Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development

Loh, Kim; Chia, June A.; Greco, Sonia; Cozzi, Sarah-Jane; Buttenshaw, Ron; Bond, Catherine; Simms, Lisa A.; Pike, Tanya; Young, Joanne; Jass, Jeremy R.; Spring, Kevin; Leggett, Barbara A.; Whitehall, Vicki

doi:10.1002/gcc.20552

Cited by 87 publications

(85 citation statements)

References 37 publications

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“…Although the role of BMP3 in the pathogenesis of cancer is unknown, several studies have demonstrated that BMP3 participates in the development of various types of cancer (17)(18)(19)(20)(21). Loh et al (17) reported that in colon cancer cell lines with methylation-dependent BMP3 downregulation, cell colony growth suppression was observed following the reintroduction of BMP3 coding sequences.…”

Section: Discussionmentioning

confidence: 99%

“…Loh et al (17) reported that in colon cancer cell lines with methylation-dependent BMP3 downregulation, cell colony growth suppression was observed following the reintroduction of BMP3 coding sequences. Methylation of the BMP3 promoter has also been described in subtypes of stomach (18), lung (20), pancreatic (19) and breast cancers (21) with downregulated BMP3 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Extrathyroidal invasion is one of the most prominent prognostic risk factors for a poor clinical outcome in patients with PTC (22). As mentioned, BMP3 may negatively regulate cellular processes including migration, proliferation and differentiation (16)(17)(18)(19). In addition, BMP3 gene expression has been identified to be downregulated with hypermethylation of the BMP3 promoter region in various types of cancer (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned, BMP3 may negatively regulate cellular processes including migration, proliferation and differentiation (16)(17)(18)(19). In addition, BMP3 gene expression has been identified to be downregulated with hypermethylation of the BMP3 promoter region in various types of cancer (17)(18)(19). The SNP rs13138132 is located in a predicted promoter enhancing region (http://asia.ensembl.org/index.html); thus, we speculated that rs13138132 affects promoter activity and methylation of the BMP3 gene, and that rs13138132 eventually contributes to extrathyroidal invasion in PTC.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro studies have also suggested a role for BMP3 as a negative growth regulator in bone marrow progenitor cells through the inhibition of DNA synthesis and proliferation (16). Additionally, recent studies have revealed that BMP3 contributes to tumor development and progression (17)(18)(19). However, to the best of our knowledge, no study of a possible genetic association between polymorphisms in BMP3 and cancer has been conducted.…”

Section: Introductionmentioning

confidence: 99%

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Polymorphisms in bone morphogenetic protein 3 and the risk of papillary thyroid cancer

Kim¹,

Hong

Eun

et al. 2012

Oncology Letters

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Abstract. Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta (TGFβ) superfamily with well-described functions in bone formation. Although disrupted BMP signaling in tumor development has been investigated, a genetic association for BMP3 in papillary thyroid cancer (PTC) has remained largely unexplored. In this study, we investigated whether BMP3 single nucleotide polymorphisms (SNPs) are associated with the development of PTC and its clinicopathological features. A total of 103 PTC patients and 324 control subjects were enrolled. One promoter SNP (rs13138132; -1919C/A) and one missense mutation (rs3733549; Arg192Gln) in BMP3 were genotyped by direct sequencing. SNPStats, SNPAnalyzer, Helixtree and Haploview version 4.2 were used to evaluate the genetic data. Multiple logistic regression models were used to calculate odds ratios (ORs), 95% confidence intervals (CIs) and P-values. The missense SNP (rs3733549) was weakly associated with the development of PTC in a codominant model (AA vs. GG; P=0.017) and a recessive model (AA vs. GG/GA; P=0.023). Additionally, in an analysis according to clinicopathological features, rs13138132 was significantly associated with extrathyroidal invasion in a codominant model (CA vs. CC; P=0.006) and a dominant model (CA/AA vs. CC; P=0.0023). We also identified that the frequency of the A allele in the promoter SNP (rs13138132) was increased in PTC patients with extrathyroidal invasion (P=0.004). Our data suggest that rs3733549 in BMP3 is associated with the development of PTC and that the A allele of rs13138932 in BMP3 is a risk factor for extrathyroidal invasion. IntroductionThyroid cancer is the most common type of endocrine malignancy, accounting for approximately 1% of all cases of cancer. It is the most rapidly increasing cancer among females and the second most rapidly increasing cancer among males. Histologically, thyroid cancer is classified as papillary thyroid cancer (PTC), follicular thyroid cancer, medullary thyroid cancer or undifferentiated or anaplastic thyroid cancer. Of these, PTC is the most common type, and it accounts for 85-90% of all thyroid malignancies (1,2). Although the etiology of PTC is unclear, environmental factors, including radiation, diet, smoking and hormones, have been identified to affect the pathogenesis of thyroid cancer (3,4). Genetic predisposition has also been implicated as a risk factor for thyroid cancer development (5,6).Bone morphogenic proteins (BMPs) have been demonstrated to play an important role during development (particularly during bone formation) and in the regulation of various cellular processes, including cell proliferation, apoptosis and differentiation (7). Evidence suggests that BMPs are important in tumorigenesis (8-10). BMPs are members of the transforming growth factor beta (TGFβ) family; thus, BMPs utilize a similar signaling cascade to that of TGFβ. BMPs have been identified to utilize the SMAD signaling pathway for their growth suppressive effects, and also to affect PTEN and p21 (W...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Polymorphisms in bone morphogenetic protein 3 and the risk of papillary thyroid cancer

