Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia: A Nonrandomized Phase 2 Trial.

IMPORTANCE: Oral targeted therapies have advanced the treatment of chronic lymphocytic leukemia (CLL). These therapies include Bruton tyrosine kinase inhibitors, used as monotherapy, and the Bcl-2 inhibitor venetoclax, typically combined with the CD20 monoclonal antibody. Preclinical studies have shown synergy between Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax. OBJECTIVE: To examine the rate of complete remission, complete remission with incomplete count recovery, and bone marrow-undetectable measurable residual disease (U-MRD) after treatment with the combination of ibrutinib and venetoclax. DESIGN, SETTING, AND PARTICIPANTS: A single-center, phase 2 nonrandomized trial enrolled patients from August 17, 2016, to June 5, 2018. Participants included previously untreated patients with CLL who met International Workshop on CLL 2008 criteria for treatment indication. Patients were required to have at least 1 of the following features: del(17p), TP53-mutated CLL, del(11q), unmutated immunoglobulin heavy-chain variable gene, or age 65 years or older. INTERVENTIONS: Therapy consisted of ibrutinib, 420 mg/d, monotherapy for 3 cycles, thereafter combined with venetoclax (standard weekly dose ramp-up to 400 mg/d) for a total of 24 cycles of combination treatment. Responses were assessed at serial points according to International Workshop on CLL 2008 criteria. Measurable residual disease (MRD) was assessed by multicolor flow cytometry with a sensitivity of 10-4. MAIN OUTCOMES AND MEASURES: Outcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate. RESULTS: Eighty patients (57 [71%] men) were treated; median age was 65 years (range, 26-83 years). The median follow-up for all 80 patients was 38.5 months (range, 5.6-51.1 months). Five patients discontinued the study during the ibrutinib monotherapy phase; the remaining 75 patients received combination therapy. On an intent-to-treat analysis of combined treatment, 45 (56%) patients achieved bone marrow U-MRD remission at 12 cycles and 53 (66%) patients achieved bone marrow U-MRD remission at 24 cycles. Overall, 60 (75%) patients achieved bone marrow U-MRD remission as their best response. Responses were seen across all high-risk subgroups, independent of the immunoglobulin heavy-chain variable gene mutation status, fluorescence in situ hybridization category, or TP53 mutation. The 3-year progression-free survival was 93%, and 3-year overall survival was 96%. No patient had CLL progression; 2 patients developed Richter transformation. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that combination therapy with ibrutinib and venetoclax might be beneficial for previously untreated patients with CLL. Remissions appeared to be durable during a follow-up of more than 3 years, with activity seen across high-risk disease subgroups, including those with del(17p)/TP53-mutated CLL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02756897.

Ibrutinib and Venetoclax for First-Line Treatment of CLL.

BACKGROUND: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination. METHODS: We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10-4). RESULTS: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax. CONCLUSIONS: In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).

SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions.

We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer.

BACKGROUND: Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. METHODS: In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. RESULTS: Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. CONCLUSIONS: The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers.

We studied a large family that presented a strong familial susceptibility to multiple early onset cancers including prostate, breast, colon, and several other uncommon cancers. Through targeted gene, linkage, and whole genome sequencing analyses, we show that the presence of a variant in the regulatory region of HNRNPA0 associated with elevated cancer incidence in this family (Hazard ratio = 7.20, p = 0.0004). Whole genome sequencing identified a second rare protein changing mutation of WIF1 that interacted with the HNRNPA0 variant resulting in extremely high risk for cancer in carriers of mutations in both genes (p = 1.98 × 10(-13)). Analysis of downstream targets of the mutations in these two genes showed that the HNRNPA0 mutation affected expression patterns in the PI3 kinase and ERK/MAPK signaling pathways, while the WIF1 variant influenced expression of genes that play a role in NAD biosynthesis. This is a first report of variation in HNRNPA0 influencing common cancers or of a striking interaction between rare variants coexisting in an extended pedigree and jointly affecting cancer risk.

Risk factors for dementia in highly educated elderly people in Tianjin, China.

