APC | Cancer Genetics Web

Sokic-Milutinovic A
Appropriate Management of Attenuated Familial Adenomatous Polyposis: Report of a Case and Review of the Literature.
Dig Dis. 2019; 37(5):400-405 [PubMed] Related Publications

Hereditary polyposis syndromes in which APC gene germline mutations can lead to colorectal carcinogenesis are familial adenomatous polyposis (FAP), attenuated FAP (AFAP) and MUTYH-associated polyposis. All 3 syndromes increase the potential for the development of colorectal cancer. AFAP is diagnosed if less than 100 adenomas are detected in the colon at presentation. AFAP is inherited in an autosomal dominant manner. We present a case of a 22-year-old female with AFAP who was treated with endoscopic polypectomy and surveilled by annual colonoscopy. Guidelines for AFAP surveillance suggest annual colonoscopy with endoscopic polypectomy in asymptomatic individuals. Indications for immediate surgery include documented or suspected cancer or significant symptoms. Preferred surgical option in AFAP is colectomy and ileo-rectal anastomosis. Surveillance of the AFAP patients should include upper GI endoscopy and duodenoscopy with random biopsies of fundic gland polyps and endoscopic resection of detected adenomas. Annual thyroid ultrasound is indicated due to increased risk for thyroid cancer. In pediatric patients tested positive for germline mutation of APC gene screening for hepatoblastoma using alpha-fetoprotein and liver ultrasound should be performed.

Related:

Mieszczanek J, van Tienen LM, Ibrahim AEK, et al.
Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models.
Nat Commun. 2019; 10(1):724 [PubMed] Free Access to Full Article Related Publications

Bcl9 and Pygo are Wnt enhanceosome components that effect β-catenin-dependent transcription. Whether they mediate β-catenin-dependent neoplasia is unclear. Here we assess their roles in intestinal tumourigenesis initiated by Apc loss-of-function (Apc

Related:

Lori G, Paoli P, Femia AP, et al.
Morin-dependent inhibition of low molecular weight protein tyrosine phosphatase (LMW-PTP) restores sensitivity to apoptosis during colon carcinogenesis: Studies in vitro and in vivo, in an Apc-driven model of colon cancer.
Mol Carcinog. 2019; 58(5):686-698 [PubMed] Related Publications

LMW-PTP has been associated with the development of colorectal cancer (CRC) and with the resistance to chemotherapy in cancer cells. To clarify its role in vivo, we studied LMW-PTP expression in Pirc rats (F344/NTac-Apc

Urbanova M, Hirschfeldova K, Obeidova L, et al.
Two Czech patients with familial adenomatous polyposis presenting mosaicism in APC gene.
Neoplasma. 2019; 66(2):294-300 [PubMed] Related Publications

During standard molecular diagnostic procedure, two Czech families with APC (Adenomatous polyposis coli gene) mosaicism have been detected. A woman with attenuated familial adenomatous polyposis (AFAP, OMIM #175100) was recently inspected by next generation sequencing. Standard bioinformatics pipeline, restricted to variants with at least 20% of reads (for germline variants) would miss mutation p.G1412X (NM_000038.5) present in 17% of reads. This novel variant was not present in any of her two children. Another woman with a clinical manifestation of attenuated FAP was tested 16 years ago without conclusive APC mutation found when denaturing gradient gel electrophoresis (DGGE), protein truncation test (PTT), multiplex ligation probe amplification (MLPA) and direct Sanger sequencing were applied. Recent inspection of her son showed clear mutation p.Q1062X (NM_000038.5, NP_000029.2) leading to premature stop codon. This finding led to re-evaluation of this protein position in his mother and detection of mosaicism (11% of allele, 22% of heterozygous cells in blood), which was primarily overlooked. Mutations in both patients were confirmed by allele-specific real time PCR (AS qPCR). In both index patients it was possible to detect and quantify the mosaic allele in biological samples of polyps, adjacent colonic mucosa and buccal swabs. In cases of sporadic appearance of FAP, besides blood we plan to preferably inspect also other samples, where mosaic fraction might be under detection limit of bioinformatics pipelines (<3%). For our future routine NGS sequencing analysis we will apply our in-house somatic variant detection pipeline to minimize the false negative calls when genes with high level of de-novo mutations are analyzed.

