Gene Summary

Gene:HHIP; hedgehog interacting protein
Aliases: HIP
Summary:This gene encodes a member of the hedgehog-interacting protein (HHIP) family. The hedgehog (HH) proteins are evolutionarily conserved protein, which are important morphogens for a wide range of developmental processes, including anteroposterior patterns of limbs and regulation of left-right asymmetry in embryonic development. Multiple cell-surface receptors are responsible for transducing and/or regulating HH signals. The HHIP encoded by this gene is a highly conserved, vertebrate-specific inhibitor of HH signaling. It interacts with all three HH family members, SHH, IHH and DHH. Two single nucleotide polymorphisms (SNPs) near this gene are significantly associated with risk of chronic obstructive pulmonary disease (COPD). A single nucleotide polymorphism in this gene is also strongly associated with human height.[provided by RefSeq, Feb 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:hedgehog-interacting protein
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HHIP (cancer-related)

Zhou X, Yan L, Bu XL, et al.
Arotinoid trometamol inhibits arsenic trioxide-stimulated keratinocyte proliferation via the Wnt, Shh, and bone morphogenetic protein signaling pathways.
J Biol Regul Homeost Agents. 2019 May-Jun; 33(3):731-743 [PubMed] Related Publications
Arsenic acts as a human carcinogen and contributes to skin cancer via mechanisms that remain largely unknown. Recent evidence implicates the perturbation of Wnt, Shh and BMP signals as a potential mechanism. We initiated studies to examine gene expression changes in these signaling pathways. Meanwhile, the antagonistic effect of retinoic acid was explored. In this study, HaCaT and NHEK cells were treated with arsenic trioxide (As2O3) alone or in combination with arotinoid trometamol (retinoic acid receptor agonist). Flow cytometric analysis, PCR array and Western blot were used to determine the potential mechanism and signaling pathways associated with arsenic carcinogenesis. The results showed that low concentration As2O3 could stimulate keratinocyte proliferation, and arotinoid trometamol inhibited the process via regulating the expression of about 20 genes. These genes included components of Wnt signaling (CSNK1A1L, CTNNB1, SFRP1, Wnt10B, Wnt11, Wnt16, Wnt5A, Wnt8A), Shh signaling (C6orf138, HHIP, PTCHD1) and BMP signaling pathway (BMP2, BMP7). The changes of some differentially expressed genes of these signaling pathways in As2O3 treatment group were counteracted by the subsequent arotinoid trometamol treatment. Our data suggest that dysregulation and cross-talk of Wnt, Shh and BMP signals play great roles in the process of arsenic-induced carcinogenesis, which could be antagonized by arotinoid trometamol.

Daghestani MH, Daghestani MH, Daghistani MH, et al.
The influence of the rs1137101 genotypes of leptin receptor gene on the demographic and metabolic profile of normal Saudi females and those suffering from polycystic ovarian syndrome.
BMC Womens Health. 2019; 19(1):10 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Polycystic ovarian syndrome (PCOS) is of frequent occurrence in Saudi females and is often associated with obesity, insulin resistance, hypogonadotropic hypogonadism, and infertility. Since these features are also associated with leptin receptor (LEP-R) deficiency, several studies have attempted to link LEP-R gene polymorphisms to PCOS.
METHODS: The purpose of this study is to assess the possible association of LEP-R gene polymorphism (rs1137101) with the main obesity-linked metabolic parameters in Saudi female patients affected by PCOS. A cohort of 122 Saudi female subjects, attending the outpatient's clinics at Makkah, Saudi Arabia and diagnosed with PCOS was investigated. Metabolic parameters in serum samples, including lipidogram, glucose, leptin, ghrelin and insulin and obesity markers (BMI, W/H ratio, HOMA) were assayed and compared with values from 130 healthy female volunteers (controls). The genotyping of rs1137101 polymorphism in the leptin receptor gene by amplification (PCR) followed by DNA sequencing, was conducted in both groups (PCOS and controls).
RESULTS: Waist/hip ratio (W/H ratio), leptin serum levels and triglycerides appeared to be associated with PCOS but, aside from W/H ratio (AA s GG p = 0.009), this association also occurred for controls. No significant association in the leptin gene polymorphic locus rs1137101 with PCOS was seen in the results of the present study. In the control group, BMI, W/H ratio, leptin, Insulin, and HOMA-IR were significantly higher in the GG genotype compared to AA.
CONCLUSION: Despite previous suggestion about a relationship between rs1137101, serum leptin levels, and PCOS, our studies do not show any statistical association and further investigations; possibly by also evaluating obese patients should be needed to elucidate this issue better.

Biermann J, Parris TZ, Nemes S, et al.
Clonal relatedness in tumour pairs of breast cancer patients.
Breast Cancer Res. 2018; 20(1):96 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Molecular classification of tumour clonality is currently not evaluated in multiple invasive breast carcinomas, despite evidence suggesting common clonal origins. There is no consensus about which type of data (e.g. copy number, mutation, histology) and especially which statistical method is most suitable to distinguish clonal recurrences from independent primary tumours.
METHODS: Thirty-seven invasive breast tumour pairs were stratified according to laterality and time interval between the diagnoses of the two tumours. In a multi-omics approach, tumour clonality was analysed by integrating clinical characteristics (n = 37), DNA copy number (n = 37), DNA methylation (n = 8), gene expression microarray (n = 7), RNA sequencing (n = 3), and SNP genotyping data (n = 3). Different statistical methods, e.g. the diagnostic similarity index (SI), were used to classify the tumours as clonally related recurrences or independent primary tumours.
RESULTS: The SI and hierarchical clustering showed similar tendencies and the highest concordance with the other methods. Concordant evidence for tumour clonality was found in 46% (17/37) of patients. Notably, no association was found between the current clinical guidelines and molecular tumour features.
CONCLUSIONS: A more accurate classification of clonal relatedness between multiple breast tumours may help to mitigate treatment failure and relapse by integrating tumour-associated molecular features, clinical parameters, and statistical methods. Guidelines need to be defined with exact thresholds to standardise clonality testing in a routine diagnostic setting.

