Attenuated Familial Adenomatous Polyposis Research Articles

Current chemoprevention approaches in Lynch syndrome and Familial adenomatous polyposis: a global clinical practice survey.

International chemoprevention preferences and approaches in Lynch syndrome (LS) and APC-associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored. To describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey. Ninety-six participants across four hereditary gastrointestinal cancer societies responded to the survey. Most respondents (91%, 87/96) completed information regarding their demographics and practice characteristics relating to hereditary gastrointestinal cancer and chemoprevention clinical practices. Sixty-nine percent (60/87) of respondents offer chemoprevention for FAP and/or LS as a part of their practice. Of the 75% (72/96) of survey respondents who were eligible to answer practice-based clinical vignettes based off of their responses to ten barrier questions regarding chemoprevention, 88% (63/72) of those participants completed at least one case vignette question to further characterize chemoprevention practices in FAP and/or LS. In FAP, 51% (32/63) would offer chemoprevention for rectal polyposis, with sulindac - 300 mg (18%, 10/56) and aspirin (16%, 9/56) being the most frequently selected options. In LS, 93% (55/59) of professionals discuss chemoprevention and 59% (35/59) frequently recommend chemoprevention. Close to half of the respondents (47%, 26/55) would recommend beginning aspirin at time of commencement of the patient's first screening colonoscopy (usually at age 25yrs). Ninety-four percent (47/50) of respondents would consider a patient's diagnosis of LS as an influential factor for aspirin use. There was no consensus on the dose of aspirin (≤100 mg, >100 mg - 325 mg or 600 mg) to offer patients with LS and there was no agreement on how other factors, such as BMI, hypertension, family history of colorectal cancer, and family history of heart disease, would affect the recommendation for aspirin use. Possible harm among older patients (>70 years) was identified as the most common reason to discourage aspirin use. Although chemoprevention is widely discussed and offered to patients with FAP and LS by an international group of hereditary gastrointestinal cancer experts, there is significant heterogeneity in how it is applied in clinical practice.

NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021.

Identifying individuals with hereditary syndromes allows for timely cancer surveillance, opportunities for risk reduction, and syndrome-specific management. Establishing criteria for hereditary cancer risk assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provides recommendations for the assessment and management of patients at risk for or diagnosed with high-risk colorectal cancer syndromes. The NCCN Genetic/Familial High-Risk Assessment: Colorectal panel meets annually to evaluate and update their recommendations based on their clinical expertise and new scientific data. These NCCN Guidelines Insights focus on familial adenomatous polyposis (FAP)/attenuated familial adenomatous polyposis (AFAP) syndrome and considerations for management of duodenal neoplasia.

IFN/STAT signaling controls tumorigenesis and the drug response in colorectal cancer

Colorectal cancer (CRC) is caused by genetic alterations, and comprehensive sequence analyses have revealed the mutation landscapes. In addition to somatic changes, genetic variations are considered important factors contributing to tumor development; however, our knowledge on this subject is limited. Familial adenomatous polyposis coli (FAP) is an autosomal‐dominant inherited disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP patients are classified into two major groups based on clinical manifestations: classical FAP (CFAP) and attenuated FAP (AFAP). In this study, we established 42 organoids from three CFAP patients and two AFAP patients. Comprehensive gene expression analysis demonstrated a close association between IFN/STAT signaling and the phenotypic features of FAP patients. Genetic disruption of Stat1 in the mouse model of FAP reduced tumor formation, demonstrating that the IFN/STAT pathway is causally associated with the tumor‐forming potential of APC‐deficient tumors. Mechanistically, STAT1 is downstream target of KRAS and is phosphorylated by its activating mutations. We found that enhanced IFN/STAT signaling in CFAP conferred resistance to MEK inhibitors. These findings reveal the crosstalk between RAS signaling and IFN/STAT signaling, which contributes to the tumor‐forming potential and drug response. These results offer a rationale for targeting of IFN/STAT signaling and for the stratification of CRC patients.