Related:

Magalhães L, Quintana LG, Lopes DCF, et al.
APC gene is modulated by hsa-miR-135b-5p in both diffuse and intestinal gastric cancer subtypes.
BMC Cancer. 2018; 18(1):1055 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Several genetic and epigenetic alterations are related to the development and progression of Gastric Cancer (GC), one of those being the deregulated microRNA (miRNA) expression profile. miRNAs are small noncoding RNAs that negatively regulate the expression of thousands of genes, including oncogenes and tumor suppressor genes. Our group identified, in previous studies, some miRNAs that are differentially expressed in GC when compared to the gastric mucosa without cancer, including hsa-miR-29c and hsa-miR-135b. The aim of the study was to modulate the expression of the miRNAs hsa-miR-29c-5p and hsa-miR-135b-5p and evaluate the expression of their target genes in 2D and 3D cell cultures.
METHODS: hsa-miR-29c-5p and hsa-miR-135b-5p expression profiles were modulated by transfecting mimics and antimiRs, respectively, in 2D and 3D cell cultures. The expression of the proteins coded by the genes CDC42, DNMT3A (target genes of hsa-miR-29c-5p) and APC (target gene of hsa-miR-135b-5p) were measured by Western Blot.
RESULTS: Results showed that mimics and antimiRs transfection significantly altered the expression of both miRNAs, increasing the expression of hsa-miR-29c-5p and reducing the expression of hsa-miR-135b-5p, especially in the 3D culture of the cell lines. When analyzing the proteins expression, we observed that AGP01 and AGP03 cell lines transfected with mimics had a reduction in the levels of CDC42 and DNMT3A and all three cell lines transfected with antimiRs had an increase in the expression of the protein APC.
CONCLUSION: We concluded that three-dimensional culture can be a more representative in vitro model that resembles better the in vivo reality. Our results also showed that hsa-miR-29c-5p is an important regulator of CDC42 and DNMT3A genes in the intestinal subtype gastric cancer and hsa-miR-135b-5p regulates the APC gene in both intestinal and diffuse subtypes of GC. Dysregulation in their expression, and consequently in their respectively signaling pathways, shows how these miRNAs can influence the carcinogenesis of different histological subtypes of gastric cancer.

Related:

MicroRNAs

Stomach Cancer

Gastric Cancer

Majumder S, Shah R, Elias J, et al.
A neoepitope derived from a novel human germline APC gene mutation in familial adenomatous polyposis shows selective immunogenicity.
PLoS One. 2018; 13(9):e0203845 [PubMed] Free Access to Full Article Related Publications

Familial adenomatous polyposis (FAP) is an inherited condition arising from genetic defects in the Adenomatous polyposis coli (APC) gene. Carriers with mutations in the APC gene develop polyps in the colon and rectum which if not managed, transition into colon cancer. In this study, we identified a novel germline mutation in the APC gene in members of an FAP-affected (Familial adenomatous polyposis) family. This unique heterozygous variant (c.735_736insT; p.Ser246PhefsTer6) was identified in ten out of twenty six family members, ranging in age from 6 to 60 years. Polyps were detected in six of the ten individuals (35-60 years) carrying this mutation. The remaining four members (6-23 years) remain polyp free. A significant fraction of FAP affected individuals eventually develop colon cancer and therapeutic interventions to prevent cancer progression remain elusive. To address this issue, we sought to determine if peptides derived from the novel APC mutation could induce a cytotoxic T cell response, thereby qualifying them as vaccine candidates. Peptides harboring the variant amino acids were first interrogated in silico for their immunogenicity using a proprietary neoepitope prioritization pipeline, OncoPeptVAC. A single 9-mer peptide was predicted to be immunogenic. Remarkably, CD8+ T cells isolated from either an FAP+/ APCmut individual, or from a FAP-/ APCmut individual, failed to respond to the peptide, whereas those from either an unaffected family member (FAP-/ APCwt) or from healthy unrelated donors, showed a robust response, suggesting that CD8+ T cells from individuals carrying this germline APC mutation have been tolerized to the mutation. Furthermore, experimental testing of six additional reported APC gene mutation-derived peptides revealed one of the six to be immunogenic. While not all APC mutant peptides are inmmunogenic, a few qualify as vaccine candidates offering novel treatment opportunities to patients with somatic APC gene mutations to delay/treat colorectal cancer.

Related:

Non-Small Cell Lung Cancer

Huang X, Wu C, Fu Y, et al.
Methylation analysis for multiple gene promoters in non-small cell lung cancers in high indoor air pollution region in China.
Bull Cancer. 2018; 105(9):746-754 [PubMed] Related Publications