Su J, Li Y, Su G, et al.
Genetic association of CTLA4 gene with polycystic ovary syndrome in the Chinese Han population.
Medicine (Baltimore). 2018; 97(29):e11422 [PubMed] Free Access to Full Article Related Publications
The autoimmune and gene etiology are implicated in the pathogenesis of polycystic ovary syndrome (PCOS). The cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is important for negative regulation of T-cell activation, and CTLA4 gene has been identified as a risk factor for some autoimmune diseases. However, none studies have been performed about the association between PCOS and the CTLA4 gene before. Here, we aimed to investigate the association of CTLA4 with PCOS in the Chinese Han population though a case-control association analysis of 606 individuals. The tagging variants rs733618 and rs231775 in the CTLA4 gene were detected using polymerase chain reaction-denaturing gradient gel electrophoresis method. Further analysis found the rs733618 was significantly different between case and control groups in either genotypic or allelic distribution (P = .01 and .009, respectively) while rs231775 not. Moreover, rs733618 was significantly associated with higher body mass index in the dominant model (P = .003) and with higher waist/hip ratio in the recessive model (P = .02). Interestingly, rs733618 was only found to have significant association with homeostatic model assessment for insulin resistance (HOMA-IR) in both dominant and recessive model (P = .009 and .0065, respectively). This is the first study to investigate the association of CTLA4 gene with PCOS. The CTLA4 gene is suggested to correlated with PCOS, and influence PCOS through regulating obesity and the HOMA-IR in a novel way.

Lao IW, Sun M, Zhao M, et al.
Lipofibromatosis-like neural tumour: a clinicopathological study of ten additional cases of an emerging novel entity.
Pathology. 2018; 50(5):519-523 [PubMed] Related Publications
We present our experience with ten cases of lipofibromatosis-like tumour (LPF-NT) to further characterise this newly described neoplasm. There were six males and four females with a mean age of 12.8 years (range 2-37 years). Tumours occurred in the neck (n = 3), buttock (n = 2), chest wall, flank, hip, hand and foot (n = 1). Histologically, they were composed of cellular fascicles of mildly to moderately atypical spindle cells displaying an infiltrative pattern reminiscent of lipofibromatosis or dermatofibrosarcoma protuberans. Immunohistochemically, all cases co-expressed S100 protein and CD34. FISH analysis revealed NTRK1 gene rearrangement in four of five cases tested. Clinical follow-up showed local recurrence in three cases but no evidence of metastasis. This study further supports that LPF-NT represents a novel entity of NTRK1-associated neoplasms. Awareness of its clinicopathological features, immunophenotypes and cytogenetic abnormalities helps pathologists arrive at the correct diagnosis.

Young EL, Thompson BA, Neklason DW, et al.
Pancreatic cancer as a sentinel for hereditary cancer predisposition.
BMC Cancer. 2018; 18(1):697 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) predisposition have been shown to play a role in pancreatic cancer susceptibility. Growing evidence suggests that pancreatic cancer may be useful as a sentinel cancer to identify families that could benefit from HBOC or CRC surveillance, but to date pancreatic cancer is only considered an indication for genetic testing in the context of additional family history.
METHODS: Preliminary data generated at the Huntsman Cancer Hospital (HCH) included variants identified on a custom 34-gene panel or 59-gene panel including both known HBOC and CRC genes for respective sets of 66 and 147 pancreatic cancer cases, unselected for family history. Given the strength of preliminary data and corresponding literature, 61 sequential pancreatic cancer cases underwent a custom 14-gene clinical panel. Sequencing data from HCH pancreatic cancer cases, pancreatic cancer cases of the Cancer Genome Atlas (TCGA), and an unselected pancreatic cancer screen from the Mayo Clinic were combined in a meta-analysis to estimate the proportion of carriers with pathogenic and high probability of pathogenic variants of uncertain significance (HiP-VUS).
RESULTS: Approximately 8.6% of unselected pancreatic cancer cases at the HCH carried a variant with potential HBOC or CRC screening recommendations. A meta-analysis of unselected pancreatic cancer cases revealed that approximately 11.5% carry a pathogenic variant or HiP-VUS.
CONCLUSION: With the inclusion of both HBOC and CRC susceptibility genes in a panel test, unselected pancreatic cancer cases act as a useful sentinel cancer to identify asymptomatic at-risk relatives who could benefit from relevant HBOC and CRC surveillance measures.

Xu J, Shang Y, Cai F, et al.
Correlation between lung cancer and the HHIP polymorphisms of chronic obstructive pulmonary disease (COPD) in the Chinese Han population.
Genes Immun. 2019; 20(4):273-280 [PubMed] Related Publications
To further investigate the relationship between lung cancer and hedgehog interacting protein (HHIP) polymorphisms of chronic obstructive pulmonary disease (COPD) patients, we conducted a case-control study in a Chinese Han population. Six HHIP SNPs with minor allele frequencies >5% (rs1489758, rs1489759, rs10519717, rs13131837, rs1492820, and rs7689420) were analyzed in 1,017 COPD patients (767 males and 246 females) and 430 non-COPD patients. Using logistic regression analysis, we found that rs7689420 was significantly associated with lung cancer in COPD patients in the Chinese Han population (P < 0.001). The recessive allele of rs7689420 was associated with the occurrence of lung cancer in all COPD patients (odds ratios [OR] of 0.609 and 0.424 for the CT and TT genotypes, respectively) as well as in serious COPD patients (OR of 0.403 and 0.305 for CT and TT, respectively). Additionally, rs1489759 and rs3131837 were associated with lung cancer in various genetic models. rs1489758, rs1489759, and rs10519717 were also associated with lung cancer in serious COPD patients. However, none of the SNPs were significantly associated with lung cancer in mild COPD patients or healthy subjects. Therefore, the HHIP SNPs of COPD patients likely play a role in lung cancer pathology in the Chinese Han population.