BACKGROUND: Low education level has been thought an important and specific risk factor for dementia. Therefore, we surveyed dementia in a highly educated population in Tianjin, China. METHODS: In total, 1324 old people (aged 55 years and over) in three cluster samples from university communities in Tianjin responded to our survey. Data from psychological tests and dementia questionnaires were analyzed. RESULTS: The prevalence of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) was 4.98%, 2.11%, and 2.27%, respectively. A history of stroke (OR=6.036), lack of fruit (OR=5.489), early parental death (OR=3.102), household financial management (OR=2.638), a history of cardiovascular disease (OR=2.434), a history of hypertension (OR=2.042), physical exercise (OR=2.556), were significantly associated with dementia in a single-factor analysis. Four independent variables were entered in a regression equation: early parental death (OR=6.417), lack of fruit in the diet (OR=3.919), personal stroke history (OR=3.901), and lack of physical exercise (OR=2.220). CONCLUSION: The prevalence of dementia was lower in highly educated elderly people in universities in Tianjin than in the general population. Risk factors for dementia included disease history, living habits, and early parental death, so corresponding interventions are required.

Putative tumor suppressor gene SEL1L was downregulated by aberrantly upregulated hsa-mir-155 in human pancreatic ductal adenocarcinoma.

Sel-1-like (SEL1L) is a putative tumor suppressor gene that is significantly downregulated in human pancreatic ductal adenocarcinoma (PDA). The mechanism of the downregulation is unclear. Here, we investigated whether aberrantly upregulated microRNAs (miRNAs) repressed the expression of SEL1L. From reported miRNA microarray studies on PDA and predicted miRNA targets, we identified seven aberrantly upregulated miRNAs that potentially target SEL1L. We assessed the expression levels of SEL1L mRNA and the seven miRNAs in human PDA tumors and normal adjacent tissues using real-time quantitative polymerase chain reaction. Then statistical methods were applied to evaluate the association between SEL1L mRNA and the miRNAs. Furthermore, the interaction was explored by functional analysis, including luciferase assay and transient miRNA overexpression. SEL1L mRNA expression levels were found to correlate inversely with the expression of hsa-mir-143, hsa-mir-155, and hsa-mir-223 (P < 0.0001, P < 0.0001, and P = 0.002, respectively). As the number of these overexpressed miRNAs increased, SEL1L mRNA expression progressively decreased (Ptrend = 0.001). Functional analysis revealed that hsa-mir-155 acted as a suppressor of SEL1L in PDA cell lines. Our study combined statistical analysis with biological approaches to determine the relationships between several miRNAs and the SEL1L gene. The finding that the expression of the putative tumor suppressor SEL1L is repressed by upregulation of hsa-mir-155 helps to elucidate the mechanism for SEL1L downregulation in some human PDA cases. Our results suggest a role for specific miRNAs in the pathogenesis of PDA and indicate that miRNAs have potential as therapeutic targets for PDA.

Reverse-phase protein array analysis to identify biomarker proteins in human pancreatic cancer.

BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death in the United States. The high mortality rate of patients with pancreatic cancer is primarily due to the difficulty of early diagnosis and a lack of effective therapies. There is an urgent need to discover novel molecular targets for early diagnosis and new therapeutic approaches to improve the clinical outcome of this deadly disease. AIM: We utilized the reverse-phase protein assay (RPPA) to identify differentially expressed biomarker proteins in tumors and matched adjacent, normal-appearing tissue samples from 15 pancreatic cancer patients. METHODS: The antibody panel used for the RPPA included 130 key proteins involved in various cancer-related pathways. The paired t test was used to determine the significant differences between matched pairs, and the false discovery rate-adjusted p values were calculated to take into account the effect of multiple comparisons. RESULTS: After correcting for multiple comparisons, we found 19 proteins that had statistically significant differences in expression between matched pairs. However, only four (AKT, ß-catenin, GAB2, and PAI-1) of them met the conservative criteria (both a q value <0.05 and a fold-change of ≥3/2 or ≤2/3) to be considered differentially expressed. Overexpression of AKT, ß-catenin, and GAB2 in pancreatic cancer tissues identified by RPPA has also been further confirmed by western blot analysis. Further analysis identified several significantly associated canonical pathways and overrepresented network functions. CONCLUSION: GAB2, a newly identified protein in pancreatic cancer, may provide additional insight into this cancer's pathogenesis. Future studies in a larger population are warranted to further confirm our results.