AIM: The prevalence and mortality rates of lung cancer in Xuanwei, Yunnan, China, are the highest in the world. The severe indoor air pollution caused by smoky coals with high benzo (a)pyrene (BaP) and quartz levels is the main environmental factor. The aim of this study was to investigate methylation profiles of promoters in eight genes in primary non-small cell lung cancers (NSCLC) exposed to smoky coals.
MATERIALS AND METHODS: Candidate genes including CDKN2A, DLEC1, CDH1, DAPK, RUNX3, APC, WIF1 and MGMT were determined for the promoter methylation status using Nested methylation-specific PCR (nMSP) in primary 23NSCLC tissues and in circulating tumor DNA (ctDNA) isolated from 42plasma samples (9matched to tissues) as well as 10healthy plasma samples, using Sanger sequencing to verify the results.
RESULTS: Seven of the 8genes, except MGMT, had relatively high methylation frequencies ranging from 39%-74% in tissues. Moreover, methylation frequencies in five genes identified in lung cancer plasma were 45% for CDKN2A, 48% for DLEC1, 76% for CDH1, 14% for DAPK, 29% for RUNX3, with a relatively good concordance of methylation among 9 tissues and paired plasma. However, the genes from all healthy plasma showed no methylation.
CONCLUSIONS: A panel of genes including CDKN2A, DLEC1, CDH1, DAPK and RUNX3 may be used as potential epigenetic biomarkers for early lung cancer detection. CDH1 promoter methylation was associated with lung cancer metastasis in areas of air pollution from buring of smoky coals. DLEC1 and CDH1 exhibited specific high methylation frequencies, different from previous reports.

Related:

WIF1

Mogensen MB, Rossing M, Østrup O, et al.
Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing.
BMC Cancer. 2018; 18(1):752 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified.
METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software.
RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes.
CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

Related:

KRAS

Sample DC, Samadder NJ, Pappas LM, et al.
Variables affecting penetrance of gastric and duodenal phenotype in familial adenomatous polyposis patients.
BMC Gastroenterol. 2018; 18(1):115 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Patients with familial adenomatous polyposis (FAP) frequently undergo colectomy to reduce the 70 to 90% lifetime risk of colorectal cancer. After risk-reducing colectomy, duodenal cancer and complications from duodenal surgeries are the main cause of morbidity. Our objective was to prospectively describe the duodenal and gastric polyp phenotype in a cohort of 150 FAP patients undergoing pre-screening for a chemoprevention trial and analyze variables that may affect recommendations for surveillance.
METHODS: Individuals with a diagnosis of FAP underwent prospective esophagogastroduodenoscopy using a uniform system of mapping of size and number of duodenal polyps for a 10 cm segment. Gastric polyps were recorded as the total number.
RESULTS: The distribution of the count and sum diameter of duodenal polyps were statistically different in two genotype groups, those with APC mutations associated with classic FAP had a greater count (median 17) and sum diameter of polyps (median 32 mm) than those with APC mutations associated with attenuated FAP (median count 4 and median sum diameter of 7 mm) (p < 0.0001). The number of gastric polyps did not differ based on genotype (p = 0.67) but advancing age correlated with severity of gastric polyposis (p = 0.019). Spigelman (modified) staging of II or greater was found in 88% of classic FAP patients and 48% attenuated FAP patients. Examples of severe and mild upper GI phenotype are observed in patients with identical APC mutations, showing that the APC mutation location is not absolutely predictive of an upper GI phenotype.
CONCLUSIONS: Most FAP patients have duodenal and gastric polyps which become more prevalent and advanced with age. Standard upper endoscopic surveillance is recommended based on personal history independent of APC mutation location.
TRIAL REGISTRATION: NCT 01187901 registered August 24, 2010, prospective to enrollment.

Related:

Stomach Cancer

Gastric Cancer

Kim SB, Zhang L, Yoon J, et al.
Truncated Adenomatous Polyposis Coli Mutation Induces Asef-Activated Golgi Fragmentation.
Mol Cell Biol. 2018; 38(17) [PubMed] Free Access to Full Article Related Publications

Adenomatous polyposis coli (APC) is a key molecule to maintain cellular homeostasis in colonic epithelium by regulating cell-cell adhesion, cell polarity, and cell migration through activating the APC-stimulated guanine nucleotide-exchange factor (Asef). The APC-activated Asef stimulates the small GTPase, which leads to decreased cell-cell adherence and cell polarity, and enhanced cell migration. In colorectal cancers, while truncated APC constitutively activates Asef and promotes cancer initiation and progression, regulation of Asef by full-length APC is still unclear. Here, we report the autoinhibition mechanism of full-length APC. We found that the armadillo repeats in full-length APC interact with the APC residues 1362 to 1540 (APC-2,3 repeats), and this interaction competes off and inhibits Asef. Deletion of APC-2,3 repeats permits Asef interactions leading to downstream signaling events, including the induction of Golgi fragmentation through the activation of the Asef-ROCK-MLC2. Truncated APC also disrupts protein trafficking and cholesterol homeostasis by inhibition of SREBP2 activity in a Golgi fragmentation-dependent manner. Our study thus uncovers the autoinhibition mechanism of full-length APC and a novel gain of function of truncated APC in regulating Golgi structure, as well as cholesterol homeostasis, which provides a potential target for pharmaceutical intervention against colon cancers.