Ruiz-Heredia Y, Sanchez-Vega B, Barrio S, et al.
Concurrent progressive multifocal leukoencephalopathy and central nervous system infiltration by multiple myeloma: A case report.
J Oncol Pharm Pract. 2019; 25(4):998-1002 [PubMed] Related Publications
Progressive multifocal leukoencephalopathy rarely occurs in patients with multiple myeloma. Intracranial central nervous system invasion is also an uncommon event in multiple myeloma, occurring in less than 1% of cases. We describe herein an exceptional case of coexisting progressive multifocal leukoencephalopathy and intraparenchymal central nervous system myeloma infiltration. A 73-year-old woman with relapsed multiple myeloma was treated with 15 cycles of lenalidomide and dexamethasone, but therapy had to be stopped because of a hip fracture after a fall. During hospitalization, the patient developed progressive multifocal leukoencephalopathy caused by John Cunningham virus, and a prominent intra-parenchymal CD138-positive infiltrate was detected. VDJ rearrangements of the immunoglobulin heavy chain gene and the mutational profile of plasma cells in bone marrow at the time of diagnosis and in brain biopsy after progression were analyzed by next generation sequencing, showing genetic differences between medullary and extramedullary myeloma cells. The role of long-term treatment with lenalidomide and dexamethasone in the development progressive multifocal leukoencephalopathy or intraparenchymal central nervous system myeloma infiltration remains unknown. However, our results suggest that both events may have arisen as a consequence of treatment-related immunosuppression. Thus, an appropriate clinical approach compatible with the simultaneous treatment of progressive multifocal leukoencephalopathy and multiple myeloma should be developed.

Zuo Y, Lv Y, Qian X, et al.
Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration.
Cell Physiol Biochem. 2018; 45(5):1840-1850 [PubMed] Related Publications
BACKGROUND/AIMS: Human hedgehog-interacting protein (HHIP) is a negative regulator of the hedgehog (HH) signaling pathway. It is deregulated in gastric cancer. The underlying molecular mechanism of HHIP-induced inhibition of HH signaling remains to be determined.
METHODS: A lentiviral HHIP expression vector ("LV-HHIP") was established to exogenously over-express HHIP in gastric cancer cells. HHIP protein and mRNA were tested by Western blotting assay and quantitative real-time PCR assay, respectively. Cell survival was tested by the Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was examined by the BrdU ELISA assay and [H3] Thymidine DNA incorporation assay. Cell invasion and migration were tested by the phagokinetic track assay and the "Transwell" assay. The bisulfite-sequencing PCR was applied to test HHIP promoter methylation.
RESULTS: In the established (AGS cell line) and primary human gastric cancer cells, LV-HHIP transfection increased HHIP expression and inhibited cancer cell survival and proliferation as well as cell migration and invasion. Furthermore, LV-HHIP significantly attenuated promoter methylation of the endogenous HHIP gene in AGS cells, causing it upregulation. Inhibition of methylation by 5-aza-dc similarly induced HHIP expression in gastric cancer cells, which inhibited cancer cell proliferation and migration.
CONCLUSIONS: Our results suggest that inhibition of HHIP promoter methylation can efficiently inhibit human gastric cancer cell proliferation and migration.

Yu D, Zheng W, Johansson M, et al.
Overall and Central Obesity and Risk of Lung Cancer: A Pooled Analysis.
J Natl Cancer Inst. 2018; 110(8):831-842 [PubMed] Free Access to Full Article Related Publications
Background: The obesity-lung cancer association remains controversial. Concerns over confounding by smoking and reverse causation persist. The influence of obesity type and effect modifications by race/ethnicity and tumor histology are largely unexplored.
Methods: We examined associations of body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR) with lung cancer risk among 1.6 million Americans, Europeans, and Asians. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. Analyses for WC/WHR were further adjusted for BMI. The joint effect of BMI and WC/WHR was also evaluated.
Results: During an average 12-year follow-up, 23 732 incident lung cancer cases were identified. While BMI was generally associated with a decreased risk, WC and WHR were associated with increased risk after controlling for BMI. These associations were seen 10 years before diagnosis in smokers and never smokers, were strongest among blacks, and varied by histological type. After excluding the first five years of follow-up, hazard ratios per 5 kg/m2 increase in BMI were 0.95 (95% CI = 0.90 to 1.00), 0.92 (95% CI = 0.89 to 0.95), and 0.89 (95% CI = 0.86 to 0.91) in never, former, and current smokers, and 0.86 (95% CI = 0.84 to 0.89), 0.94 (95% CI = 0.90 to 0.99), and 1.09 (95% CI = 1.03 to 1.15) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Hazard ratios per 10 cm increase in WC were 1.09 (95% CI = 1.00 to 1.18), 1.12 (95% CI = 1.07 to 1.17), and 1.11 (95% CI = 1.07 to 1.16) in never, former, and current smokers, and 1.06 (95% CI = 1.01 to 1.12), 1.20 (95% CI = 1.12 to 1.29), and 1.13 (95% CI = 1.04 to 1.23) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Participants with BMIs of less than 25 kg/m2 but high WC had a 40% higher risk (HR = 1.40, 95% CI = 1.26 to 1.56) than those with BMIs of 25 kg/m2 or greater but normal/moderate WC.
Conclusions: The inverse BMI-lung cancer association is not entirely due to smoking and reverse causation. Central obesity, particularly concurrent with low BMI, may help identify high-risk populations for lung cancer.

