scholarly journals Identification of a Novel Pathogenic Rearrangement Variant of the APC Gene Associated with a Variable Spectrum of Familial Cancer

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 411
Author(s):  
María Lourdes Garza-Rodríguez ◽  
Víctor Treviño ◽  
Antonio Alí Pérez-Maya ◽  
Hazyadee Frecia Rodríguez-Gutiérrez ◽  
Moisés González-Escamilla ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Familial Cancer ◽  
Apc Gene ◽  
Colorectal Adenomas ◽  
Cancer Genetic Counseling ◽  
Adenomatous Polyposis ◽  
Germline Variants ◽  
Novel Variant ◽  
Suitable Treatment ◽  
Next Generation Sequencing Ngs

Familial adenomatous polyposis (FAP) is an autosomal-dominant condition characterized by the presence of multiple colorectal adenomas, caused by germline variants in the adenomatous polyposis coli (APC) gene. More than 300 germline variants have been characterized. The detection of novel variants is important to understand the mechanisms of pathophysiology. We identified a novel pathogenic germline variant using next-generation sequencing (NGS) in a proband patient. The variant is a complex rearrangement (c.422+1123_532-577 del ins 423-1933_423-1687 inv) that generates a complete deletion of exon 5 of the APC gene. To study the variant in other family members, we designed an endpoint PCR method followed by Sanger sequencing. The variant was identified in the proband patient’s mother, one daughter, her brother, two cousins, a niece, and a second nephew. In patients where the variant was identified, we found atypical clinical symptoms, including mandibular, ovarian, breast, pancreatic, and gastric cancer. Genetic counseling and cancer prevention strategies were provided for the family. According to the American College of Medical Genetics (ACMG) guidelines, this novel variant is considered a PVS1 variant (very strong evidence of pathogenicity), and it can be useful in association with clinical data for early surveillance and suitable treatment.

Biology of the Adenomatous Polyposis Coli Tumor Suppressor

2000 ◽  
Vol 18 (9) ◽  
pp. 1967-1979 ◽  
Author(s):  
Kathleen Heppner Goss ◽  
Joanna Groden
Keyword(s):  
Colon Cancer ◽  
Tumor Suppressor ◽  
Adenomatous Polyposis Coli ◽  
Cancer Progression ◽  
Apc Gene ◽  
Colorectal Adenomas ◽  
Beta Catenin ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Familial Adenomatous Polyposis Coli

ABSTRACT: The adenomatous polyposis coli (APC) gene was first identified as the gene mutated in an inherited syndrome of colon cancer predisposition known as familial adenomatous polyposis coli (FAP). Mutation of APC is also found in 80% of all colorectal adenomas and carcinomas and is one of the earliest mutations in colon cancer progression. Similar to other tumor suppressor genes, both APC alleles are inactivated by mutation in colon tumors, resulting in the loss of full-length protein in tumor cells. The functional significance of altering APC is the dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, which include cell cycle progression, migration, differentiation, and apoptosis. Roles for APC in some of these processes are in large part attributable to its ability to regulate cytosolic levels of the signaling molecule beta-catenin and to affect the transcriptional profile in cells. This article summarizes numerous genetic, biochemical, and cell biologic studies on the mechanisms of APC-mediated tumor suppression. Mouse models of FAP, in which the APC gene has been genetically inactivated, have been particularly useful in testing therapeutic and chemopreventive strategies. These data have significant implications for colorectal cancer treatment approaches as well as for understanding other disease genes and cancers of other tissue types.

scholarly journals Variable phenotype of familial adenomatous polyposis in pedigrees with 3′ mutation in the APC gene

Gut ◽  
1998 ◽  
Vol 43 (4) ◽  
pp. 548-552 ◽  
Author(s):  
J D Brensinger ◽  
S J Laken ◽  
M C Luce ◽  
S M Powell ◽  
G H Vance ◽  
...  
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Case Series ◽  
Colorectal Polyps ◽  
Apc Gene ◽  
Colorectal Adenomas ◽  
Adenomatous Polyposis ◽  
Lower Gastrointestinal Tract ◽  
Polyposis Coli ◽  
Extracolonic Manifestations ◽  
Variable Phenotype