A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway.

The Hippo-YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity and organ size. To identify components of this pathway, we performed an RNAi-based kinome screen in human cells. Our screen identified several kinases not previously associated with Hippo signalling that control multiple cellular processes. One of the hits, LKB1, is a common tumour suppressor whose mechanism of action is only partially understood. We demonstrate that LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases. Our data also indicate that YAP is functionally important for the tumour suppressive effects of LKB1. Our results identify a signalling axis that links YAP activation with LKB1 mutations, and have implications for the treatment of LKB1-mutant human malignancies. In addition, our findings provide insight into upstream signals of the Hippo-YAP signalling cascade.

A pilot study comparing protein expression in different segments of the normal colon and rectum and in normal colon versus adenoma in patients with Lynch syndrome.

PURPOSE: Lynch syndrome (LS) is a common inherited predisposition to colorectal cancer (CRC). In LS patients, CRC is predominantly located in the right colon, as opposed to sporadic CRC, which usually affects the left colon or rectum. Previous studies have demonstrated a clear distinction in gene expression between sporadic CRC and normal colon at different locations in the colorectum. However, little is known about LS gene expression profiles in different areas of the colorectum. Here, we compared the protein expression profiles for normal colorectal samples among different locations as well as between adenomas and matched normal tissue in LS. METHODS: Protein from 33 tissue samples (27 normal tissues and 6 adenomas) from 9 patients with LS was extracted for reverse-phase protein array (RPPA) analysis. The antibody panel used for RPPA included 109 key proteins involved in various cancer-related pathways. Cluster 3.0 was used for unsupervised and supervised clustering analysis. RESULTS: IGF1R and COL6A1 were expressed significantly differently between the normal right and normal left colon (q < 0.05); FN1, COL6A1, and IGF1R were expressed significantly differently between the normal right colon and normal rectum (q < 0.05). In the adenomas and matched normal tissue, PEA-15 was the only protein with significantly different expression (q < 0.05). CONCLUSION: We found differences in protein expression between normal tissues from the right colon, left colon, and rectum as well as between adenomas and matched normal tissue. However, those differences should be further confirmed in a larger sample size.

Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress.

BACKGROUND: FGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury. METHODS: In this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases. RESULTS: We found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects. CONCLUSION: FGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans.

Cell cycle-related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients.

Heterogeneity in age of onset of colorectal cancer in individuals with mutations in DNA mismatch repair genes (Lynch syndrome) suggests the influence of other lifestyle and genetic modifiers. We hypothesized that genes regulating the cell cycle influence the observed heterogeneity as cell cycle-related genes respond to DNA damage by arresting the cell cycle to provide time for repair and induce transcription of genes that facilitate repair. We examined the association of 1456 single nucleotide polymorphisms (SNPs) in 128 cell cycle-related genes and 31 DNA repair-related genes in 485 non-Hispanic white participants with Lynch syndrome to determine whether there are SNPs associated with age of onset of colorectal cancer. Genotyping was performed on an Illumina GoldenGate platform, and data were analyzed using Kaplan-Meier survival analysis, Cox regression analysis and classification and regression tree (CART) methods. Ten SNPs were independently significant in a multivariable Cox proportional hazards regression model after correcting for multiple comparisons (P < 5 × 10(-4)). Furthermore, risk modeling using CART analysis defined combinations of genotypes for these SNPs with which subjects could be classified into low-risk, moderate-risk and high-risk groups that had median ages of colorectal cancer onset of 63, 50 and 42 years, respectively. The age-associated risk of colorectal cancer in the high-risk group was more than four times the risk in the low-risk group (hazard ratio = 4.67, 95% CI = 3.16-6.92). The additional genetic markers identified may help in refining risk groups for more tailored screening and follow-up of non-Hispanic white patients with Lynch syndrome.

Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 regions identifies functional and histology-specific lung cancer susceptibility loci in African-Americans.