Beck A, Trippel F, Wagner A, et al.
Overexpression of
Clin Epigenetics. 2018; 10:27 [PubMed] Free Access to Full Article Related Publications
Background: Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification.
Results: We examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB-associated tumor suppressor genes (TSGs)
Conclusion: These findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that

Amanatullah DF, Tamaresis JS, Chu P, et al.
Local estrogen axis in the human bone microenvironment regulates estrogen receptor-positive breast cancer cells.
Breast Cancer Res. 2017; 19(1):121 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Approximately 70% of all breast cancers express the estrogen receptor, and are regulated by estrogen. While the ovaries are the primary source of estrogen in premenopausal women, most breast cancer is diagnosed following menopause, when systemic levels of this hormone decline. Estrogen production from androgen precursors is catalyzed by the aromatase enzyme. Although aromatase expression and local estrogen production in breast adipose tissue have been implicated in the development of primary breast cancer, the source of estrogen involved in the regulation of estrogen receptor-positive (ER+) metastatic breast cancer progression is less clear.
METHODS: Bone is the most common distant site of breast cancer metastasis, particularly for ER+ breast cancers. We employed a co-culture model using trabecular  bone tissues obtained from total hip replacement (THR) surgery specimens to study ER+ and estrogen receptor-negative (ER-) breast cancer cells within the human bone microenvironment. Luciferase-expressing ER+ (MCF-7, T-47D, ZR-75) and ER- (SK-BR-3, MDA-MB-231, MCF-10A) breast cancer cells were cultured directly on bone tissue fragments or in bone tissue-conditioned media, and monitored over time with bioluminescence imaging (BLI). Bone tissue-conditioned media were generated in the presence vs. absence of aromatase inhibitors, and testosterone. Bone tissue fragments were analyzed for aromatase expression by immunohistochemistry.
RESULTS: ER+ breast cancer cells were preferentially sustained in co-cultures with bone tissues and bone tissue-conditioned media relative to ER- cells. Bone fragments analyzed by immunohistochemistry revealed expression of the aromatase enzyme. Bone tissue-conditioned media generated in the presence of testosterone had increased estrogen levels and heightened capacity to stimulate ER+ breast cancer cell proliferation. Pretreatment of cultured bone tissues with aromatase inhibitors, which inhibited estrogen production, reduced the capacity of conditioned media to stimulate ER+ cell proliferation.
CONCLUSIONS: These results suggest that a local estrogen signaling axis regulates ER+ breast cancer cell viability and proliferation within the bone metastatic niche, and that aromatase inhibitors modulate this axis. Although endocrine therapies are highly effective in the treatment of ER+ breast cancer, resistance to these treatments reduces their efficacy. Characterization of estrogen signaling networks within the bone microenvironment will identify new strategies for combating metastatic progression and endocrine resistance.

Zhang QL, Zhao LG, Li HL, et al.
The joint effects of major lifestyle factors on colorectal cancer risk among Chinese men: A prospective cohort study.
Int J Cancer. 2018; 142(6):1093-1101 [PubMed] Free Access to Full Article Related Publications
Previous studies have suggested individual healthy lifestyle factors are related to lower risk of colorectal cancer. Their joint effects, however, have rarely been investigated. We aimed to assess the combined lifestyle impact on colorectal cancer risk and to estimate the population attributable risks of these lifestyle factors. Using data from the Shanghai Men's Health Study (2002-2013), we constructed healthy lifestyle index composing the following lifestyle factors: smoking, alcohol consumption, diet, waist-hip ratio and exercise participation. Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Over a median of 9.28 years' follow-up, 671 colorectal cancer cases occurred (400 colon cancer and 274 rectal cancer) among 59,503 men. Each increment of healthy lifestyle index was associated with a 17% lower risk of colorectal cancer (HR = 0.83, 95% CI: 0.78, 0.89), 10% of colon cancer (HR = 0.90, 95% CI: 0.83, 0.99) and 27% of rectal cancer (HR = 0.73, 95% CI: 0.66, 0.82). If all men in the cohort followed a lifestyle as defined by these five factors, 21% colorectal cancer cases would have been prevented (PAR = 21%, 95% CI: 4%, 36%). In conclusion, combined lifestyle factors are significantly related to lower risk of colorectal cancer and the effects are more pronounced on rectal cancer than on colon cancer.

Avilés-Vázquez S, Chávez-González A, Hidalgo-Miranda A, et al.
Global gene expression profiles of hematopoietic stem and progenitor cells from patients with chronic myeloid leukemia: the effect of in vitro culture with or without imatinib.
Cancer Med. 2017; 6(12):2942-2956 [PubMed] Free Access to Full Article Related Publications
In this study, we determined the gene expression profiles of bone marrow-derived cell fractions, obtained from normal subjects and Chronic Myeloid Leukemia (CML) patients, that were highly enriched for hematopoietic stem (HSCs) and progenitor (HPCs) cells. Our results indicate that the profiles of CML HSCs and HPCs were closer to that of normal progenitors, whereas normal HSCs showed the most different expression profile of all. We found that the expression profiles of HSCs and HPCs from CML marrow were closer to each other than those of HSCs and HPCs from normal marrow. The major biologic processes dysregulated in CML cells included DNA repair, cell cycle, chromosome condensation, cell adhesion, and the immune response. We also determined the genomic changes in both normal and CML progenitor cells under culture conditions, and found that several genes involved in cell cycle, steroid biosynthesis, and chromosome segregation were upregulated, whereas genes involved in transcription regulation and apoptosis were downregulated. Interestingly, these changes were the same, regardless of the addition of Imatinib (IM) to the culture. Finally, we identified three genes-PIEZO2, RXFP1, and MAMDC2- that are preferentially expressed by CML primitive cells and that encode for cell membrane proteins; thus, they could be used as biomarkers for CML stem cells.

