Benign Neoplasms of the Colon and Rectum
Philip H. Gordon, Santhat Nivatvongs, Lee E. Smith, Scott Thorn Barrows, Carla Gunn, Gregory Blew, David Ehlert, Craig Kiefer, Kim Martens in Neoplasms of the Colon, Rectum, and Anus, 2007
The molecular mechanisms that explain why certain APC mutations result in a classic phenotype and others in an attenuated phenotype are currently being elucidated. Most models are predicated on the “two-hit hypothesis”—which states that both alleles of APC must be inactivated in order to initiate tumorigenesis. In Figure 19 (153), both copies of chromosome 5 are shown. In classic FAP (panel A), the biallelic inactivation of APC is typically achieved by the combination of an inherited germ-line mutation in one allele (black X) and a chromosomal deletion of the remaining wild-type allele; this is called loss of heterozygosity. In some cases, the germ-line APC mutation (red X) can result in the production of a protein that can inhibit the activity of the wild-type protein (white X). This dominant negative effect functionally results in biallelic inactivation.
Cancer: A Genetic Disease
Jeremy R. Jass in Understanding Pathology, 2020
Solomon et al. (1984) studied cancers from subjects with the hereditary disorder FAP, and were able to demonstrate the loss of chromosome 5 and particularly the region of chromosome 5 where the APC gene was located. This established the fact that APC was a tumour suppressor gene. It should be explained that it is not possible to demonstrate LOH unless it is present in a large clone of cells (all derived from a single cell). If LOH is limited to a small group of normal cells, the DNA signal will be too weak to be picked up. For LOH to be found throughout a large clonal population (such as a cancer) it must be providing some form of ‘evolutionary’ growth advantage. This may be described as the removal of the handbrake function of the normal copy of the tumour suppressor gene when the footbrake function of the other copy has been previously inactivated by a mutation. With both brakes not functioning, there is loss of control of cell proliferation.
Other Tumors
Wojciech Gorczyca in Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
Leroux et al. [20] reported clonal and mostly complex chromosomal aberrations in 66% of patients with BPDCN. The recurrent abnormalities involved the long arm of chromosome 5 (targeting two regions, 5q21 or 5q34; 72%), 12p (64%), 13q (64%), −6q/del(6q23–qter) (50%), −15q, (43%), and −9 (28%) [20]. Recurrent aberrations of chromosomes 4, 9, and 13 have also been reported [21]. In a series reported by Lucioni et al. [15], there was a mean of seven copy number alterations per case (21 cases analyzed), with prevalence of losses over gains. The most affected were chromosomes 9 (71%), 13 (61%), 12 (57%), 5 (19%), 7 (19%), 14 (19%), and 15 (15%). Deletion of 9p21.3 locus containing CDKN2A, CDKN2B, and MTAP was identified in 14 patients (66.6%)—5 homozygous and 9 hemizygous[15]. The median overall survival was 11 months for cases with homozygous loss, compared with 26 months for homozygous loss.
Parental germline mosaic transmission of 5p13.2 microduplication in two siblings of a Chinese family
Published in Journal of Obstetrics and Gynaecology, 2022
Qi Tian, Li-Li Xu, Dong-Zhi Li
An ultrasound at 12 weeks’ gestation revealed a single fetus with a crown-rump length of 54 mm and a nuchal translucency of 1.3 mm. Although the parents were explained that the recurrence risk is very low for a de novo duplication, chorionic villous sampling (CVS) was still required by the woman due to the indication of advanced maternal age. Unexpectedly, CNV-seq of the CVS sample detected again the familial 5p13 duplication. The karyotype was 46,XX. The pregnancy was terminated on parents’ request. Parental mosaicism was then considered in this family. The skin tissue of the aborted fetus, combined with the blood samples of the four family members, was sent for further investigation using whole genome sequencing (WGS) for the purpose of precise duplication determination, searching possible single-gene variants and single nucleotide polymorphism (SNP) genotyping. This approach detected a 1.1-Mb duplication on 5p13.2 (HG19:chr5:36,195,246-37,371,079) in the fetus and the male patient, but not in other family members. No potentially causative monogenic variants were detected in the patient. Paternal mosaicism was confirmed by the haplotype analysis of chromosome 5 in this family (Figure 1). Genomic DNA of a sperm sample was obtained from 1 ml semen of the father, and WGS detected a variant allelic fraction of 13. 8%. Thus far, the paternal germline mosaicism origin for the “de novo” duplication was clear.
Torpedo-like lesions in the ocular fundi of Gardner syndrome: hiding in plain view
Published in Ophthalmic Genetics, 2021
Kirk Packo, Morton F. Goldberg
The APC gene (Adenomatous Polyposis Coli), located on chromosome 5, is noteworthy for its approximately 700 mutations spread along its length like a string of pearls. Their varied clinical abnormalities include the following: supernumerary teeth, cranial osteomas, epidermal cysts, intestinal polyposis, brain and other tumors (both benign and malignant), as well as a variety of pigmentary abnormalities in the fundus. Each of these abnormalities in Gardner syndrome/FAP can be inherited singly or in combination, or, importantly, not at all. Variability in appearance is typical, depending on how many (and which) exons harbor the different mutations. For example, Olschwang et al. (48) showed that varied extracolonic manifestations of the FAP syndrome are correlated with specific mutations in the APC gene; and, as noted by Alberge et al. (47), the RPE lesions in FAP are due to varied APC mutations between codons 541 and 1309. Additionally, the number of colonic polyps is correlated with different but specific mutations in the APC gene. When the number of polyps is small, the different clinical phenotype is separately named “Attenuated FAP”. In summary, the clinical appearance of affected individuals depends on the highly varied pleiotropic expressions of the abnormal gene in individual patients. Such varied clinical expressions are frequently observed in autosomal dominant diseases.
Prenatal Diagnosis of 5p Deletion Syndrome with Brain Abnormalities by Ultrasonography and Fetal Magnetic Resonance Imaging: A Case Report
Published in Fetal and Pediatric Pathology, 2020
Didem Kaymak, Verda Alpay, Hakan Erenel, İbrahim Adaletli, Nil Comunoglu, Riza Madazli
Cri du chat syndrome or 5p deletion syndrome, first described by Lejeune and collaborators in 1963, is a clinically recognizable and one of the most common contiguous gene deletion disorder, with an estimated frequency of 1:15,000 to 1:50,000 live births [1]. This syndrome results from a deletion of the short arm of chromosome 5, ranging from the entire short arm to the critical region of 5p15.2 [1]. Clinical features of cri du chat syndrome include, a high-pitched catlike cry, craniofacial dysmorphic features such as round face, micrognathia, hypertelorism, epicanthal folds, low-set ears, abnormal dermatoglyphics, microcephaly and severe psychomotor and developmental delay [2]. The deletion of multiple genes on the distal part of the short arm of chromosome 5 is assumed to be responsible for the phenotype. Although the features of 5p deletion syndrome are well known postnatally, prenatal findings are generally related to abnormal ultrasound findings and few cases have been reported in the literature [3]. We present sonographic features and magnetic resonance imaging (MRI) findings of pontocerebellar hypoplasia, vermis hypoplasia, mild ventriculomegaly, and cortical hypoplasia in a case of prenatally diagnosed 5p deletion syndrome.
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