CD36 \u2013 a plausible modifier of disease phenotype in familial adenomatous polyposis

BackgroundFamilial adenomatous polyposis (FAP) is a well characterised genetic predisposition to early onset colorectal cancer (CRC) that is characterised by polyposis of the colon and rectum. Animal models have consistently suggested the role of modifier genes in determining disease phenotype, yet none have been substantiated in the human population. The mouse homologue of cluster of differentiation 36 (CD36) has been proposed as a modifier of disease in the MIN mouse model of FAP.MethodsThree single nucleotide polymorphisms (SNPs); rs1049673, rs1761667 and rs1984112 in CD36, have been investigated in 275 FAP patients to determine if they were associated with age of polyposis or risk of developing disease.ResultsThe results revealed a substantially lower age of polyposis diagnosis for patients belonging to the severe FAP group (harbouring adenomatous polyposis coli (APC) variants in the mutation cluster region (MCR)) and high age for patients in the attenuated familial adenomatous polyposis (AFAP) group for SNPs rs1761667 and rs1984112.ConclusionsThis study provides evidence for patients belonging to the MCR and AFAP groups harbouring specific genotypes for SNPs in CD36 to initiate screening/treatment for FAP at much earlier (MCR) and much later (AFAP) ages than the norm in today’s clinical practice. The findings need to be verified in an independent FAP patient cohort.

Association between the age and the development of colorectal cancer in patients with familial adenomatous polyposis: a multi-institutional study.

To investigate the incidence of colorectal cancer among familial adenomatous polyposis (FAP) patients by phenotype using the latest modalities. We collected data on 303 patients who underwent surgery for FAP at one of 23 institutions between 2000 and 2012. The incidence of colorectal cancer was investigated by phenotype. Colorectal cancer was diagnosed in 115 (38.0%) of the 303 patients. Overall, colorectal cancer with the attenuated, sparse, and profuse phenotypes was diagnosed at 30, 31, and 28years of age, respectively, in 10% of the patients and at 59, 48, and 41years of age, respectively, in 50% of the patients (P=0.013). The patients with colorectal cancer were older than those without colorectal cancer for all phenotypes. The optimal cut-off age for predicting the development of colorectal cancer in the attenuated, sparse, and profuse phenotypes was 46, 31, and 27years, respectively. Patients with profuse and sparse phenotypes should undergo prophylactic proctocolectomy before their mid-to-late 20s. On the other hand, the timing and type of surgery for patients with attenuated FAP (AFAP) should be decided individually with reference to the colonoscopic findings.

Abstract 4491: Pseudoexons may underlie unbalanced expression of APC alleles in familial adenomatous polyposis

Abstract Familial Adenomatous Polyposis (FAP) is caused by germline mutations in the APC gene. Clinically, the disease can be subdivided into classical FAP with hundreds or thousands of polyps throughout the colon and rectum and Attenuated Familial Adenomatous Polyposis (AFAP) with a milder polyposis. Conventional screening protocols fail to detect any APC mutation in a considerable fraction of adenomatous polyposis families, especially those representing AFAP. We investigated 56 FAP and AFAP families from Finland that had remained APC mutation-negative after protein truncation test, exon-specific Sanger sequencing, and multiplex ligation-dependent probe amplification. Of particular interest were four families with constitutionally unbalanced mRNA expression of APC alleles by Single Nucleotide Primer Extension. These families were interrogated by next generation sequencing of the whole genomes (WGS) and RNA (RNA-seq); additionally, APC promoter methylation was addressed by methylation-specific multiplex ligation-dependent probe amplification. RNA-seq raised the suspicion of a pseudoexon (erroneous inclusion of intronic sequence in the mature mRNA) in three families. A pseudoexon between exons 5 and 6 of the APC gene was present in one family and a pseudoexon between exons 10 and 11 in two families. By WGS, the exon 5-6 pseudoexon consisted of c.646-1806 T>G, which generated a cryptic splice site leading to a 127-bp intronic insertion in the APC mRNA. This pseudoexon was associated with classical FAP. Two alternative genetic changes underlay the exon 10-11 pseudoexon: c.1408+729 A>G was present in one family (AFAP) and c.1408+731 C>T in another family (FAP); both created a new splice donor site leading to an identical 83-bp insertion in APC mRNA. The exon 10-11 pseudoexon resulting from c.1408+731 C>T has previously been described in two unrelated German patients with FAP; the remaining two pseudoexon-associated mutations are novel. All three pseudoexons were predicted to cause premature stop codons leading to APC protein truncation. Sanger sequencing was used to confirm the mutations and to test their presence in the entire series of 56 families; no additional mutation-positive cases were detected. Taken together, deep intronic mutations of the APC gene may explain a proportion of FAP and AFAP families that screen mutation-negative by traditional methods. Specifically, such mutations accounted for three out of four families with the unbalanced expression phenotype of APC in our study. We further conclude that RNA-seq is an effective method to reveal deep intronic mutations and is worth considering in apparent mutation-negative families. Citation Format: Taina Tuulikki Nieminen, Walter Pavicic, Noora Porkka, Heikki J. Jarvinen, Anna Lepisto, Paivi Peltomaki. Pseudoexons may underlie unbalanced expression of APC alleles in familial adenomatous polyposis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4491.