Related:

Signal Transduction

Mekky MA, Salama RH, Abdel-Aal MF, et al.
Studying the frequency of aberrant DNA methylation of APC, P14, and E-cadherin genes in HCV-related hepatocarcinogenesis.
Cancer Biomark. 2018; 22(3):503-509 [PubMed] Related Publications

BACKGROUND: Data about the molecular pathogenesis of hepatitis C-related hepatocellular carcinoma (HCC) are still challenging.
OBJECTIVES: Therefore, we tried to investigate the epigenetic study of three nominated genes (APC, P14, and E-cadherin) in the pathogenesis of HCV-related HCC in Egyptian.
METHODS: Between March 2016 and March 2017, the DNA methylation, and quantification using (epigenetic ELISA kit) for E-cadherin, APC, and P14 genes were studied in three groups of patients: HCV related liver cirrhosis without HCC group (LC-group; n= 20), HCC on top of HCV-related cirrhosis (HCC-group; n= 20), and a third apparently healthy control group (control-group; n= 10).
RESULTS: E-cad methylation showed non-significant differences between groups. P14 methylation was occurred only in HCC-group (45%). APC methylation was the highest in HCC group (70%). Methylation level was high in HCC group in comparison to both LC and control groups (P< 0.001). DNA methylation at a cutoff point > 2.9 ng/ml predicts HCC in LC-group with 90% sensitivity and 80% specificity and at level > 2.3 ng/ml had 95% sensitivity and 90% specificity in control-group. The pooled sensitivity, specificity, positive and negative predictive values and accuracy were 90%, 60%, 69.2, 85.7 and 75% respectively.
CONCLUSION: Aberrant DNA methylation of multiple genes is associated with disease progression in HCV related cirrhosis. Moreover, early detection of promotor methylation of these may sever as good biomarker for early detection and therapeutic targets in high risk patients.

Related:

Liver Cancer

Sarvepalli S, Burke CA, Monachese M, et al.
Natural history of colonic polyposis in young patients with familial adenomatous polyposis.
Gastrointest Endosc. 2018; 88(4):726-733 [PubMed] Related Publications

BACKGROUND AND AIMS: Proctocolectomy prevents colorectal cancer in familial adenomatous polyposis (FAP). Colorectal polyp progression is one of the indications for surgery. No data exist regarding the natural history of colorectal polyposis in young patients with FAP. This study examined the rate of polyposis progression and factors associated with it.
METHODS: Patients with FAP <30 years old who had undergone ≥2 colonoscopies since 2000 were identified. Rate of polyposis progression was calculated by review of polyp counts obtained from baseline and last colonoscopy, accounting for any polyps removed during the observation period. Endoscopic and non-endoscopic factors affecting the rate of polyposis progression were evaluated. Multivariate analysis was performed to identify factors associated with rate of polyposis progression.
RESULTS: One hundred sixty-eight patients (52% female; median age, 13.5 years) were included. Median rate of polyposis progression was 25.4 polyps/year (interquartile range, 9.5-69.8). Highest median rate of polyposis progression (89 polyps/year) was associated with mutation in codon 1309. The rate of polyposis progression was independently associated with the location of mutation in the adenomatous polyposis coli gene, the number of polyps at the initial colonoscopy, and exposure to chemoprevention. Of the 39.9% of patients who underwent surgery, an increase in polyp number was the most common indication (53.7%).
CONCLUSIONS: The rate of polyposis progression in young patients with FAP varies with a median of about 25 new polyps per year. Progression is associated with distinct factors, which can be used in discussion with patients regarding the need for and timing of prophylactic colorectal surgery.

Related:

Zhang M, Yang D, Gold B
The Adenomatous Polyposis Coli (APC) mutation spectra in different anatomical regions of the large intestine in colorectal cancer.
Mutat Res. 2018; 810:1-5 [PubMed] Related Publications

The enhanced incidence of colorectal cancer (CRC) in the U.S.A. has been linked to promutagens, such as heterocyclic aromatic amines, in the western diet that are produced by high temperature cooking of meat. However, a prior analysis of driver nonsense mutations in the Adenomatous Polyposis Coli (APC) gene, which is mutated in 75% of human CRC, indicated that the C·G → A·T transversions produced by this class of mutagens were not enriched but actually lower than what would be statistically anticipated. Moreover, the APC mutation patterns in the U.S.A. vs. China were indistinguishable despite differences in diet. In the present study, we have dissected the APC mutation pattern in tumors that arise in the different anatomical regions of the large intestine. The results show that the nonsense mutation pattern in APC differ in the different regions and that there is a statistically significant increase in C·G → A·T transversions in the rectum vs. the other regions, albeit, the percent of C·G → A·T mutations still remains lower than predicted based on random mutagenesis.