Dubey B, Jackson MD, Zeigler-Johnson C, et al.
Inflammation polymorphisms and prostate cancer risk in Jamaican men: Role of obesity/body size.
Gene. 2017; 636:96-102 [PubMed] Free Access to Full Article Related Publications
African ancestry and obesity are associated with higher risk of prostate cancer (PC). In a pilot study, we explored interactions between obesity (as measured by waist to hip ratio (WHR)) and inflammatory SNPs in relation to PC risk among Jamaican men. This study evaluated 87 chemokine and cytokine associated SNPs in obese and normal weight cases (N=109) and controls (N=102) using a stepwise penalized logistic regression approach in multivariable analyses. Upon stratification by WHR (normal weight (WHR<0.90) or obese (WHR≥0.90)), inheritance of CCR6 rs2023305 AG+GG (OR=1.75, p=0.007), CCR9 rs7613548 AG+GG (OR=1.71, p=0.012) and IL10ra rs2229113 AG+GG (OR=1.45, p=0.01) genotypes was associated with increase in overall or low grade (Gleason score<7) PC risk among normal weight men. These odds were elevated among obese men who possessed the CCR5 rs1799987 AG+GG (OR=1.95, p=0.003) and RNASEL rs12135247 CT+TT genotypes (OR=1.59, p=0.05). CCR7 rs3136685 AG+GG (p=0.032) was associated with a 1.52-1.70 fold increase in the risk of high grade cancer (Gleason score≥7) among obese men. CCR7 variant emerged as an important factor associated with high grade PC risk among obese men in our analyses. Overall, genetic loci found significant in normal weight men were not significant in obese men and vice-versa, partially explaining the role of obesity on PC risk among black men. Also, older age was an important risk factor both in normal weight and obese men but only with regard to low grade PC. Associations of inflammatory SNPs with obesity are suggestive and require further validation in larger cohorts to help develop an understanding of PC risk among obese and non-obese men of African descent.

Biermann J, Nemes S, Parris TZ, et al.
A Novel 18-Marker Panel Predicting Clinical Outcome in Breast Cancer.
Cancer Epidemiol Biomarkers Prev. 2017; 26(11):1619-1628 [PubMed] Related Publications

Chism CB, Crawford L, Tchakarov A, et al.
PTEN hamartoma of the soft tissue: the initial manifestation of an underlying PTEN hamartoma tumor syndrome in a 4-year-old female.
Skeletal Radiol. 2017; 46(11):1591-1595 [PubMed] Related Publications
A 4-year-old female was referred to pediatric orthopedic surgery for left leg pain and limping for 3 months following a motor vehicle collision. Recently, the patient's mother had noted left knee swelling and dragging of the left leg when walking. Past medical history was significant for hip dysplasia with slight leg length discrepancy. The patient was otherwise healthy. Physical examination was remarkable for left pre-patellar soft tissue fullness with normal range of motion. There was no warmth or tenderness. Subsequent ultrasound revealed a heterogeneous soft tissue mass superior and medial to the patella with a moderate degree of internal vascularity. MR exhibited a heterogeneous soft tissue mass with heterogeneous signal on both T1- and T2-weighted images centered within the vastus medialis obliquus muscle infiltrating the quadriceps tendon. Excisional biopsy was performed with a histopathologic diagnosis of fibroadipose tissue with anomalous vessels, suggestive of phosphatase and tensin homolog (PTEN) hamartoma of the soft tissue (PHOST). The patient was found to be positive for the PTEN gene mutation on genetic testing. The child was also determined to be macrocephalic, a major criterion for PTEN hamartoma tumor syndrome (PHTS). The geneticist advised the patient to undergo yearly physical examinations and early, routine surveillance for several malignancies occurring with PHTS. This case report presents the ultrasound and MRI appearance of a rare benign tumor typically appearing in pediatric patients. The strong association between PHOST and other soft tissue malignancies and the resulting need for life-long surveillance make PHOST an important pathology to recognize.

Martinussen T, Vansteelandt S, Tchetgen Tchetgen EJ, Zucker DM
Instrumental variables estimation of exposure effects on a time-to-event endpoint using structural cumulative survival models.
Biometrics. 2017; 73(4):1140-1149 [PubMed] Free Access to Full Article Related Publications
The use of instrumental variables for estimating the effect of an exposure on an outcome is popular in econometrics, and increasingly so in epidemiology. This increasing popularity may be attributed to the natural occurrence of instrumental variables in observational studies that incorporate elements of randomization, either by design or by nature (e.g., random inheritance of genes). Instrumental variables estimation of exposure effects is well established for continuous outcomes and to some extent for binary outcomes. It is, however, largely lacking for time-to-event outcomes because of complications due to censoring and survivorship bias. In this article, we make a novel proposal under a class of structural cumulative survival models which parameterize time-varying effects of a point exposure directly on the scale of the survival function; these models are essentially equivalent with a semi-parametric variant of the instrumental variables additive hazards model. We propose a class of recursive instrumental variable estimators for these exposure effects, and derive their large sample properties along with inferential tools. We examine the performance of the proposed method in simulation studies and illustrate it in a Mendelian randomization study to evaluate the effect of diabetes on mortality using data from the Health and Retirement Study. We further use the proposed method to investigate potential benefit from breast cancer screening on subsequent breast cancer mortality based on the HIP-study.