Attenuated familial adenomatous polyposis with desmoids caused by an APC mutation

We present here a case of attenuated familial adenomatous polyposis (AFAP) with a family history of desmoids and thyroid tumors. This patient had no colonic polyps but did have multiple desmoids. Genetic analysis identified a 4-bp deletion in codon 2644 (c.7932_7935delTTAT: p.Tyr2645LysfsX14) of the adenomatous polyposis coli (APC) gene. In cases with limited numbers of colonic polyps and desmoids, AFAP may be caused by a mutation in the 3′ region of APC.

ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

A Rare Case of Attenuated Familial Adenomatous Polyposis

Introduction: Attenuated familial adenomatous polyposis (AFAP) is a rare, less-aggressive subset of familial adenomatous polyposis (FAP). We report a rare case of AFAP presenting as symptomatic iron deficiency anemia. Case Report: A 61-year-old female with a history of iron deficiency anemia, on iron replacement therapy, with a base line hemoglobin of 8.5 g/dL presented with complaints of fatigue and a 26-pound weight gain over a 6-month period. The patient denied melena, hematochezia, hematemesis and change in stool caliber, color or shape. The patient reports a family history of unknown colon cancer in her father at age 76 years, mother at age 78 years, and sister at age 48 years. Physical exam findings are unremarkable. Labs: hemoglobin 5.8 g/dL, WBC 10.3 K/uL, Fe 21 ug/dL, Fe% Sat 5%, and TIBC 419 ug/dL. Colonoscopy was positive for sporadic polyps (2-3) in the rectum, sigmoid, and descending colon, innumerable polyps (estimated to be less than 100) in the cecum, transverse colon, and ascending colon, culminating into a 10-cm-long circumferential ulcerated mass beginning distal to the ileocecal valve. Biopsies were positive for invasive adenocarcinoma. The patient elected to undergo treatment with colectomy. Discussion: AFAP is a subset of FAP. FAP is a rare manifestation of colorectal adenomatous disease in which without treatment will lead to a lifetime cancer risk as high as 100%. FAP typically presents as hundreds to thousands of adenomas in the colon and rectum, usually before the age of 30 years, with progression to cancer before the patient is 40 years old. FAP is responsible for less than 1% of all gastrointestinal cancers. AFAP is less aggressive than FAP, in that the patient develops less than 100 colorectal polyps and is usually diagnosed in their 40s with progression to colorectal cancer in their 60s. Like FAP, AFAP patients have a lifetime cancer risk as high as 100%. Recent studies have demonstrated that AFAP is an autosomal dominant disease that may be caused by mutations in the adenomatous polyposis coli gene (APC) or the mutY homologue gene (MUTYH), but the exact mechanism of the disease in unknown. AFAP most commonly presents with vague abdominal complaints, constipation, lower abdominal pain, or anemia. AFAP is most commonly diagnosed by colonoscopy. Prophylactic colectomy is recommended for the prevention of progression to colorectal cancer, however, it has been reported that AFAP can have extracolonic manifestations, such as gastroduodenal lesions. Conclusion: AFAP is a rare, less-aggressive subtype of FAP, characterized by fewer polyps and with an older age of onset, diagnosis, and progression to colorectal cancer.

The evolution of colorectal cancer genetics-Part 2: clinical implications and applications.

The genetic understanding of colorectal cancer (CRC) continues to grow, and it is now estimated that 10% of the population has a known hereditary CRC syndrome. This article will examine the evolving surgical and medical management of hereditary CRC syndromes, and the impact of tumor genetics on therapy. This review will focus on the most common hereditary CRC-prone diseases seen in clinical practice, which include Lynch syndrome (LS), familial adenomatous polyposis (FAP) & attenuated FAP (AFAP), MutYH-associated polyposis (MAP), and serrated polyposis syndrome (SPS). Each section will review the current recommendations in the evaluation and treatment of these syndromes, as well as review surgical management and operative planning. A highly detailed multigeneration cancer family history with verified genealogy and pathology documentation whenever possible, coupled with germline mutation testing when indicated, is critically important to management decisions. Although caring for patients with these syndromes remains complex, the application of this knowledge facilitates better treatment of both individuals and their affected family members for generations to come.