Background—Germline mutation in the adenomatous polyposis coli (APC) gene on chromosome 5 causes familial adenomatous polyposis. “Attenuated” phenotype has been reported with mutation in the 5′ end of the gene (5′ to codon 158), but genotype-phenotype relations at the 3′ end (3′ to codon 1596) have not been described fully.Aims—To describe and compare colorectal and extracolonic phenotypes in a case series of families with mutation in the 3′ end of the APC gene.Methods—Thirty one at risk or affected members from four families with a mutation in the APC gene located at codon 1979 or 2644 were evaluated.Results—Variable intrapedigree colorectal phenotype was observed: some members at older age had oligopolyposis (fewer than one hundred colorectal adenomas) whereas other members had classic polyposis at young age. Colorectal cancer was diagnosed at older mean age (50 (7) years) in the four families than in classic FAP pedigrees (39 (14) years). Extracolonic lesions characteristic of FAP occurred with 3′ APC mutations, but variability in intrapedigree and interpedigree extracolonic phenotype and dissociation of severity of extracolonic manifestations from number of colorectal polyps was noted.Conclusions—Families with 3′ mutations of the APC gene exhibit variable intrapedigree phenotype similar to the heterogeneity noted in families with proximal 5′ mutations. Genotyping of FAP and oligopolyposis pedigrees can guide appropriate surveillance of the upper and lower gastrointestinal tract in affected members.

scholarly journals A novel variant in the COL4A3 gene: etiology of Alport syndrome type 2 in a 38-year-old male with suspected hereditary kidney disease

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Paula Sienes Bailo ◽  
José Luis Bancalero Flores ◽  
Raquel Lahoz Alonso ◽  
María Santamaría González ◽  
Alex Gutiérrez Dalmau ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Alport Syndrome ◽  
Clinical Symptoms ◽  
Molecular Testing ◽  
Syndrome Type ◽  
Variant Of Uncertain Significance ◽  
Type Iv ◽  
Novel Variant ◽  
End Stage

ABSTRACT Objectives Patients with Alport syndrome develop progressive kidney function deterioration, sensorineural hearing loss, and ocular abnormalities. This condition is caused by mutations in COL4A5 (X-linked inheritance), COL4A3 and COL4A4 (autosomal dominant or recessive inheritance), and encoding type IV collagen α3, α4, and α5, respectively. If left untreated, clinical symptoms progress from microscopic hematuria to proteinuria, progressive kidney failure, and end-stage kidney disease. At present, kidney transplantation is the only effective approach. Next-generation sequencing is the method of choice for the diagnosis of this condition. Case presentation We report the case of a young man with chronic kidney disease who eventually underwent transplantation. Molecular testing made it possible to determine the etiology of his clinical symptoms and autosomal recessive Alport syndrome type 2. The patient was found to be a compound heterozygote for two missense variants (trans configuration) in the COL4A3 gene: A likely pathogenic variant c.4981C>T (p.Arg1661Cys) in exon 52 inherited from the mother (described elsewhere), and another variant of uncertain significance, c.943G>A (p.Gly315Ser), in exon 17 inherited from the father that has not been previously reported in the literature or found in relevant databases. Conclusions Following genetic confirmation, genetic counseling was provided to the patient and his direct relatives.

A novel mitochondrial m.14430A>G (MT-ND6, p.W82R) variant causes complex I deficiency and mitochondrial Leigh syndrome

2020 ◽  
Vol 58 (11) ◽  
pp. 1809-1817
Author(s):  
Miaomiao Du ◽  
Xiujuan Wei ◽  
Pu Xu ◽  
Anran Xie ◽  
Xiyue Zhou ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Complex I ◽  
Clinical Symptoms ◽  
Lactate Production ◽  
Mitochondrial Diseases ◽  
Leigh Syndrome ◽  
Extracellular Lactate ◽  
Next Generation Sequencing Ngs ◽  
Mutant Cells ◽  
Generation Sequencing

