RT Journal Article SR Electronic T1 Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin against metastases in breast cancer JF bioRxiv FD Cold Spring Harbor Laboratory SP 152405 DO 10.1101/152405 A1 Knut M. Wittkowski A1 Christina Dadurian A1 Han Sang Kim A1 Ayuko Hoshino A1 David Lyden YR 2017 UL http://biorxiv.org/content/early/2017/06/20/152405.abstract AB Most breast cancer (BC) deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs are urgently needed.This study reanalyzed existing data from genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in epilepsy and identified a potential drug against disruption of language development in autism. Compared to many traditional bioinformatics approaches, muGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance in samples of 600–2000 subjects only.Results from three independent breast cancer GWAS not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in GWAS, also consistently identified many endo-exocytosis (EEC) pathway genes, most of which had already been observed in functional and expression studies of breast cancer, including genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids via alpha-cyclodextrin (aCD) as a potential intervention to control packaging of exosomes (which prepare distant microenvironment for organ-specific metastases) and endocytosis of β1 integrins (which are required for mesenchymal migration of tumor cells).Beta-cyclodextrin (βCD) had already been shown to be effective in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller aCD also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirmed hydroxypropyl (HP)-aCD to be at least twice as effective as HPβCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer.If the previous successful animal studies with βCDs are replicated with the safer and more effective aCDs, clinical trials of aCDs are warranted in women with triple-negative breast cancer, who have few treatment options and poor prognosis.Author Summary (200 Words) Although a family history of breast cancer (BC) substantially increases breast cancer risk, the known mutations in BRCA1/2 explain only 5–10% of all cases. Patients with hormone-receptor positive cancer initially respond well to anti-hormone therapy, but later have as limited treatment options as women with triple-negative breast cancer. Taking advantage of increases in computer memory since the advent of 32-bit operating system in 2001, we use a novel computational biostatistics approach, which does not screen for individual genetic “letters” (SNPs, which would typically be selected against if they increased risk), but for genetic “words” (combinations of neighboring SNPs, for which selection is less effective). This “nonparametric” approach also avoids false positive results due to unrealistic assumptions. Finally, we adjust decision criteria to the specifics of the study. In combination, these methodological advances confirm hormone-receptor signaling and transcriptional control consistently across three independent studies, but also point to upregulation of tumor cell migration as a novel common risk factor. In an in vitro study, alpha-cyclodextrin (aCD) was twice as effective as βCD in reducing migration of breast cancer cells. Hence preventing metastases with aCD might reduce breast cancer deaths with fewer side effects (including hair loss) than cytotoxic drugs and radiation.