Attenuated familial adenomatous polyposis manifests as autosomal dominant late-onset colorectal cancer

Colorectal cancer (CRC) risk is well defined for families of patients with classical familial adenomatous polyposis (FAP). However, the risk for those with an attenuated form of FAP is less well characterised. In this study, we estimated CRC risks for carriers of a novel germline mutation in the APC gene that causes attenuated FAP (AFAP). We performed genetic testing on 53 individuals from seven AFAP families harbouring an identical APC:c.288T>A mutation. Using a modified segregation analysis, we estimated relative and absolute CRC risks for mutation carriers. Twenty-three individuals harboured the disease causing mutation. CRC occurred in 28 individuals (mean 61.7 years, range 32-80 years). The estimated CRC relative risks for mutation carriers aged 60-69 and ≥70 years were 19 (95% CI: 1.77-204.08) and 45 (95% CI: 11.32-180.10), respectively, while the absolute CRC lifetime risk for men was 94% (95% CI: 67.5-99.9%), and for women, 84% (95% CI: 50.9-99.0%). This study shows that AFAP can manifest as autosomal dominant late-onset CRC. These findings highlight a subgroup of inherited CRCs that require new criteria for identification and surveillance.

Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines

J. Balmana1, F. Balaguer2, A. Cervantes3 & D. Arnold4, on behalf of the ESMO Guidelines Working Group* Department of Medical Oncology, Hospital Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona; Department of Gastroenterology, Hospital Clinic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona; Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain; Department of Medical Oncology, Tumor Biology Clinic, Albert Ludwigs University, Freiburg, Germany;

A Novel Germline Mutation in Exon 15 of the APC Gene in Attenuated Familial Adenomatous Polyposis: A Report of Two Cases

Attenuated familial adenomatous polyposis (AFAP) is a variant of familial adenomatous polyposis with fewer than one hundred colorectal polyps and a later age of onset of the cancer. Here, we report two cases of AFAP within family members. Each patient demonstrated the same novel germ line mutation in exon 15 of the adenomatous polyposis coli (APC) gene and was successfully managed with sulindac after refusal to perform colectomy: a 23-year-old man with incidentally diagnosed gastric adenoma and fundic gland polyps underwent colonoscopy, and fewer than 100 colorectal polyps were found; a 48-year-old woman who happened to be the mother of the 23-year-old man also showed fewer than 100 colorectal polyps on colonoscopy. Genetic analysis revealed a novel frameshift mutation in exon 15 of the APC gene. The deletion of adenine-guanine with the insertion of thymine in c.3833-3834 resulted in the formation of stop codon 1,287 in both patients. The patients were treated with sulindac due to their refusal to undergo colectomy. The annual follow-up upper endoscopy and colonoscopy in the following 2 years revealed significant regression of the colorectal polyps in both patients.

Hereditary gastrointestinal polyposis: Diagnosis, genetic test and risk assessment

Colorectal cancer (CRC) is the second cause of cancer deaths, with over 1 million new cases estimated every year. Familial adenomatous polyposis, MUTYH-associated polyposis and hamartomatous polyposis are inherited syndromes that account for 2%-5% of all colon cancer. The mutated genes responsible for the vast majority of these disorders, are now known (MLH1, MSH2, MSH6, PMS2, APC, MYH, LKB1, SMAD4, BMPR1A, and PTEN) and specific mutations have been identified. Molecular caracterization of inherited CRCs allows pre-symptomatic diagnosis identifying at-risk individuals and improving cancer surveillance. Adenomatous polyposis includes familial adenomatous polyposis (FAP), attenuated FAP (AFAP), and MUTYH-associated polyposis (MAP). Hamartomatous polyposis comprises Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS) and “PTEN hamartoma tumour syndrome” (PHTS). MAP is an autosomal recessive condition, while all other disorders are inherited in an autosomal dominant manner. Differential dyagnosis could be very difficult between syndromes because of their phenotypic variability. Attenuated FAP, MAP and Lynch syndrome could be all associated with fewer numbers of adenomas (3-10 polyps), nevertheless, each syndrome has distinct cancer risks, characteristic clinical features, and separate genetic etiologies. Thus, differential diagnosis is essential for correct management of the specific disease. In our laboratory we set up a methodology for genetic tests of the colorectal polyposis syndrome. In these reviews we summarize the literature data and our experience about diagnosis, genetic tests and cancer risk assesment associated with colorectal polyposis. According to literature data, in our experience, there is a portion of analyzing patients that remain without identified mutation, after molecular screening of the specific gene involved in the pathogenesis of the disease. Since the sensibility of used techniques, such as DHPLC, MLPA and sequencing, is now very high, we suggest that a different approach to molecular diagnosis of polyposis syndromes is necessary. In our laboratory, we are now planning to set up analysis of a larger pannel of genes that could be involved in colorectal poliposis syndromes, using a next generation sequencing techniques. In our opinion, a better characterization of molecular basis of the polyposis syndromes will allow a more efficient cancer prevention.