Kim¹,

Hong

Eun

et al. 2012

Oncology Letters

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A de novo microtriplication at 4q21.21‐q21.22 in a patient with a vascular malignant hemangioma, elongated sigmoid colon, developmental delay, and absence of speech

Lebedev

Назаренко

Skryabin

et al. 2016

American J of Med Genetics Pt A

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The widespread application of array comparative genomic hybridization (aCGH) has provided new insights into the clinical significance of copy number variations (CNVs) in the human genome. Many microdeletion syndromes have recently been linked to corresponding reciprocal microduplication syndromes related to CNVs in the same chromosomal regions. However, the extent of CNVs may not be restricted to only microduplications but may also include microtriplications or even quadruplications. 4q21 microdeletion syndrome is one of these recently described syndromes. The phenotype includes growth restriction, neonatal hypotonia, severe developmental delay, absent or delayed speech, and distinct facial features. The minimal critical deleted region, which is 1.3 Mb in size, contains the PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1 genes. Here, we report a 5.4-year-old girl with developmental delay, absence of speech, muscular hypertension, macrocephaly, a broad forehead, frontal bossing, relatively elongated extremities, a vascular malignant hemangioma in anamnesis, and elongated sigmoid colon. aCGH revealed a microtriplication at 4q21.21-q21.22 that was 1.61 Mb in size. This de novo microtriplication included nine genes (BMP3, PRKG2, RASGEF1B, HNRNPD, HNRPDL, ENOPH1, TMEM150C, LINC00575, and SCD5) and overlapped with the minimal critical region for 4q21 microdeletion syndrome. Some clinical features of the patient were similar to those of 4q21 microdeletion (macrocephaly, frontal bossing, developmental delay, absence of speech, and anxiety), whereas others were mirrored (elongated extremities and muscular hypertension). The first identified case of a de novo microtriplication at 4q21.21-q21.22 emphasizes the clinical significance of CNVs at 4q21 for patients with developmental delay and absence of speech. © 2016 Wiley Periodicals, Inc.

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Combined SEPT9 and BMP3 methylation in plasma for colorectal cancer early detection and screening in a Brazilian population

et al. 2023

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BackgroundColorectal cancer (CRC) screening can help to reduce its incidence and mortality. Noninvasive strategies, such as plasma analysis of epigenetic alterations, can constitute important biomarkers of CRC detection.ObjectiveThis study aimed to evaluate the plasma methylation status of SEPT9 and BMP3 promoters as biomarkers for detection of CRC and its precursor lesions in a Brazilian population.MethodsPlasma samples from 262 participants of the CRC screening program of Barretos Cancer Hospital who had a positive fecal occult blood test and underwent colonoscopy and cancer patients were analyzed. Participants were grouped according to the worst lesion detected in the colonoscopy. Cell‐free circulating DNA (cfDNA) was bisulfite treated followed by the analysis of SEPT9 and BMP3 methylation status using a droplet digital PCR system (ddPCR). The best methylation cutoff value for group discrimination was calculated by receiver operating characteristic (ROC) curve analysis.ResultsAmong the 262 participants, 38 were diagnosed with CRC, 46 with advanced adenomas 119 with nonadvanced adenomas, three with sessile serrated lesions, and 13 with hyperplastic polyps. In 43 participants, no lesion was detected in the colonoscopy and were used as controls. The CRC group showed the highest cfDNA concentration (10.4 ng/mL). For the SEPT9 gene, a cutoff of 2.5% (AUC = 0.681) that discriminates between CRC and the control group resulted in CRC sensitivity and specificity of 50% and 90%, respectively. Concerning the BMP3 gene, a cutoff of 2.3% (AUC = 0.576) showed 40% and 90% of sensitivity and specificity for CRC detection, respectively. Combining SEPT9, BMP3 status, and age over 60 years resulted in a better performance for detecting CRC (AUC = 0.845) than the individual gene models, yielding 80% and 81% of sensitivity and specificity, respectively.ConclusionThe present study suggests that a combination of SEPT9 and BMP3 plasma methylation, along with age over 60 years, showed the highest performance in detecting CRC in a Brazilian population. These noninvasive biomarkers can potentially serve as useful tools for CRC screening programs.

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Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development

Cited by 87 publications

References 37 publications

Polymorphisms in bone morphogenetic protein 3 and the risk of papillary thyroid cancer

Polymorphisms in bone morphogenetic protein 3 and the risk of papillary thyroid cancer

A de novo microtriplication at 4q21.21‐q21.22 in a patient with a vascular malignant hemangioma, elongated sigmoid colon, developmental delay, and absence of speech

Combined SEPT9 and BMP3 methylation in plasma for colorectal cancer early detection and screening in a Brazilian population

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