Related:

USA

Trobaugh-Lotrario AD, López-Terrada D, Li P, Feusner JH
Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening.
Pediatr Blood Cancer. 2018; 65(8):e27103 [PubMed] Related Publications

Familial adenomatous polyposis (FAP) due to APC mutation is associated with an increased risk of hepatoblastoma. All cases of hepatoblastoma in patients with FAP reported in the literature were reviewed. One hundred and nine patients were identified. Thirty-five patients (of 49 with data) were diagnosed with hepatoblastoma prior to a later diagnosis of FAP (often in association with advanced colorectal carcinoma), emphasizing a need to identify patients earlier with germline APC mutations for early colorectal carcinoma screening. Hepatoblastoma may present at birth, and screening for hepatoblastoma in infancy in families with FAP prior to APC mutation testing results may be warranted.

Related:

Hepatoblastoma

Liver Cancer

Childhood Liver Cancer

Seidlitz T, Merker SR, Rothe A, et al.
Human gastric cancer modelling using organoids.
Gut. 2019; 68(2):207-217 [PubMed] Free Access to Full Article Related Publications

OBJECTIVE: Gastric cancer is the second leading cause of cancer-related deaths and the fifth most common malignancy worldwide. In this study, human and mouse gastric cancer organoids were generated to model the disease and perform drug testing to delineate treatment strategies.
DESIGN: Human gastric cancer organoid cultures were established, samples classified according to their molecular profile and their response to conventional chemotherapeutics tested. Targeted treatment was performed according to specific druggable mutations. Mouse gastric cancer organoid cultures were generated carrying molecular subtype-specific alterations.
RESULTS: Twenty human gastric cancer organoid cultures were established and four selected for a comprehensive in-depth analysis. Organoids demonstrated divergent growth characteristics and morphologies. Immunohistochemistry showed similar characteristics to the corresponding primary tissue. A divergent response to 5-fluoruracil, oxaliplatin, irinotecan, epirubicin and docetaxel treatment was observed. Whole genome sequencing revealed a mutational spectrum that corresponded to the previously identified microsatellite instable, genomic stable and chromosomal instable subtypes of gastric cancer. The mutational landscape allowed targeted therapy with trastuzumab for
CONCLUSION: We generated human and mouse gastric cancer organoids modelling typical characteristics and altered pathways of human gastric cancer. Successful interference with activated pathways demonstrates their potential usefulness as living biomarkers for therapy response testing.

Related:

Stomach Cancer

Gastric Cancer

Trastuzumab (Herceptin)

TP53

Kruger C, Zhou Y
Red meat and colon cancer: A review of mechanistic evidence for heme in the context of risk assessment methodology.
Food Chem Toxicol. 2018; 118:131-153 [PubMed] Related Publications

On October 26, 2015, IARC published a summary of their findings regarding the association of cancer with consumption of red meat or processed meat (IARC 2015; The Lancet Oncology 2015). The Working Group concluded that there is limited evidence in human beings for carcinogenicity from the consumption of red meat and inadequate evidence in experimental animals for the carcinogenicity of consumption of red meat. Nevertheless, the working group concluded that there is strong mechanistic evidence by which ingestion of red meat can be linked to human colorectal cancer and assigned red meat to Group 2A "probably carcinogenic to humans". The Working Group cited supporting mechanistic evidence for multiple meat components, including those formed from meat processing, such as N-nitroso compounds (NOC) and heterocyclic aromatic amines, and the endogenous compound, heme iron. The mechanism of action for each of these components is different and so it is critical to evaluate the evidence for each component separately. Consequently, this review critically examined studies that investigated mechanistic evidence associated with heme iron to assess the weight of the evidence associating exposure to red meat with colorectal cancer. The evidence from in vitro studies utilized conditions that are not necessarily relevant for a normal dietary intake and thus do not provide sufficient evidence that heme exposure from typical red meat consumption would increase the risk of colon cancer. Animal studies utilized models that tested promotion of preneoplastic conditions utilizing diets low in calcium, high in fat combined with exaggerations of heme exposure that in many instances represented intakes that were orders of magnitude above normal dietary consumption of red meat. Finally, clinical evidence suggests that the type of NOC found after ingestion of red meat in humans consists mainly of nitrosyl iron and nitrosothiols, products that have profoundly different chemistries from certain N-nitroso species which have been shown to be tumorigenic through the formation of DNA adducts. In conclusion, the methodologies employed in current studies of heme have not provided sufficient documentation that the mechanisms studied would contribute to an increased risk of promotion of preneoplasia or colon cancer at usual dietary intakes of red meat in the context of a normal diet.

