) and 95% confidence intervals (CI) were fit using Cox proportional hazards models adjusting for cancer treatments and tumor characteristics. Results A total of 223 (23.9%) women died due to breast cancer during the 21-year study period. Compared to women with luminal A tumors, women with HER2-enriched (HR 2.56, 95% CI 1.53–4.29) and luminal B tumors (HR 1.96, 95% CI: 1.08–3.54) had roughly a two-fold increased adjusted risk of breast cancer mortality. In addition, the survival curves suggest that risk of late mortality persists in women with luminal A tumors. Conclusion Among women with healthcare coverage, molecular subtypes were important predictors of breast cancer mortality. Women with HER2-enriched tumors and luminal B subtypes had the poorest survival despite adjusting for important covariates. Impact In a cohort followed over 20 years, women with HER2 enriched tumors had worse survival, but interestingly, the survival curve for women with luminal A tumors continued to steadily decline after 10 years of follow-up.

We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.

Tumor cells expressing programmed cell death ligand 1 (PD-L1) interact with PD-1 on CD8+ cytotoxic T lymphocytes (CTLs) to inhibit CTL effector function. In gastric cancer, the mechanism regulating PD-L1 is unclear. The Hedgehog (Hh) signaling pathway is reactivated in various cancers including gastric. Here we tested the hypothesis that Hh-induced PD-L1 inactivates effector T cell function and allows gastric cancer cell proliferation. Mouse organoids were generated from tumors of a triple-transgenic mouse model engineered to express an activated GLI2 allele, GLI2A, in Lgr5-expressing stem cells, (mTGOs) or normal mouse stomachs (mGOs). Bone marrow-derived dendritic cells (DCs) were pulsed with conditioned media collected from normal (mGOCM) or cancer (mTGOCM) organoids. Pulsed DCs and CTLs were then co-cultured with either mGOs or mTGOs in the presence of PD-L1 neutralizing antibody (PD-L1Ab). Human-derived gastric cancer organoids (huTGOs) were used in drug and xenograft assays. Hh/Gli inhibitor, GANT-61 significantly reduced the expression of PD-L1 and tumor cell proliferation both in vivo and in vitro. PD-L1Ab treatment induced tumor cell apoptosis in mTGO/immune cell co-cultures. GANT-61 treatment sensitized huTGOs to standard-of-care chemotherapeutic drugs both in vivo and in vitro. Thus, Hh signaling mediates PD-L1 expression in gastric cancer cells and subsequently promotes tumor proliferation.