Diamandis EP, Stanczyk FZ, Wheeler S, et al.
Serum complexed and free prostate-specific antigen (PSA) for the diagnosis of the polycystic ovarian syndrome (PCOS).
Clin Chem Lab Med. 2017; 55(11):1789-1797 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Polycystic ovarian syndrome (PCOS) is a common cause of reproductive and metabolic dysfunction. We hypothesized that serum prostate-specific antigen (PSA) may constitute a new biomarker for hyperandrogenism in PCOS.
METHODS: We conducted a cross-sectional study of 45 women with PCOS and 40 controls. Serum from these women was analyzed for androgenic steroids and for complexed PSA (cPSA) and free PSA (fPSA) with a novel fifth- generation assay with a sensitivity of ~10 fg/mL for cPSA and 140 fg/mL for fPSA.
RESULTS: cPSA and fPSA levels were about three times higher in PCOS compared to controls. However, in PCOS, cPSA and fPSA did not differ according to waist-to-hip ratio, Ferriman-Gallwey score, or degree of hyperandrogenemia or oligo-ovulation. In PCOS and control women, serum cPSA and fPSA levels were highly correlated with each other, and with free and total testosterone levels, but not with other hormones. Adjusting for age, body mass index (BMI) and race, cPSA was significantly associated with PCOS, with an odds ratio (OR) of 5.67 (95% confidence interval [CI]: 1.86, 22.0). The OR of PCOS for fPSA was 7.04 (95% CI: 1.65, 40.4). A multivariate model that included age, BMI, race and cPSA yielded an area-under-the-receiver-operating-characteristic curve of 0.89.
CONCLUSIONS: Serum cPSA and fPSA are novel biomarkers for hyperandrogenism in PCOS and may have value for disease diagnosis.

Ward HA, Wark PA, Muller DC, et al.
Measured Adiposity in Relation to Head and Neck Cancer Risk in the European Prospective Investigation into Cancer and Nutrition.
Cancer Epidemiol Biomarkers Prev. 2017; 26(6):895-904 [PubMed] Free Access to Full Article Related Publications

Shafiee MN, Mongan N, Seedhouse C, et al.
Sterol regulatory element binding protein-1 (SREBP1) gene expression is similarly increased in polycystic ovary syndrome and endometrial cancer.
Acta Obstet Gynecol Scand. 2017; 96(5):556-562 [PubMed] Related Publications
INTRODUCTION: Women with polycystic ovary syndrome have a three-fold higher risk of endometrial cancer. Insulin resistance and hyperlipidemia may be pertinent factors in the pathogenesis of both conditions. The aim of this study was to investigate endometrial sterol regulatory element binding protein-1 gene expression in polycystic ovary syndrome and endometrial cancer endometrium, and to correlate endometrial sterol regulatory element binding protein-1 gene expression with serum lipid profiles.
MATERIAL AND METHODS: A cross-sectional study was performed at Nottingham University Hospital, UK. A total of 102 women (polycystic ovary syndrome, endometrial cancer and controls; 34 participants in each group) were recruited. Clinical and biochemical assessments were performed before endometrial biopsies were obtained from all participants. Taqman real-time polymerase chain reaction for endometrial sterol regulatory element binding protein-1 gene and its systemic protein expression were analyzed.
RESULTS: The body mass indices of women with polycystic ovary syndrome (29.28 ± 2.91 kg/m
CONCLUSIONS: Sterol regulatory element binding protein-1 gene expression is significantly increased in the endometrium of women with polycystic ovary syndrome and women with endometrial cancer compared with controls and positively correlates with serum triglyceride in both polycystic ovary syndrome and endometrial cancer.

Sun X, Wu X, Duan Y, et al.
Family-Based Association Study of rs17300539 and rs12495941 Polymorphism in Adiponectin Gene and Polycystic Ovary Syndrome in a Chinese Population.
Med Sci Monit. 2017; 23:78-84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Polycystic ovary syndrome (PCOS) is a complex disease that has both genetic and environmental components. Adiponectin plays an important role in the regulation of insulin sensitivity and insulin resistance (IR) in PCOS. The aim of this study was to determine 2 single-nucleotide polymorphisms (SNPs) variants (rs12495941 and rs17300539) of the adiponectin gene (ADIPOQ) in polycystic ovary syndrome (PCOS) families. MATERIAL AND METHODS We recruited 197 PCOS probands, their biological parents, and 192 controls. Anthropometric variables, including hip circumference (HC) and waist circumference (WC), were measured in all subjects during their first visit to the outpatient department. Serum T, FBG, FINS, TC, TG, LDL, and HDL levels were measured. PCOS patients were divided into 2 groups based on BMI: group A (BMI <25 kg/m²) and group B (BMI ≥25 kg/m²). Parents of PCOS were accordingly categorized into group C and group D (fathers), and group E and group F (mothers). The associations among ADIPOQ rs12495941, rs17300539, and PCOS were analyzed using the transmission disequilibrium test (TDT). RESULTS A significant association was found between SNP rs17300539 and PCOS in our Chinese population. The levels of TG and FINS and the genotype frequencies of rs17300539 are significantly different between overweight and lean PCOS. No significant association was detected for rs12495941. CONCLUSIONS TDT confirms that rs17300539 of ADIPOQ is strongly associated with the risk of PCOS in a Chinese Han population, but rs12495941 of ADIPOQ is not associated with the occurrence of PCOS.

Kaz AM, Wong CJ, Varadan V, et al.
Global DNA methylation patterns in Barrett's esophagus, dysplastic Barrett's, and esophageal adenocarcinoma are associated with BMI, gender, and tobacco use.
Clin Epigenetics. 2016; 8:111 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The risk of developing Barrett's esophagus (BE) and/or esophageal adenocarcinoma (EAC) is associated with specific demographic and behavioral factors, including gender, obesity/elevated body mass index (BMI), and tobacco use. Alterations in DNA methylation, an epigenetic modification that can affect gene expression and that can be influenced by environmental factors, is frequently present in both BE and EAC and is believed to play a role in the formation of BE and its progression to EAC. It is currently unknown whether obesity or tobacco smoking influences the risk of developing BE/EAC via the induction of alterations in DNA methylation. To investigate this possibility, we assessed the genome-wide methylation status of 81 esophageal tissues, including BE, dysplastic BE, and EAC epithelia using HumanMethylation450 BeadChips (Illumina).
RESULTS: We found numerous differentially methylated loci in the esophagus tissues when comparing males to females, obese to lean individuals, and smokers to nonsmokers. Differences in DNA methylation between these groups were seen in a variety of functional genomic regions and both within and outside of CpG islands. Several cancer-related pathways were found to have differentially methylated genes between these comparison groups.
CONCLUSIONS: Our findings suggest obesity and tobacco smoking may influence DNA methylation in the esophagus and raise the possibility that these risk factors affect the development of BE, dysplastic BE, and EAC through influencing the epigenetic status of specific loci that have a biologically plausible role in cancer formation.

