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Abstract Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared to pediatric ALL. Age, as a continuous variable, is negatively correlated with prognosis, in spite of risk-adapted combination chemotherapy. To better understand the etiology of ALL in this age group, we performed the first genome-wide association study (GWAS) to comprehensively examine germline single nucleotide polymorphisms (SNPs) for their association with susceptibility to B-ALL in AYAs. In the discovery GWAS, we compared genotype frequency at 635,297 SNPs between 308 AYA ALL cases (age 16-39 years, treated on the Children’s Oncology Group [COG], the Alliance-Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, MD Anderson Cancer Center, and St. Jude Children’s Research Hospital trials) vs. 6,661 non-ALL controls. The association between genotypes at each SNP and ALL susceptibility was tested by using a logistic regression model after adjusting for genetic ancestries to control for population stratification. SNPs that reached P≤ 5×10-8 in the discovery GWAS were tested in an independent cohort of 82 AYA ALL cases from the COG protocols and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus on 10p14 signified by two SNPs within the GATA3 gene: rs3824662, P=2.8x10-10, odds ratio (OR)=1.77; rs3781093, P=3.2x10-9, OR=1.73, both of which were validated in the replication cohort (P=1.9x10-8 and P=4.3x10-5, respectively). We also examined the association signals in AYAs for susceptibility loci previously identified in pediatric ALL: ARID5B, IKZF1 and PIP4K2A variants were nominally significant in AYAs in the discovery GWAS and/or in the replication analysis, whereas CEBPE or CDKN2A/CDKN2B were not significant. These results imply both similarities and differences in genetic predisposition to ALL between children and AYAs. At the GATA3 locus, rs3824662 risk variant was over-represented in Philadelphia chromosome (Ph)-like ALL in AYAs (P=0.02), confirming our previous report of Ph-like ALL susceptibility variants in GATA3 (Nat Genet 45:1494). Importantly, even after excluding Ph-like cases, rs3824662 remained associated with the risk of developing ALL in AYAs, suggesting that the influence of the GATA3risk variant on ALL susceptibility in AYAs extends beyond the predisposition to Ph-like subtype. We next examined the relationship between GATA3 risk allele frequency and age at diagnosis in a cohort of unselected childhood and adolescent ALL cases enrolled in the COG P9900 protocols (N=1,827). Dividing patients into four consecutives age groups (<5, 5-10, 10-15 and >15 years), we observed a clear progressive increase in the risk allele frequency at rs3824662 (P=6.29×10-11) with increasing allelic odds ratio (i.e. relative risk of ALL conferred by each copy of the risk allele). This correlation between genotype and age was evident regardless of genetic ancestry, although the risk variant was more common among individuals with higher Native American ancestry. In contrast, the frequency of ALL susceptibility variant in ARID5B decreased progressively with increasing age at diagnosis (P=0.006), whereas PIP4K2A, CDKN2A/CDKN2B, IKZF1 and CEBPE variants were not related to age. Finally, we compared rs3824662 risk variant frequency by age in the COG P9900 protocols after stratifying the ALL cases into TCF3-PBX1, ETV6-RUNX1, hyperdiploid, MLL-rearranged and B-other. There was a trend that the risk allele was more frequent in cases older than 16 years compared to those below 16 in the five subtypes examined. In conclusion, we have identified inherited GATA3 genetic variants that strongly influence ALL susceptibility in adolescent and young adults, indicating potential age-related differences in ALL biology. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 664 Background: Survivors of childhood acute lymphoblastic leukemia (ALL) who received prophylactic cranial radiation therapy (CRT) are at increased risk for deficits in neurocognitive skills, including attention, working memory and processing speed. As survivors age, global brain injury from CRT may reduce cognitive reserve, placing them at risk for early onset dementia or long-term memory deficits. The prevalence of dementia and memory abnormalities in adult survivors of childhood ALL has not previously been established. Methods: Analyses were conducted on 265 of 445 (60%) eligible survivors of childhood ALL (median age 36 years, range 26–54 years; 52% female) treated with 18Gy (n=127) or 24Gy (n=138) CRT with a median time from CRT of 30 years (range 15–46 years). Participants completed the Wechsler Memory Scale IV, including the Brief Cognitive Status Exam (BSCE), and the Wechsler Abbreviated Scale of Intelligence (WASI). Age-adjusted standard scores were calculated and the BSCE was also adjusted for education level. Prevalence of memory impairment (<1 SD below age-expected mean), stratified by RT dose exposure, is reported and logistic regression used to identify risk factors for impairment. A subset of survivors (n=85) completed brain magnetic resonance imaging (MRI), including assessment of hippocampal volume, cortical thickness, white matter volume, diffusion tensor imaging, and functional MRI (fMRI) during a cued-recall memory task. Results: Survivors who received 24 Gy CRT had increased impairment on global measures of both short-term recall (33%; p<0.001) and long-term recall (30%; p<0.001), while no increase in impairment was seen after 18Gy. Impaired short-term recall was associated with smaller right (p=0.02) and left (p<0.01) temporal lobe volumes, while impaired long-term recall was associated with thinner parietal and frontal cortices. On subtests evaluating narrative memory (i.e. story recall) and design memory, increasing RT dose (24 vs. 18Gy) was associated with an increased prevalence of long-term memory impairment (narrative: 28% vs. 12%, p=0.001; designs: 13% vs. 3.2%, p=0.003). However, no CRT dose response was identified for short term narrative and design memory. Survivors with impaired long-term memory for designs demonstrated a compensatory increase in left hippocampal fMRI activation (p=0.005), and the effect was greater in the higher dose group (p = 0.04). The mean score for long-term narrative memory among survivors who received 24Gy was equivalent to the mean score of a 70–74 year old adult population. Neither young age (0–4 years) at CRT (Odds Ratio [OR] 1.4, 95% confidence interval [CI] 0.8–2.7), time from CRT (OR 1.0, 95% CI 0.9–1.1) nor intrathecal methotrexate exposure (OR 3.9, 95% CI 0.4–36.1) were significantly associated with long-term memory deficits. Reduced cognitive status (by BSCE) was identified after 18Gy (9%, p=0.11) and 24Gy (18%, p<0.001), suggesting a CRT dose-response effect. On diffusion tensor imaging, increased radial diffusivity in the frontal, parietal and temporal regions, an inverse measure of white matter integrity, was associated with reduced BSCE. Current employment rates were equivalent (63%) in both CRT dose groups, suggesting no difference in functional status. Conclusions: Aging adult survivors of ALL who received 24Gy CRT have reduced cognitive status and significant impairment in short-term and long-term memory. There appears to be a dose response effect selective for long-term narrative and design memory, but not for short term narrative and design memory. These patterns are consistent with early onset of age-related (long-term) memory loss, and early stage dementia, yet at a median age of only 36 years. After 24Gy, survivors have the narrative memory equivalent to a 70 year-old in the general population. Survivors with memory impairment demonstrated reduced integrity on structural and functional neuroimaging in anatomical regions established as essential for memory formation and long-term recall. However, these memory impairments do not seem to affect functional status (employment rates) suggesting that, rather than frank dementia, deficits in middle adulthood are consistent with mild cognitive impairment (MCI). Longitudinal evaluation of this population is needed as MCI often progresses into early onset dementia with age. Disclosures: No relevant conflicts of interest to declare.

Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss‐of‐function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org ).

Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3’ enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination.

Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein–coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m‐tolyl 5‐chloro‐2‐[ethylsulfonyl] pyrimidine‐4‐carboxylate [SBI‐115]), and (3) a combination of SBI‐115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA‐treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5−/− ;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq) proteins was increased 2‐fold to 3‐fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5‐deficient TGR5−/−;Pkhd1del2/del2 mice. TGR5 expression and its colocalization with Gαs were increased ∼2‐fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI‐115 alone and by ∼50% when SBI‐115 was combined with pasireotide. Conclusion: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197‐1218).

Abstract A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10−19 (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10−23) and SLC22A3 (P = 3.2 × 10−52). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10−13; OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P &lt; 1.0 × 10−8). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. Cancer Discov; 5(8); 878–91. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 783

Key PointsIn this first ALL GWAS in AYAs, we determined that inherited GATA3 variants strongly influence ALL susceptibility in this age group. These findings revealed similarities and differences in the genetic basis of ALL susceptibility between young children and AYAs.

Background— Recurrent functional mitral regurgitation (MR) has been reported after mitral valve repair with annuloplasty in patients with dilated cardiomyopathy, but the mechanism is not understood completely. The authors sought to identify abnormalities of the mitral valve and left ventricle that are associated with recurrent MR after mitral annuloplasty. Method and Results— In 104 patients with idiopathic dilated cardiomyopathy who underwent annuloplasty for functional MR, basal mitral anterior leaflet angle, distal mitral anterior leaflet angle (ALA tip ), posterior leaflet angle, coaptation depth, tenting area, mitral annular dimensions, left ventricular volumes, and MR severity were quantified by echocardiography before surgery and at 6-month intervals after it. Compared with patients without MR recurrence (n=79), patients with recurrent MR (defined as ≥2+) (n=25) had greater ALA tip ( P <0.001) and basal mitral anterior leaflet angle ( P <0.001), greater coaptation depth and tenting area ( P <0.001), larger left ventricular volumes ( P <0.001), and worse left ventricular ejection fraction ( P <0.05) but similar mitral annular dimensions and postoperative exaggeration in posterior leaflet angle. Multivariable analysis identified postoperative ALA tip as the major determinant of postoperative MR. Receiver operator characteristic curves identified preoperative ALA tip as the best predictor of MR recurrence (area under curve, 0.98). For ALA tip >25°, the sensitivity, specificity, and positive and negative predictive values in predicting recurrent MR were 88%, 94%, 82%, and 93%, respectively. Three distinct patterns of anterior leaflet tethering (minimal, basal, and distal) with an increasing risk of recurrent MR were identified. Conclusions— Posterior leaflet tethering is invariable after mitral annuloplasty, rendering postoperative mitral competence highly dependent on distal anterior leaflet mobility.