AbstractObjectivesLeigh syndrome (LS) is one of the most common mitochondrial diseases and has variable clinical symptoms. However, the genetic variant spectrum of this disease is incomplete.MethodsNext-generation sequencing (NGS) was used to identify the m.14430A > G (p.W82R) variant in a patient with LS. The pathogenesis of this novel complex I (CI) variant was verified by determining the mitochondrial respiration, assembly of CI, ATP, MMP and lactate production, and cell growth rate in cybrids with and without this variant.ResultsA novel m.14430A > G (p.W82R) variant in the NADH dehydrogenase 6 (ND6) gene was identified in the patient; the mutant loads of m.14430A > G (p.W82R) in the patient were much higher than those in his mother. Although the transmitochondrial cybrid-based study showed that mitochondrial CI assembly remains unaffected in cells with the m.14430G variant, control cells had significantly higher endogenous and CI-dependent mitochondrial respiration than mutant cells. Accordingly, mutant cells had a lower ATP, MMP and higher extracellular lactate production than control cells. Notably, mutant cells had impaired growth in a galactose-containing medium when compared to wild-type cells.ConclusionsA novel m.14430A > G (p.W82R) variant in the ND6 gene was identified from a patient suspected to have LS, and this variant impaired mitochondrial respiration by decreasing the activity of mitochondrial CI.

scholarly journals Two Czech patients with familial adenomatous polyposis presenting mosaicism in APC gene

Neoplasma ◽  
2019 ◽  
Vol 66 (02) ◽  
pp. 294-300
Author(s):  
M. Urbanova ◽  
K. Hirschfeldova ◽  
L. Obeidova ◽  
B. Janosikova ◽  
J. Lastuvkova ◽  
...  
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Apc Gene ◽  
Adenomatous Polyposis

Clinical impact of pathogenic germline variants in pancreatic cancer: Results from a multicenter prospective universal genetic testing study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4118-4118
Author(s):  
Pedro Luiz Serrano Uson Junior ◽  
Douglas Riegert-Johnson ◽  
Lisa A. Boardman ◽  
Mitesh J. Borad ◽  
Daniel H. Ahn ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Outcomes ◽  
Cancer Susceptibility ◽  
Familial Cancer ◽  
Family Counseling ◽  
Disease Stage ◽  
Germline Variants ◽  
Sequencing Platform ◽  
Cancer Susceptibility Genes ◽  
Gene Panel Testing

4118 Background: Germline variations in cancer susceptibility genes have important implications on treatment and family counseling in pancreatic cancer (PC). We report the prevalence and clinical outcomes of unselected PC patients with pathogenic germline variants (PGV) detected using a universal testing approach. Methods: We undertook a prospective multi-site study of germline sequencing using an >80 gene next-generation sequencing platform among 250 PC patients (not selected for age or family cancer history) between April 1, 2018 and March 31, 2020. Demographic, tumor characteristics and clinical outcomes were compared between PGV carriers and non-carriers. Results: Of 250 patients, the mean age was 65 years (SD 8.7), 56% were male, 83.6% were white and 65.6% had advanced disease (Stage III and IV). PGV were found in 15.2% (N=38) of patients, two patients had more than one PGV. Variants of uncertain significance were found in 44.4% (N=111). Family history of cancer (OR 2.36, 95% CI: 1.14-5.19, p=0.025) was associated with a higher risk of PGV. In a median follow up of 16.5 months, median overall survival was 16.8 months in PGV carriers compared with 16.5 months in non-carriers (HR 0.51, 95 %CI, 0.25-1.01, p=0.05). Higher levels of CA 19-9 and advanced stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair (HRR) genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, RAD51C. In 65% of HRR gene carrier’s systemic therapy with platinum was used. Conclusions: Universal multi-gene panel testing in pancreatic cancer reveals that 1 in 6 patients are carriers of PGV and is associated with improved survival. Multi-gene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling. Distribution of the 40 PGV by penetrance status.[Table: see text]

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