Salamanna F, Borsari V, Brogini S, et al.
An in vitro 3D bone metastasis model by using a human bone tissue culture and human sex-related cancer cells.
Oncotarget. 2016; 7(47):76966-76983 [PubMed] Free Access to Full Article Related Publications
One of the main limitations, when studying cancer-bone metastasis, is the complex nature of the native bone environment and the lack of reliable, simple, inexpensive models that closely mimic the biological processes occurring in patients and allowing the correct translation of results. To enhance the understanding of the mechanisms underlying human bone metastases and in order to find new therapies, we developed an in vitro three-dimensional (3D) cancer-bone metastasis model by culturing human breast or prostate cancer cells with human bone tissue isolated from female and male patients, respectively. Bone tissue discarded from total hip replacement surgery was cultured in a rolling apparatus system in a normoxic or hypoxic environment. Gene expression profile, protein levels, histological, immunohistochemical and four-dimensional (4D) micro-CT analyses showed a noticeable specificity of breast and prostate cancer cells for bone colonization and ingrowth, thus highlighting the species-specific and sex-specific osteotropism and the need to widen the current knowledge on cancer-bone metastasis spread in human bone tissues. The results of this study support the application of this model in preclinical studies on bone metastases and also follow the 3R principles, the guiding principles, aimed at replacing/reducing/refining (3R) animal use and their suffering for scientific purposes.

Paluszczak J, Wiśniewska D, Kostrzewska-Poczekaj M, et al.
Prognostic significance of the methylation of Wnt pathway antagonists-CXXC4, DACT2, and the inhibitors of sonic hedgehog signaling-ZIC1, ZIC4, and HHIP in head and neck squamous cell carcinomas.
Clin Oral Investig. 2017; 21(5):1777-1788 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: Aberrations in Wnt and Shh signaling pathways are related to the pathogenesis of head and neck carcinomas, and their activation frequently results from epigenetic alterations. This study aimed to assess the frequency of methylation of negative regulators of Wnt signaling: CXXC4, DACT2, HDPR1, and FBXW11 and Shh signaling: HHIP, PTCH1, SUFU, ZIC1, and ZIC4 and correlate it with clinicopathological features in this group of patients.
MATERIALS AND METHODS: Methylation-specific PCR was used to detect gene promoter methylation, and real-time PCR was used to assess gene expression level.
RESULTS: The analysis of the occurrence of gene promoter methylation in head and neck carcinoma cell lines indicated that CXXC4, DACT2, HHIP, ZIC1, and ZIC4 are methylated in these tumors. These genes were further analyzed in tumor sections from oral and laryngeal cancer patients. Gene methylation rate was higher in laryngeal tumors. The methylation index in tumor samples correlated with the overall survival in a subgroup of oral cancer patients who died of the disease. Moreover, ZIC4 methylation correlated with lymph node involvement in oral cancer patients.
CONCLUSIONS: Our findings corroborate that the activation of Wnt signaling in head and neck squamous cell carcinoma (HNSCC) is related to epigenetic silencing of its negative regulators. Moreover, the results indicate that the same mechanism of activation may operate in the case of Shh signaling.
CLINICAL RELEVANCE: The methylation of ZIC4 may be considered a new prognostic marker in oral cavity and oropharyngeal tumors. Further investigations should determine the diagnostic significance of methylation of ZIC4, HHIP, and DACT2 in head and neck carcinomas.

Ożegowska K, Bogacz A, Bartkowiak-Wieczorek J, et al.
Is there an association between the development of metabolic syndrome in PCOS patients and the C677T MTHFR gene polymorphism?
Ginekol Pol. 2016; 87(4):246-53 [PubMed] Related Publications
INTRODUCTION: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. PCOS is characterized by anovulation, polycystic ovaries, hyperandrogenism leading to infertility, dermatological and psychological problems, as well as the risk of developing Metabolic Syndrome (MetS) and cardiovascular disease (CVD). The exact cause of PCOS remains unclear. Various biochemical and genetic markers have been implicated in predisposition to PCOS, but no single variant has been associated with the syndrome. Some authors connect hyperhomocysteinemia (HHcy) with MetS and its components. The MTHFR gene C677T polymorphism is a common genetic abnormality leading to hyperhomocysteinemia.
OBJECTIVES: The aim of the study was to confirm the existence of a possible correlation between metabolic disturbances in PCOS and the MTHFR C677T polymorphism.
MATERIAL AND METHODS: A total of 98 patients diagnosed with PCOS according to the Rotterdam criteria and 101 age-matched healthy controls were included in the study. Genotyping of MTHFR C677T was performed by the real time PCR method.
RESULTS: Statistically significant differences were observed between those two groups with regard to body mass index (BMI), waist circumference (WC), hip circumference (HC), fasting insulin, total cholesterol (TC), and triglycerides (TG). No significant differences in the prevalence of the genotypes of the MTHFR C677T gene polymorphism were found between the PCOS group and controls. Despite the lack of significant differences, we observed a tendency for a higher prevalence of the TT genotype in the PCOS group (p = 0.06). No statistically significant differences were observed between the PCOS group and the control group in terms of the presence of the MetS components and the predisposition to develop MetS.
CONCLUSIONS: Our study did not confirm an association between the MTHFR C677T gene polymorphism and the development of MetS in PCOS. Further studies with larger sample size might be useful to determine this association.