Colon Cancer Prevention by Detection of APC Gene Mutation in a Family with Attenuated Familial Adenomatous Polyposis

Genetic mutation is a significant factor in colon CA pathogenesis. Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary disease characterized by multiple colorectal adenomatous polyps affecting a number of cases in the family. This report focuses on a family with attenuated familial adenomatous polyposis (AFAP) with exon 4 mutation, c.481C>T p.Q161X of the APC gene. We analyzed 20 members of a family with AFAP. Clinical and endoscopic data were collected for phenotype determination. Genetic analysis was also performed by direct sequencing of the APC gene. Five patients with a phenotype of AFAP were found. Endoscopic polyposis was demonstrated among the second generation with genotype mutation of the disease (age > 50 years) consistent with delayed phenotypic adenomatous polyposis in AFAP. APC gene mutation was identified in exon 4 of the APC gene, with mutation points of c.481C>T p.Q161X. Laparoscopic subtotal colectomy was performed to prevent carcinogenesis. A family with attenuated familial adenomatous polyposis of APC related to exon 4 mutation, c.481C>T p.Q161X, was reported and the phenotypic finding was confirmed by endoscopic examination. Genetic mutation analysis might be advantageous in AFAP for long term colon cancer prevention and management due to subtle or asymptomatic phenotype presentation in early adulthood.

First Case of a New Variant of the APC Gene in a Patient with Newly Diagnosed Attenuated FAP

Introduction: Familial adenomatous polyposis (FAP) represents about 1% of all colon cancer and is caused by germline mutations in the adenomatous polyposis coli (APC) gene. The clinical manifestation includes classic FAP, attenuated FAP (AFAP), Gardner Syndrome and Turcot Syndrome. We present a patient with newly diagnosed AFAP due to a new variant resulting in the substitution of valine for isoleucine at amino acid position 1746 (I1746V) of the APC protein. Case Presentation: This is a 52-year-old woman with past medical history significant for coronary artery disease, hypertension and uncontrolled diabetes who presented for evaluation of abdominal pain, nausea, vomiting, diarrhea, and bloating for several years which had worsened. CT showed a dilated stomach and small bowel loops without evidence of obstruction. Upper endoscopy was unremarkable. Colonoscopy revealed >40 polyps varying in sizes (5-20 mm) and shapes (flat, umbilicated, and sessile) throughout the entire colon with predominant sessile serrated adenomas interspersed with tubular adenomas and hyperplastic polyps. She had three colonoscopies with removal of >10 polyps at each session but continued to have multiple flat polyps throughout the colon. She had an older sister with history of colonic polyps and another sister who died from an unknown cancer. She was referred for genetic counseling with normal MYH testing but was found to have the first reported APC variant (I1746V) due to the substitution of valine for isoleucine at amino acid position 1746 of the APC protein. Given this variant was the first ever identified the effect on the function of the APC protein is unknown. Hence, it is unclear what the significance of this finding is in regard to her risk of colon cancer. However, since the lifetime risk of colon cancer for AFAP in other APC abnormalities is high, she was referred for evaluation of a subtotal colectomy. Discussion: Multiple APC mutations have been found since the identification of the APC gene as the cause of FAP. We now report the first case of a new APC variant (I1746V) in a patient with newly diagnosed AFAP. Management of this patient was challenging given the lack of data on the significance and risk of colon cancer for this new variant. However, given the lifetime risk of colon cancer in patients with FAP and AFAP is 80-100% and the young age of the patient a subtotal colectomy was recommended. Conclusion: The availability of genetic testing has allowed for the detection of new genetic variants. However, it is unclear how these variants translate phenotypically. More studies will be needed to evaluate the effects of these variants in order to provide the best management practice for these patients.

APCI1307K Mutations and Forkhead Box Gene (FOXO1A): Another Piece of an Interesting Correlation

Germline nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene are found in approximately 90% of individuals affected by familial adenomatous polyposis (FAP) and a genotype-phenotype relationship has been observed. Missense mutations have also been found in a few cases, even if their role in FAP is still unknown. An association between a missense mutation, APC I1307K, and the risk of sporadic colorectal cancer (CRC) has been reported. In order to improve the knowledge about the genetic effect of APC I1307K on the phenotype, we tried a new approach using matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS). An APC mutation (I1307K) was found in an index case of a non-Jewish woman and her son with attenuated familial adenomatous polyposis (A-FAP) and no family history of cancer. In order to evaluate whether the presence and abundance of the ionic species are related to the presence of cancer or the presence of mutation, comparative analyses of 11 healthy clean-colon subjects, 59 patients with CRC (stage II n=19, stage III n=23, stage IV n=17) without polyps, and 9 FAP patients, carriers of a nonsense mutation in the APC gene, were evaluated. Comparative analysis of serum protein profiles of the index patient and her healthy son, FAP and sporadic CRC patients, and subjects with preneoplastic lesions showed a characteristic abundance of ionic species at m/z 905, which was not present in healthy controls. Two peptides were identified from MALDI/MS/MS spectra of m/z 905 belonging to the kininogen-1 precursor and the human forkhead box protein 01A (FOXO1A). FOXO1A was present in only two subjects carrying I1307K, but not in other patients. Our findings seem to suggest a relationship between m/z 905, FOXO1A and the development and growth of colorectal cancer. FOXO1A fragment determination in serum with MALDI/MS might be a promising approach for early detection of colon carcinoma or for the development of targeted therapies.

Abstract 3765: APC and MUTYH mutation spectrum in Brazil: First genotype characterization of brazilian FAP and AFAP patients identifies 6 novel mutations

Abstract Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited colorectal cancer predisposing syndrome caused by mutations in the adenomatous polyposis coli (APC) gene. The most prominent clinical manifestation is the presence of hundreds to thousands of colorectal polyps. A milder phenotype is found in patients affected with attenuated FAP (AFAP), which can be caused by mutations in the untranslated region or the alternative spliced exon 9 of APC, or by biallelic mutations in the base-excision repair gene MUTYH. Characterization of causative mutations in these genes allows presymptomatic diagnosis, close follow-up and prophylactic intervention in affected families. We scanned the APC and MUTYH genes for disease-causing mutations in 16 unrelated Brazilian probands affected by classical or attenuated FAP. We performed DNA sequencing of the complete coding region of both genes, as well as long range PCR and allele specific PCR for confirmation of mutations. Patients with classical FAP (11) were first screened for APC mutations while patients with the attenuated phenotype or indicative of recessive heritance (5) were first screened for MUTYH mutations. We identified a specific mutation in 15 of the 16 probands (93,75%) – 11 in APC gene and 4 in MUTYH; 5 are novel germline pathogenic mutations, 9 are previously described mutations and one is a novel sequence variant in exon 15 of APC with unknown significance. This variant was classified by prediction programs SIFT and Polyhen as being tolerable and possibly damaging, respectively. In APC, most mutations resulted in premature truncation of translation caused by non-sense (36%) or change in reading frame (54%) due to small deletions (4), insertions (1) or duplications (1). The majority of mutations were located in exon 15 (64%), 2 in exon 8 and 1 in exon 4. Biallelic germline mutations in MUTYH were identified in 4 of the 16 patients (25%). Two patients presented the hotspot missense mutation p.Tyr179Cys accompanied by a truncation mutation (one deletion and one duplication). The biallelic nature of the mutations was confirmed by allele specific PCR and segregation analysis in unaffected relatives. One patient was homozygote by common origin for the missense mutation p.Arg241Trp and one was homozygote for a deletion of exons 4-15, identified by long range PCR. Finally, one patient had no mutation by the methods previously described and will be further screened by deep-sequencing of whole exonic regions. Analysis of the genotype/phenotype correlations showed similar results to those observed in other populations. This is the first comprehensive report of APC and MUTYH germline mutation spectrum in Brazil. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3765. doi:10.1158/1538-7445.AM2011-3765

Clinical utility gene card for: Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP)

Clinical utility gene card for: Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP)

Descriptive review and comparison of clinical outcomes of AFAP patients

Objective This study aimed to examine the colonic polyp phenotype, the surgical outcomes, and the reasons for colectomy in individuals with Attenuated Familial Adenomatous Polyposis (AFAP).