BACKGROUND: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans. METHODS: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate. RESULTS: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25-1.97; P, 1.1 × 10(-4)) and variants in the 5'-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48-0.85; P, 1.82 × 10(-3)). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73-0.93; P, 1.1 × 10(-3)). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65-0.86; P, 8.1 × 10(-5)). CONCLUSIONS: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma. IMPACT: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.

Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans.

Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-American controls from three centers were genotyped for 378 single nucleotide polymorphisms (SNPs) spanning the sixteen human nAChR genes. Associations between SNPs and the risk of lung cancer were estimated using logistic regression, adjusted for relevant covariates. Seven SNPs in three nAChR genes were significantly associated with lung cancer at a strict Bonferroni-corrected level, including a novel association on chromosome 2 near the promoter of CHRNA1 (rs3755486: OR = 1.40, 95% CI = 1.18-1.67, P = 1.0 x 10-4). Association analysis of an additional 305 imputed SNPs on 2q31.1 supported this association. Publicly available expression data demonstrated that the rs3755486 risk allele correlates with increased CHRNA1 gene expression. Additional SNP associations were observed on 15q25.1 in genes previously associated with lung cancer, including a missense variant in CHRNA5 (rs16969968: OR = 1.60, 95% CI = 1.27-2.01, P = 5.9 x 10-5). Risk alleles on 15q25.1 also correlated with an increased number of cigarettes smoked per day among the controls. These findings identify a novel lung cancer risk locus on 2q31.1 which correlates with CHRNA1 expression and replicate previous associations on 15q25.1 in African-Americans.

The LKB1 tumor suppressor controls spindle orientation and localization of activated AMPK in mitotic epithelial cells.

Orientation of mitotic spindles plays an integral role in determining the relative positions of daughter cells in a tissue. LKB1 is a tumor suppressor that controls cell polarity, metabolism, and microtubule stability. Here, we show that germline LKB1 mutation in mice impairs spindle orientation in cells of the upper gastrointestinal tract and causes dramatic mislocalization of the LKB1 substrate AMPK in mitotic cells. RNAi of LKB1 causes spindle misorientation in three-dimensional MDCK cell cysts. Maintaining proper spindle orientation, possibly mediated by effects on the downstream kinase AMPK, could be an important tumor suppressor function of LKB1.

Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry.

The spectrum of cancers seen in a hospital based Lynch syndrome registry of mismatch repair gene mutation carriers was examined to determine the distribution of cancers and examine excess cancer risk. Overall there were 504 cancers recorded in 368 mutation carriers from 176 families. These included 236 (46.8 %) colorectal and 268 (53.2 %) extracolonic cancers. MLH1 mutation carriers had a higher frequency of colorectal cancers whereas MSH2, MSH6 and PMS2 mutation carriers had more extracolonic cancers although these differences were not statistically significant. Men had fewer extracolonic cancers than colorectal (45.3 vs. 54.7 %), whereas women had more extracolonic than colorectal cancers (59.0 vs. 41.0 %). The mean age at diagnosis overall for extracolonic cancers was older than for colorectal, 49.1 versus 44.8 years (P ≤ 0.001). As expected, the index cancer was colorectal in 58.1 % of patients and among the extracolonic index cancers, endometrial was the most common (13.8 %). A significant number of non-Lynch syndrome index cancers were recorded including breast (n = 5) prostate (n = 3), thyroid (n = 3), cervix (n = 3), melanoma (n = 3), and 1 case each of thymoma, sinus cavity, and adenocarcinoma of the lung. However, standardized incidence ratios calculated to assess excess cancer risk showed that only those cancers known to be associated with Lynch syndrome were significant in our sample. We found that Lynch syndrome patients can often present with cancers that are not considered part of Lynch syndrome. This has clinical relevance both for diagnosis of Lynch syndrome and surveillance for cancers of different sites during follow-up of these patients.

A single-nucleotide polymorphism in tumor suppressor gene SEL1L as a predictive and prognostic marker for pancreatic ductal adenocarcinoma in Caucasians.

SEL1L is a putative tumor suppressor gene that is frequently down-regulated in pancreatic ductal adenocarcinoma (PDA). A single-nucleotide polymorphism (SNP) rs12435998 in intron3 of SEL1L has previously been reported to be associated with susceptibility to Alzheimer's disease. We hypothesized that this SNP may influence clinical outcomes of patients with PDA. We analyzed DNA samples from 497 Caucasian patients with pathologically confirmed primary PDA. Of these, 98 had been enrolled in a clinical trial of neoadjuvant chemo-radiotherapy and 77 of the 98 had subsequently undergone pancreaticoduodenectomy (PD). We performed Kaplan-Meier analysis to evaluate the correlation between different SNP genotypes and age at diagnosis, survival time after diagnosis, and survival time after PD. In nonsmokers, we found a significant difference in median age at diagnosis between variant genotypes (AG/GG) carriers and wild-type genotype (AA) carriers (58 vs. 62 yr; log-rank test, P = 0.017). Patients with variant genotypes also showed an increased hazard ratio (HR) of 1.45 [95% confidence interval (CI), 1.07-1.97] relative to wild-type genotype. Among the patients in the clinical trial, the variant genotypes carriers had a median post-PD survival time that was 34.7 months shorter than wild-type genotype carriers (log-rank test, P = 0.019; HR, 1.91; 95% CI, 1.09-3.34). Our results suggest that the rs12435998 SNP in SEL1L gene plays a role in modifying age at diagnosis of PDA in Caucasian nonsmokers. In addition, this SNP may serve as a prognostic marker in PDA patients who undergo the same or similar treatment as the clinical trials.

A case-control study of a sex-specific association between a 15q25 variant and lung cancer risk.

BACKGROUND: Genetic variants located at 15q25, including those in the cholinergic receptor nicotinic cluster (CHRNA5) have been implicated in both lung cancer risk and nicotine dependence in recent genome-wide association studies. Among these variants, a 22-bp insertion/deletion, rs3841324 showed the strongest association with CHRNA5 mRNA expression levels. However the influence of rs3841324 on lung cancer risk has not been studied in depth. METHODS: We have, therefore, evaluated the association of rs3841324 genotypes with lung cancer risk in a case-control study of 624 Caucasian subjects with lung cancer and 766 age- and sex-matched cancer-free Caucasian controls. We also evaluated the joint effects of rs3841324 with single-nucleotide polymorphisms (SNP) rs16969968 and rs8034191 in the 15q25 region that have been consistently implicated in lung cancer risk. RESULTS: We found that the homozygous genotype with both short alleles (SS) of rs3841324 was associated with a decreased lung cancer risk in female ever smokers relative to the homozygous wild-type (LL) and heterozygous (LS) genotypes combined in a recessive model [OR(adjusted) = 0.55, 95% confidence interval (CI), 0.31-0.89, P = 0.0168]. There was no evidence for a sex difference in the association between this variant and cigarettes smoked per day (CPD). Diplotype analysis of rs3841324 with either rs16969968 or rs8034191 showed that these polymorphisms influenced the lung cancer risk independently. CONCLUSIONS AND IMPACT: This study has shown a sex difference in the association between the 15q25 variant rs3841324 and lung cancers. Further research is warranted to elucidate the mechanisms underlying these observations.

Cyclin D1b represses breast cancer cell growth by antagonizing the action of cyclin D1a on estrogen receptor alpha-mediated transcription.

Alternate splicing of the cyclin D1 gene gives rise to transcripts a and b which encode two protein isoforms cyclin D1a and cyclin D1b. Cyclin D1a can substitute for estrogen to activate estrogen receptor alpha- (ERalpha) mediated transcription and can induce the proliferation of estrogen responsive tissues. However, little is known about the biological role of cyclin D1b in transcriptional regulation. In this study, we determined that cyclin D1b is incapable of inducing ERalpha-mediated transcription because it fails to recruit steroid receptor coactivator-1 (SRC-1) to ERalpha. Moreover, cyclin D1b antagonizes cyclin D1a-induced ERalpha-mediated transcription by competing with cyclin D1a for ERalpha binding. Cell proliferation assay showed that cyclin D1b repressed the ERalpha-positive breast cancer T47D cell growth. Our findings suggest that the cyclin D1b represses breast cancer cell growth by antagonizing the action of cyclin D1a on ERalpha-mediated transcription.