Related:

Acute Myeloid Leukemia (AML)

Angelousi A, Settas N, Faucz FR, et al.
Medullary thyroid cancer, leukemia, mesothelioma and meningioma associated with germline APC and RASAL1 variants: a new syndrome?
Hormones (Athens). 2017; 16(4):423-428 [PubMed] Free Access to Full Article Related Publications

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor hereditary in 35% of cases. The most common syndromic form is in the context of the multiple endocrine neoplasia type 2 (MEN 2) syndromes in association with other tumors and due to germline RET mutations. We describe a 57-year-old female patient diagnosed with sporadic MTC. The patient had a history of other neoplasias, such as acute myeloid leukemia, for which she had received chemotherapy, and two other solid tumors, peritoneal mesothelioma and meningioma. Genetic analyses were carried out including whole exome and Sanger sequencing (WES and SS) and loss-of-heterozygosity (LOH) testing for the respective loci. Immunohistochemistry (IHC) was used for the detection of proteins of interest. WES showed two germline variants in the APC and RASAL1 genes confirmed by SS. In MTC tissue only there was a RETvariant identified by SS; germline studies did not show any RETsequence changes. The pattern of tumors in this patient is unusual for either one of the APC- orRASAL1-associated neoplasms and her non-MEN 2-associated MTC contained a RET variant like other sporadic MTCs. As in other patients with more than one genetic variant predisposing to tumors, it is possible that this case represents a unique association.

Related:

Mesothelioma

Thyroid Cancer

RASAL1

Lee YS, Chin YT, Shih YJ, et al.
Thyroid Hormone Promotes β-Catenin Activation and Cell Proliferation in Colorectal Cancer.
Horm Cancer. 2018; 9(3):156-165 [PubMed] Related Publications

Thyroid hormone status has long been implicated in cancer development. Here we investigated the role of thyroxine (T

Related:

PCNA: Proliferating cell nuclear antigen

Shiroky JS, Lerner-Ellis JP, Govindarajan A, et al.
Characteristics of Adrenal Masses in Familial Adenomatous Polyposis.
Dis Colon Rectum. 2018; 61(6):679-685 [PubMed] Related Publications

BACKGROUND: Adrenal masses are a known extraintestinal manifestation of familial adenomatous polyposis. However, the literature on this association is largely confined to case reports.
OBJECTIVE: This study aimed to determine the characteristics of adrenal masses in familial adenomatous polyposis and their clinical significance, as well as to estimate their prevalence. Mutational analysis was conducted to determine if any potential genotype-phenotype correlations exist.
DESIGN: This is a retrospective cohort study.
SETTING: Analysis included all patients meeting the criteria of classic familial adenomatous polyposis who were registered with the Familial Gastrointestinal Cancer Registry, a national Canadian database.
PATIENTS: Appropriate imaging or autopsy reports were available in 311 registry patients. Patients with adrenal metastases were excluded.
OUTCOME MEASURES: Data collection included demographic data, mutation genotype, adrenal mass characteristics, surgical interventions and mortality.
RESULTS: The prevalence of adrenal masses was 16% (n = 48/311). The median age at diagnosis of adrenal mass was 45 years. The median diameter of adrenal mass at diagnosis was 1.7 cm (interquartile range, 1.4-3.0) with a median maximal diameter of 2.5 cm (interquartile range, 1.7-4.1) with median imaging follow-up of 48 months. The majority of adrenal masses were benign (97%, n = 61/63). Surgery was performed on 7 patients because of concerns for size, malignancy, or hormonal secretion. One adrenal-related death was due to an adrenocortical carcinoma. Mutation analysis did not identify any specific genotype-phenotype correlations.
LIMITATIONS: There were incomplete or insufficient endocrinology data available in the registry to allow for the analysis of hormone secretion patterns.
CONCLUSIONS: Adrenal masses are approximately twice as prevalent in the familial adenomatous polyposis population as in previous studies of the general population. Nearly all mutations led to truncation of the APC gene; however, there was no genetic signature to help predict those at increased risk. The majority of adrenal lesions identified were of benign etiology; thus, an intensive management or surveillance strategy with imaging screening is likely unwarranted. See Video Abstract at http://links.lww.com/DCR/A507.

Related:

Canada

Stevenson P, Rodins K, Susman R
The association between multiple pilomatrixomas and APC gene mutations.
Australas J Dermatol. 2018; 59(4):e273-e274 [PubMed] Related Publications

Related:

Skin Cancer

Ciavarella M, Miccoli S, Prossomariti A, et al.
Somatic APC mosaicism and oligogenic inheritance in genetically unsolved colorectal adenomatous polyposis patients.
Eur J Hum Genet. 2018; 26(3):387-395 [PubMed] Free Access to Full Article Related Publications

