Germline APC Gene Mutation Research Articles

Malignant transformation of fundic gland polyps in familial adenomatous polyposis

Sporadic fundic gland polyps (FGPs) are ubiquitous benign lesions with no potential for malignant transformation. Familial adenomatous polyposis (FAP) is associated with the development of FGPs that are morphologically identical to but genetically distinct from those seen in sporadic cases. The shared aetiology involves disruption of the WNT signalling pathway, however FAP associated cases are predominantly driven by germline APC gene mutations rather than the somatic CTNNB1 gene mutations prevalent in sporadic lesions.

Age- and Gender-Specific Risk of Thyroid Cancer in Patients With Familial Adenomatous Polyposis.

The cribriform-morula variant of papillary thyroid carcinoma (CMV-PTC) is a rare variant of PTC and is associated with familial adenomatous polyposis (FAP). However, the incidence and the nature of CMV-PTC among FAP patients have not been well characterized. The aim of this study was to determine the incidence and characteristics of thyroid cancer screened by neck ultrasonography for FAP patients. Design, Patients, and Intervention: A total of 129 FAP patients were included in this study. Neck ultrasonography was performed using a 12.0-MHz transducer probe. Germline APC gene mutation was examined for by the protein truncation test or DNA sequencing methods. A total of 129 FAP patients were included in this study. Neck ultrasonography was performed using a 12.0-MHz transducer probe. Germline APC gene mutation was examined for by the protein truncation test or DNA sequencing methods. Twenty-one patients (16.3%) had solid nodules, and 24 patients (18.6%) had benign cystic nodules. In total, PTC was found in 11 patients (16% of the women and 0% of the men), 8 of which were CMV-PTC and the rest were classical PTC. In 17 female patients with thyroid nodules, CMV-PTC occurred in 8 of 9 patients who were 35 years age or younger but in none of the 8 patients who were older than 35 (P = .0004 by Fisher's exact test). The APC germline mutations in 8 patients with CMV-PTC were present at the 5' side of the profuse type of FAP region (codons 1249-1330). The prevalence of CMV-PTC in FAP patients was higher than previously reported and this type of tumor was found preferentially in younger (under age 35) female patients with FAP in this cohort.

Two Metachronous Neoplasms in the Radiotherapy Fields of a Young Man With Familial Adenomatous Polyposis.

Background: It is recognized that various radiation-induced malignancies often follow childhood radiotherapy. Radiation-induced neoplasms have been shown to occur with increased frequency in syndromes due to mutated tumor suppressor genes. There exist no recommendations for the management of cancer patients with germline APC gene mutations. Preclinical data suggest that APC gene mutations cause enhanced radiosensitivity, but no clinical observations exist that show that patients with this mutation are at higher risk for radiation-induced malignancies. Results: We report the case of a 32-year-old man with a genetic diagnosis of familial adenomatous polyposis (FAP) who initially presented at age 10 with a medulloblastoma treated with radiotherapy and surgery. Radiation-induced papillary thyroid carcinoma followed 13 years later. Finally, radiation-induced soft tissue osteosarcoma occurred with widespread metastasis 20 years thereafter. Conclusions: This is the first report of 2 malignancies in the prior radiotherapy fields of a patient with a genetic diagnosis of FAP. More important, this suggests that APC-defective cells are at an enhanced sensitivity to the carcinogenic effects of radiotherapy compared with APC-proficient cells. This could argue for genetic screening in affected members of these families and for creation of treatment recommendations to more seriously consider the risks of radiation therapy.

CTNNB1 Genotyping and APC Screening in Pediatric Desmoid Tumors: A Proposed Algorithm

Desmoid fibromatosis is a rare, locally aggressive fibroblastic/myofibroblastic tumor that occasionally involves children. We examined a series of pediatric desmoids for CTNNB1 mutations, seen in sporadic tumors, and APC germline mutations, associated with familial adenomatous polyposis (FAP). Forty-four desmoids in pediatric patients were identified in the pathology files of 2 large referral centers (1995-2009). Clinical charts were reviewed for history of FAP. Germline APC gene mutations were determined on blood samples from patients presenting with FAP. Immunohistochemistry for beta-catenin was performed. CTNNB1 genotyping was done by Sanger sequencing on formalin-fixed paraffin-embedded tissue. CTNNB1 mutations were observed in 29 of 44 (66%) desmoids, with 3 mutations identified: T41A (64%), S45F (29%), and S45P (7%). Germline APC mutations were present in 7 (16%) desmoid patients. Eight (18%) patients had desmoids that were wild type for CTNNB1 and had no known clinical signs or family history suspicious for FAP at the time of testing or with extended follow up (n = 6). Beta-catenin nuclear labeling was observed in 38 of 41 (92%) tested cases, 34 (89%) of which showed mutations in either CTNNB1 (n = 29) or APC (n = 5). Nuclear localization of beta-catenin was seen in the majority of pediatric desmoids and was most often associated with somatic mutations in CTNNB1. However, a significant proportion of pediatric patients harbored germline mutations in APC. Given the implications, genetic counseling is recommended for children diagnosed with desmoid tumors lacking CTNNB1 mutations because this population is enriched for FAP patients.