Niramitmahapanya S, Deerochanawong C, Sarinnapakorn V, et al.
Somatic HRPT2 Mutation (Arg234X) of Parathyroid Carcinoma Associated with Slipped Capital Femoral Epiphysis: A First Case Report.
J Med Assoc Thai. 2016; 99 Suppl 2:S201-5 [PubMed] Related Publications
A 14-year-old boy was admitted to the orthopedic clinic of Rajavithi Hospital complaining of pain in the left hip. A year earlier, pain had developed in his left joint and had gradually increased in intensity in both hips. A month before he was referred, radiographs obtained at another hospital showed bilateral slipped capital femoral epiphysis (SCFE). The patient's biochemical laboratory data showed hypercalcemia, hypophosphatemia, and a high level of intact parathyroid hormone (iPTH) compatible with primary hyperparathyroidism. HRPT2 gene analysis found heterozygosity for c. 700 C > T mutation (Arg234X) of HRPT2 gene at exon 7. This is the first report in the literature about somatic mutation of the HRPT2 gene of parathyroid carcinoma associated with slipped capital femoral epiphysis.

Crispo A, Montella M, Buono G, et al.
Body weight and risk of molecular breast cancer subtypes among postmenopausal Mediterranean women.
Curr Res Transl Med. 2016 Jan-Mar; 64(1):15-20 [PubMed] Related Publications
Breast cancer (BC) is the most common malignant tumor in women, obesity is associated with increased BC incidence and mortality and high levels of circulating insulin may negatively impact on cancer incidence. In the present study, we investigated whether the strength of several anthropometric and metabolic parameters varies between BC molecular subtypes. Eligible cases were 991 non-metastatic BC patients recruited between January 2009 and December 2013. Anthropometric, clinical and immunohistochemical features were measured. Multivariate logistic regression models were built to assess HER2 positive BC risk, comparing (a) triple positive (TP) with luminal A, luminal B and triple negative (TN) and (b) HER2-enriched group with luminal A, luminal B and TN. We stratified patients in pre- and post-menopause: significant differences emerged for luminal A in relation to age: they were more likely to be older compared to other groups. Among postmenopausal patients, the adjusted multivariate analysis showed that high BMI and high waist circumference were inversely correlated to TP subtype when compared to luminal B (OR=0.48 and OR=0.49, respectively). Conversely, HOMA-IR was a risk factor for TP when compared to luminal A and TN (OR=2.47 and OR=3.15, respectively). Our findings suggest a potential role of higher abdominal fat in the development of specific BC molecular subtypes in postmenopausal women. Moreover, they support a potential role of insulin resistance in the development of HER2 positive BC, although this role appears to be stronger when hormone receptors are co-expressed, suggesting a difference in the etiology of these two BC subtypes.

His M, Fagherazzi G, Mesrine S, et al.
Prediagnostic body size and breast cancer survival in the E3N cohort study.
Int J Cancer. 2016; 139(5):1053-64 [PubMed] Related Publications
Obesity has been associated with poor breast cancer prognosis, however most studies have focused on body mass index (BMI) and few have considered the distribution of adipose tissue. We investigated associations between prediagnostic adiposity and breast cancer survival, considering BMI, waist and hip circumferences (WC and HC), and waist-to-hip ratio (WHR). Analyses included 3,006 women from the French E3N prospective cohort study diagnosed with primary invasive breast cancer between 1995 and 2008. We investigated overall, breast cancer-specific, and disease-free survival, overall and according to stage, menopausal and hormonal status and year of diagnosis, using Cox proportional hazard models adjusted for tumor characteristics and lifestyle risk factors. Women with a prediagnostic HC > 100 cm were at increased risk of death from all causes (hazard ratio (HR)>100 vs < 95 cm  = 1.38, 95% Confidence Interval (CI) = 1.02-1.86, Ptrend  = 0.02) and from breast cancer (HR>100 vs < 95 cm  = 1.50, CI = 1.03-2.17, Ptrend  = 0.03), and of second invasive cancer event (HR>100 vs < 95 cm  = 1.36, CI = 1.11-1.67, Ptrend  = 0.002), compared to those with HC <95 cm. Associations were stronger after adjustment for BMI. BMI, WC and WHR were not associated with survival after breast cancer. Our study underlines the importance of going beyond BMI when studying the association between adiposity and breast cancer survival. Further studies should be conducted to confirm our results on hip circumference.

Moreno-Lorenzana D, Avilés-Vazquez S, Sandoval Esquivel MA, et al.
CDKIs p18(INK4c) and p57(Kip2) are involved in quiescence of CML leukemic stem cells after treatment with TKI.
Cell Cycle. 2016; 15(9):1276-87 [PubMed] Free Access to Full Article Related Publications
Chronic Myeloid Leukemia (CML) is sustained by a small population of cells with stem cell characteristics known as Leukemic Stem Cells that are positive to BCR-ABL fusion protein, involved with several abnormalities in cell proliferation, expansion, apoptosis and cell cycle regulation. Current treatment options for CML involve the use of Tirosine Kinase Inhibitor (Imatinib, Nilotinib and Dasatinib), that efficiently reduce proliferation proliferative cells but do not kill non proliferating CML primitive cells that remain and contributes to the persistence of the disease. In order to understand the role of Cyclin Dependent Kinase Inhibitors in CML LSC permanence after TKI treatment, in this study we analyzed cell cycle status, the levels of several CDKIs and the subcellular localization of such molecules in different CML cell lines, as well as primary CD34(+)CD38(-)lin(-) LSC and HSC. Our results demonstrate that cellular location of p18(INK4c) and p57(Kip2) seems to be implicated in the antiproliferative activity of Imatinib and Dasatinib in CML cells and also suggest that the permanence of quiescent stem cells after TKI treatment could be associated with a decrease in p18(INK4c) and p57(Kip2) nuclear location. The differences in p18(INK4c)and p57(Kip2)activities in CML and normal stem cells suggest a different cell cycle regulation and provide a platform that could be considered in the development of new therapeutic options to eliminate LSC.

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