Germline variants in the APC gene cause familial adenomatous polyposis. Inherited variants in MutYH, POLE, POLD1, NTHL1, and MSH3 genes and somatic APC mosaicism have been reported as alternative causes of polyposis. However, ~30-50% of cases of polyposis remain genetically unsolved. Thus, the aim of this study was to investigate the genetic causes of unexplained adenomatous polyposis. Eight sporadic cases with >20 adenomatous polyps by 35 years of age or >50 adenomatous polyps by 55 years of age, and no causative germline variants in APC and/or MutYH, were enrolled from a cohort of 56 subjects with adenomatous colorectal polyposis. APC gene mosaicism was investigated on DNA from colonic adenomas by Sanger sequencing or Whole Exome Sequencing (WES). Mosaicism extension to other tissues (peripheral blood, saliva, hair follicles) was evaluated using Sanger sequencing and/or digital PCR. APC second hit was investigated in adenomas from mosaic patients. WES was performed on DNA from peripheral blood to identify additional polyposis candidate variants. We identified APC mosaicism in 50% of patients. In three cases mosaicism was restricted to the colon, while in one it also extended to the duodenum and saliva. One patient without APC mosaicism, carrying an APC in-frame deletion of uncertain significance, was found to harbor rare germline variants in OGG1, POLQ, and EXO1 genes. In conclusion, our restrictive selection criteria improved the detection of mosaic APC patients. In addition, we showed for the first time that an oligogenic inheritance of rare variants might have a cooperative role in sporadic colorectal polyposis onset.

Related:

Yeh YS, Chang YT, Ma CJ, et al.
First-decade patient with colorectal cancer carrying both germline and somatic mutations in APC gene.
BMC Cancer. 2017; 17(1):849 [PubMed] Free Access to Full Article Related Publications

BACKGROUND: Colorectal carcinoma (CRC) is one of the most common causes of cancer-related deaths. The mean age of patients with CRC ranges from 49 to 60 years. Pediatric CRC is unusual, which often escapes early diagnosis because of a lack of awareness of its occurrence in children. The association between the mutation of APC and the occurrence of CRC in the first decade of life remains unknown.
CASE PRESENTATION: We report a 10-year-old child with CRC; he was diagnosed with stage IIIB advanced transverse colon cancer without distal metastases. We detected a heterozygous germline mutation at c.5465 T > A in both blood and tissue samples and a heterozygous somatic mutation at c.7397C > T in the tissue sample. Both of these mutations can cause CRC tumorigenesis in the first decade of life.
CONCLUSIONS: The rare genetic features of this 10-year-old patient might be the predisposing cause of pediatric CRC. Therefore, screening patients with early-onset CRC through clinical and genetic characterizations is suggested.

Related:

Kallenberg FGJ, Latchford A, Lips NC, et al.
Duodenal Adenomas in Patients With Multiple Colorectal Adenomas Without Germline APC or MUTYH Mutations.
Dis Colon Rectum. 2018; 61(1):58-66 [PubMed] Related Publications

BACKGROUND: Patients with genetic adenomatous polyposis syndromes have an increased risk for duodenal cancer, and clear surveillance recommendations exist for this group. However, limited data are available on the duodenal phenotype of patients with multiple colorectal adenomas (10-99) without a germline APC or MUTYH mutation.
OBJECTIVE: We aimed to assess the frequency, extent, and progression of duodenal adenomas in patients with multiple colorectal adenomas without a germline APC or MUTYH mutation.
DESIGN: This was an historical cohort study.
SETTINGS: This study was undertaken at 2 polyposis registries: the Academic Medical Center in the Netherlands, and St. Mark's Hospital in the United Kingdom.
PATIENTS: We collected data on all patients with 10 to 99 colorectal adenomas and absent APC and MUTYH mutations, who underwent ≥1 esophagogastroduodenoscopy.
MAIN OUTCOME MEASURES: The frequency, extent, and progression of duodenal adenomas were measured. Demographic and endoscopic data were collected, described, and compared between patients with and without duodenal adenomas.
RESULTS: Eighty-three patients were identified, of which 8 (9.6%) had duodenal adenomas, detected at a median of 58 years (range, 45-75 y). Duodenal adenomas were detected in 6 of 8 patients at first esophagogastroduodenoscopy. At diagnosis, all 8 patients had Spigelman stage I or II disease. Two of 5 patients with duodenal adenomas who underwent follow-up esophagogastroduodenoscopies increased to stage III disease. The other 3 remained stable. No one developed duodenal cancer. No differences in demographic and endoscopic data were found between patients with and without duodenal adenomas.
LIMITATIONS: This study was limited by its retrospective design, selection bias, and small sample size.
CONCLUSIONS: Duodenal adenomas are found in a minority of patients with multiple colorectal adenomas without a germline APC or MUTYH mutation, at an average age of 58 years, and, at diagnosis, disease severity is mild. These results are a first step in unraveling the duodenal phenotype of these patients, which is needed to provide appropriate upper GI screening and surveillance recommendations. See Video Abstract at http://links.lww.com/DCR/A357.