Congenital Hypertrophy Retinal Pigment Epithelium as a Manifestation of Colon Cancer

Purpose: Congenital hypertrophy of retinal pigment epithelium (CHRPE) is a benign lesion of the optic fundus that is an associated extracolonic manifestation of familial adenomatous polyposis (FAP). However, there are no reports of its association with a solitary colonic neoplasm. To our knowledge, we present the first case of CHRPE in a patient with a solitary colonic neoplasm. A 73-year old female with past medical history of cataracts was following a retina specialist for a routine examination. Upon examination she was found to have acute, multiple CHRPE lesions in both eyes (Figure A). Her previous fundoscopic exam did not show any CHRPE lesions. She was referred to a gastroenterologist for immediate colonoscopy. The patient never had a screening colonoscopy in the past. She had a history of long-term constipation, but no hematochezia, change in bowel habits, or change in bowel caliber. There was no family history of colon cancer or familial adenomatous polyposis (FAP). The colonoscopy showed a fungating non-obstructing mass, 25 mm from the anal verge, encompassing one-third of the circumference of the sigmoid lumen (Figure B). Biopsies were taken, which showed high-grade dysplasia. The patient had an exploratory laparotomy and colon resection with primary end-to-side anastomosis. The pathology confirmed tubular villous adenoma. The margins were free of malignancy with 17 benign lymph nodes. CT scan showed no metastasis. The patient tolerated the procedure well and was discharged 6-days post-op without any need for chemotherapy or radiation. CHRPE is a flat, black, well-defined lesion of the retinal pigment epithelium. This fundoscopic finding is almost always benign, and estimates of its prevalence in the normal population vary widely (0.3%-40%). However, it is a phenotypical extracolonic manifestation of FAP when found acutely and in bilateral retinas. It is thought that since CHRPE is not an age-dependent lesion it could provide a useful marker of patients with a germline APC gene mutation; however, several authors have studied this with inconclusive results. The setting for this case, however, is different than most; to our knowledge, this is the first case of a CHRPE patient who did not have a medical or family history of FAP presenting with a solitary colonic neoplasm.Figure: A: Black arrows point to multiple CHRPE lesions seen on fundoscopic exam. Figure B: Mass seen in sigmoid.

Familial adenomatous polyposis

A multimodal approach of complementary techniques targeting primarily truncating, deletion and rearrangement mutations provides a robust screening protocol that identifies the vast majority of pathogenic germline APC gene mutations in FAP patients. Patients in whom no mutation is identified through this mutation protocol, may be sub-cohorts representing a different FAP pathogenesis including MYH associated polyposis and somatic cell mosaicism for APC gene mutations.

Cribriform‐morular variant of Papillary Thyroid Carcinoma: Clue to Early Detection of Familial Adenomatous Polyposis‐associated Colon Cancer

The cribriform-morular variant (CMV) of papillary thyroid carcinoma (PTC) is a rare histologic subtype of PTC that shows a combination of growth patterns including cribriform and spindle cell areas. The thyroid cancer with this unique histology was originally reported in patients with familial adenomatous polyposis (FAP), although it was later found in patients without polyposis as well. Because of its rarity, its clinical features are not clear. We reviewed seven patients with CMV-PTC who were found among 4194 patients with PTC in our pathology files between June 1991 and March 2003. The prevalence of CMV was 0.16% among all PTCs. We invited these patients to our hospital so we could obtain a detailed family history and recommend colonoscopic examination and germline APC gene analysis. Two patients without subjective symptoms had polyposis of the colon and colon cancers. Germline APC gene mutations were found in both patients. The father of a patient who refused the invitation was revealed to have undergone surgery for colon polyposis. In the remaining four patients, neither polyposis nor APC gene mutation was found. Common clinical features included a young age (mean 25 years), predominance of females, circumscribed tumors, negative node metastasis, and no recurrence of the thyroid cancer after surgery. Two of the three patients with colon polyposis had bilateral multiple thyroid tumors, whereas the remaining four (without polyposis) had a solitary tumor. The histopathology of CMV in patients with PTC should arouse a suspicion of FAP, especially if there are multiple tumors. This finding can lead to early detection of colon cancer.

Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors.

Primitive neuroectodermal tumors (PNETs) represent the most frequent malignant brain tumors in childhood. The majority of these neoplasms occur in the cerebellum and are classified as medulloblastomas (MB). Most PNETs develop sporadically; however, their incidence is highly elevated in patients carrying germline APC gene mutations. The APC gene encodes a central component of the WNT/wingless developmental signaling pathway. It regulates the levels of cytoplasmic beta-catenin protein that plays a central role in neural development and cell proliferation. We analyzed 87 sporadic PNETs and 10 PNET cell lines for mutations of the APC gene and beta-catenin (CTNNB1) gene using single strand conformational polymorphism (SSCP) and sequencing analysis. We examined the mutation cluster region of APC (codons 1255--1641) for germline variants and somatic mutations. The medulloblastoma cell line MHH-MED-2 carried a Glu1317Gln missense germline variant and a sporadic MB sample showed a somatic Pro1319Leu substitution. Mutational analysis of exon 3 of CTNNB1 uncovered 4 PNETs (4.8%) with somatic missense mutations. These mutations caused amino acid substitutions in 3 of 80 medulloblastomas (Ser33Phe, Ser33Cys and Ser37Cys) and 1 of 4 supratentorial PNETs (Gly34Val). All mutations affected GSK-3 beta phosphorylation sites of the degradation targeting box of beta-catenin and resulted in nuclear beta-catenin protein accumulation. Deletions of CTNNB1 were not detected by PCR amplification with primers spanning exons 1--5. Our data indicate that inappropriate activation of the WNT/wingless signaling pathway by mutations of its components may contribute to the pathogenesis of a subset of PNETs.

Familial adenomatous polyposis presentig with childhood desmoids

colorectal polyps, confirmed on biopsy to be tubulovillous adenomas. He subsequently underwent restorative proctocolectomy at which a Dukes B adenocarcinoma of the rectum was resected. A sebaceous cyst had been excised from his scalp some years before. Computed tomograph scanning has recently shown mass lesions, compatible with desmoids, in the left erector spinae muscle and the small bowel mesentery. Germline mutations of the APC gene on chromosome 5q22 are responsible for familial adenomatous polyposis (FAP), an autosomal dominantly inherited condition characterised by the development of multiple colorectal adenomas. Desmoids, osteomas, and sebaceous cysts are well documented manifestations of FAP, and their occurrence together is still sometimes known as Gardner’s syndrome. Most desmoids occur in early adulthood after the diagnosis of FAP has been made. More than 85% are in the abdomen or in the abdominal wall, and presentation of FAP with desmoids of the head and neck is rare. DNA heteroduplex analysis and sequencing showed these three patients to have a previously undescribed germline APC gene mutation—a 2 base-pair (AG) deletion at nucleotide 4393 (codon 1464), generating a premature stop codon (P1467X). This finding is consistent with recent suggestions that the phenotype in FAP is related to the position within the gene of the germline APC mutation and, in particular, that desmoids occur more frequently in patients with mutations located 3' of codon 1444 than in those with mutations sited more proximally to this. It has been reported that families with mutations at the far 3' end of the APC gene inherit aggressive and atypical desmoid disease with a high degree of penetrance, but may have only scanty colorectal polyps of rather later onset than in typical FAP. Nonetheless, long-term colorectal screening is still essential in this group. This family illustrates an important principle. Young people with rare tumours, especially if multiple and affecting more than one sibling, should be investigated for a tumour predisposition syndrome. A careful family history, repeated regularly, is one of the essential components of this process.

Association of Extracolonic Manifestations of Familial Adenomatous Polyposis with Acetylation Phenotype in a Large FAP Kindred

Familial adenomatous polyposis coli (FAP) has been shown to be associated with germline mutations of the adenomatous polyposis gene (APC) on chromosome 5. Extra-colonic manifestations also occur in FAP and include desmoid tumors, epidermoid cysts and osteomas. The combination of FAP with extracolonic symptoms is commonly referred to as Gardner's syndrome. It remains difficult, however, to predict which patients may have a propensity to develop extracolonic manifestations. The rapid acetylation phenotype is believed to be associated with an increased likelihood of sporadic colorectal cancer, whereas the slow acetylation phenotype is recognized as a predisposing factor for bladder cancer. The slow acetylation phenotype is caused by mutant alleles of the cytosolic enzyme N-acetyltransferase (NAT2). In this study, we determined the NAT2 genotype in members of one large FAP family and three smaller ones all of which had been shown to harbor the same germline APC gene mutation. We observed a significant correlation between slow acetylation genotypes and extracolonic manifestations of the disease. Rapid acetylation genotypes were not overrepresented in colorectal cancer cases in this family as compared to the frequency of this genotype in the normal Caucasian population.