Related:

He S, Du J, Liu F
[Advance in research on the correlation between genotypes of susceptible mutations and clinical phenotype of familial adenomatous polyposis].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2017; 34(6):919-923 [PubMed] Related Publications

Familial adenomatous polyposis (FAP) is one of the most common hereditary colorectal cancers. Its intestinal and extra-intestinal manifestations are correlated with mutation sties of the APC gene. Potential gene modulation sites in patients who have typical clinical manifestations but with unidentified APC mutations are also discussed, which included MUTYH gene, AXIN gene and certain epigenetic changes. With the generalization of Precision Medicine, to offer individualized treatment and surveillance strategy based on the genotype-phenotype correlation will be of great value for FAP patients. This review focuses on the research advance in genotype - phenotype correlation studies of FAP patients.

Related:

Borowsky J, Dumenil T, Bettington M, et al.
The role of APC in WNT pathway activation in serrated neoplasia.
Mod Pathol. 2018; 31(3):495-504 [PubMed] Related Publications

Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear β-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of β-catenin and truncating APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear β-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P=0.0001). However, unlike the conventional pathway, truncating APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations common in conventional adenomas.

Related:

Ayala-Calvillo E, Mojica-Vázquez LH, García-Carrancá A, González-Maya L
Wnt/β‑catenin pathway activation and silencing of the APC gene in HPV‑positive human cervical cancer‑derived cells.
Mol Med Rep. 2018; 17(1):200-208 [PubMed] Free Access to Full Article Related Publications

Although persistent infections with high‑risk human papilloma virus (HPV) constitute the most significant cofactor for the development of cervical cancer, they are insufficient on their own. Mutations or epigenetic inactivation of the tumor suppressor adenomatous polyposis coli (APC), the two acting as prominent oncogenic mechanisms in a number of types of cancer, are frequently associated with aberrant activation of the Wnt/β‑catenin pathway. According to these observations, it was hypothesized that APC alteration may lead to β‑catenin deregulation and the abnormal expression of direct targets of the Wnt pathway in HPV‑infected cervical cancer cells. The present study confirmed that the stabilization of β‑catenin correlates with enhanced transcriptional activity of the β‑catenin/T‑cell factor complex in cervical cancer cell lines. Sequence analysis of the 'hot‑spot' in the mutation cluster region did not exhibit genetic alterations that may be associated with APC gene inactivation. In addition, it was identified that there was a good correlation with the hypermethylation status of the APC promoter 1A and the abnormal accumulation of endogenous β‑catenin in cell lines and biopsies infected with HPV16, although not HPV18. Removal of the epigenetic markers led to an increase in APC levels and a reduction of β‑catenin expression in two transcriptional targets of the Wnt pathway: Matrix metalloproteinase‑7 and vascular endothelial growth factor. The present study suggested that the increase in Wnt activity in certain cervical cancer‑derived cells may be associated with an alteration in the methylation status of the APC gene promoter 1A.

Related:

Cervical Cancer

McCluggage WG, Irving JA, Chong AS, et al.
Ovarian Microcystic Stromal Tumors Are Characterized by Alterations in the Beta-Catenin-APC Pathway and May be an Extracolonic Manifestation of Familial Adenomatous Polyposis.
Am J Surg Pathol. 2018; 42(1):137-139 [PubMed] Related Publications

Related:

Ovarian Cancer

Signal Transduction

Faluyi OO, Fitch P, Howie SEM
An increased CD25-positive intestinal regulatory T lymphocyte population is dependent upon Cox-2 activity in the Apc
Clin Exp Immunol. 2018; 191(1):32-41 [PubMed] Free Access to Full Article Related Publications

Only mismatch repair (MMR)-deficient colorectal cancer (CRC) appears to respond well to programmed death (PD)-1 inhibition at the present time. Emerging evidence suggests a role for micro-environmental factors such as CD25

Related:

COX2 (PTGS2)

Cytokines

Byun MR, Hwang JH, Kim AR, et al.
SRC activates TAZ for intestinal tumorigenesis and regeneration.
Cancer Lett. 2017; 410:32-40 [PubMed] Related Publications

Proto-oncogene tyrosine-protein kinase Src (cSRC) is involved in colorectal cancer (CRC) development and damage-induced intestinal regeneration, although the cellular mechanisms involved are poorly understood. Here, we report that transcriptional coactivator with PDZ binding domain (TAZ) is activated by cSRC, regulating CRC cell proliferation and tumor formation, where cSRC overexpression increases TAZ expression in CRC cells. In contrast, knockdown of cSRC decreases TAZ expression. Additionally, direct phosphorylation of TAZ at Tyr316 by cSRC stimulates nuclear localization and facilitates transcriptional enhancer factor TEF-3 (TEAD4)-mediated transcription. However, a TAZ phosphorylation mutant significantly decreased cell proliferation, wound healing, colony forming, and tumor formation. In a CRC mouse model, Apc

Related: