A novel pathogenic germline mutation in the adenomatous polyposis coli gene in a Tunisian family with FAP

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder which typically presents with colorectal cancer in early adult life, secondary to extensive adenomatous polyps of the colon. In addition to the colonic manifestations, the syndrome presents several extracolonic features including, congenital hypertrophy of the retinal pigment, osteomata and desmoid tumors. In this study, we aimed to investigate the clinical and genetic features in a Tunisian family with FAP. Sequence of the APC gene (Adenomatous Polyposis Coli) revealed a novel mutation (c.2016-2017 del TA) in exon 15, present in all affected individuals in an heterozygous state. The frameshift mutation generates a premature stop codon at amino acid 677 of the APC protein (p. H672Qfs X5). The unaffected family members did not harbor this mutation, however, a first degree relative of the patient aged of 32 year-old was phenotypically normal but carries the c.2016-2017 del TA mutation. This discrepancy can be explained by the effect of modifier gene which can affect the expressivity of the disease.     

A novel pathogenic germline mutation in the adenomatous polyposis coli gene in a Chinese family with familial adenomatous coli

Familial adenomatous polyposis (FAP) is an autosomal dominant disease manifesting as colorectal cancer in middle-aged patients. Mutations of the adenomatous polyposis coli (APC) gene contribute to both FAP and sporadic or familial colorectal carcinogenesis. Here we describe the identification of the causative APC gene defects associated with FAP in a Chinese pedigree. All patients with FAP were diagnosed by their combination of clinical features, family history, colonoscopy, and pathology examinations. Blood samples were collected and genomic DNA was extracted. Mutation analysis of APC was conducted by targeted next-generation sequencing, long-range PCR and Sanger sequencing. A novel mutation in exon 14–15(c.1936_-2148 del) and intron 14 of the APC gene was demonstrated in all FAP patients and was absent in unaffected family members. This novel deletion causing FAP in Chinese kindred expands the germline mutation spectrum of the APC gene in the Chinese population.     

Two Chinese pedigrees for adenomatous polyposis coli: new mutations at codon 1309 and predisposition to phenotypic variations

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease caused by a mutation in the adenomatous polyposis coli (APC) gene. Some studies have attempted to correlate mutations at codon 1309 with classic FAP (≥100 colorectal polyps). We report two Chinese FAP pedigrees with new frameshift mutations at codon 1309, in which affected individuals manifest phenotypic variations. Comprehensive physical examinations were performed for all living individuals and the medical data of deceased patients were collected. Screening of the APC and human mutY homolog (MUTYH) genes for germline mutations was conducted by direct polymerase chain reaction (PCR) sequencing. In two pedigrees, a heterozygous deletion in exon 16 of the APC gene was present in all FAP patients but absent in the unaffected individuals. There were no changes to the MUTYH gene. The first pedigree, with a new frameshift mutation at c.3926_3930 del AAAAG (p. Glu1309Aspfs X4), exhibited obvious differences in the polyp number such that the proband manifested only three colorectal polyps, whereas another patients showed the symptoms of classic FAP. The second pedigree, also traced a new mutation at c.3922_3925 del AAAG (p. Glu1309Argfs X11). Although all of the patients presented with classic polyposis, one of them exhibited a delayed onset of colorectal cancer in his 50s. Two novel mutations at codon 1309 in two Chinese families suffering from FAP could enrich the germline mutation spectrum of the APC gene. Families of individuals might manifest different phenotypes, even with an identical codon 1309 mutation, unlike in previous studies.     

<Emphasis Type="Italic">APC</Emphasis> mosaicism in a young woman with desmoid type fibromatosis and familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is usually caused by germline mutations in the adenomatous polyposis coli (APC) gene. The classic form is characterized by hundreds to thousands of adenomas in the colorectum and early onset colorectal cancer (CRC) if left untreated. FAP is also associated with multiple extra-colonic manifestations such as gastroduodenal polyps, osteomas, epidermoid cysts, fibromas and desmoids. Most desmoid tumours in FAP patients occur intra-abdominally. Approximately 15–20% of the APC mutations are de novo mutations. Somatic mosaicism has been reported in some sporadic cases of polyposis but is probably an underestimated cause of the disease. This case report presents the detection of a mosaic APC mutation in a 26-year-old woman who as a child had been diagnosed with desmoid type fibromatosis. FAP was suggested when she presented with extensive extra abdominal fibromatosis. Our findings indicate that APC mutations may be suspected in patients presenting with a desmoid regardless of its location. If there is clinical evidence that the patient has FAP, adenomas and colonic mucosa in addition to leukocyte DNA should be included in the screening, preferably using methods that are more sensitive than Sanger sequencing.     

Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis

Desmoids represent the most important cause of death, after colorectal cancer, in patients affected with familial adenomatous polyposis (FAP), an inherited disease due to mutations in the APC gene. The aims of our study were to estimate the risk of developing desmoids in FAP patients and to evaluate the association between desmoids and different risk factors. The occurrence of desmoids, colorectal cancer and other extra-colonic manifestations were assessed in 897 FAP patients, 653 of whom were also investigated for APC mutations. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed using an unconditional multiple logistic regression model. Desmoids developed in 107 patients (11.9%), with a cumulative risk of 20.6%. Females had a significantly higher risk than males (OR = 2.1; 95% CI 1.4-3.1). Family history of desmoids (OR = 8.75; 95% CI 5.66-13.51), osteomas (OR = 2.9; 95% CI 1.8-4.8) and epidermoid cysts (OR = 1.8; 95% CI 1.1-3.2) was also significantly associated with the occurrence of disease. Subjects with APC mutations beyond codon 1444 had a 12-fold increased risk, compared with patients with mutations located upstream. Mutations beyond codon 1309 conferred a 17-fold higher risk, compared with mutations upstream codon 452. Multivariate analysis identified as independent predictors mutation beyond codon 1444 (OR = 6.2; 95% CI 2.5-15.8), family history of desmoids (OR = 5.8; 95% CI 3.1-10.6), female gender (OR = 2.1; 95% CI 1.1-3.8) and the presence of osteomas (OR = 1.9; 95% CI 1.1-3.4). Our results indicate that integrating genetic and clinical data is helpful in defining subgroups of patients at higher risk for desmoids, who may benefit from specific prevention programs.     

Mutation analysis of the <Emphasis Type="Italic">APC</Emphasis> gene in Taiwanese FAP families: low incidence of <Emphasis Type="Italic">APC</Emphasis> germline mutation in a distinct subgroup of FAP families

Familial adenomatous polyposis (FAP) is an autosomal-dominant disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. The affected individuals develop colorectal polyposis and show various extra-colonic manifestations. In this study, we aimed to investigate the genetic and clinical characteristics of FAP in Taiwanese families and analyze the genotype–phenotype correlations. Blood samples were obtained from 66 FAP patients registered in the hereditary colorectal cancer database. Then, germline mutations in the APC genes of these 66 polyposis patients from 47 unrelated FAP families were analyzed. The germline-mutation-negative cases were analyzed by performing multiplex ligation-dependent probe amplification (MLPA) and single-strand conformation polymorphism (SSCP) analysis of the MUTYH gene. Among the analyzed families, 79% (37/47) of the families showed 28 APC mutations, including 19 frameshift mutations, 4 nonsense mutations, 3 genomic deletion mutations, 1 missense mutation, and 1 splice-site mutation. In addition, we identified 15 novel mutations in 32% (15/47) of the families. The cases in which APC mutations were not identified showed significantly lower incidence of profuse polyposis (P = 0.034) and gastroduodenal polyps (P = 0.027). Furthermore, FAP families in which some affected individuals had less than 100 polyps showed significant association with low incidence of APC germline mutations (P = 0.002). We have added the APC germline-mutation data for Taiwanese FAP patients and indicated the presence of an FAP subgroup comprising affected individuals with nonadenomatous polyps or less than 100 adenomatous polyps; this form of FAP is less frequently caused by germline mutations of the APC gene.     

Working through a diagnostic challenge: colonic polyposis,Amsterdam criteria,and a mismatch repair mutation

The two most common causes of hereditary colorectal cancer are Lynch syndrome and familial adenomatous polyposis (FAP). The phenotype of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is differentiated in part from FAP by the lack of profuse colonic polyposis. Here we describe a proband who presented with greater than 50 adenomatous colonic polyps prior to developing cancer of the colon and urinary bladder, and a family history that fulfills the Amsterdam criteria. Germline analyses of APC and MYH in the proband did not reveal any mutations. Comprehensive analysis of the mismatch repair genes associated with Lynch syndrome revealed a germline hMSH6 missense mutation 2314C>T (arg772trp) and normal sequencing for hMSH2 and hMLH1. We outline evidence supporting the pathogenicity of the identified hMSH6 mutation (arg772trp) and suggest possible etiologies for the unexplained colonic adenomatous polyposis.     

Molecular and clinical study of familial adenomatous polyposis for genetic testing and management

Familial adenomatous polyposis (FAP) is an inherited predisposition to colorectal cancer characterized by the development of numerous adenomatous polyps, predominantly in the colorectal region. Germline mutations of the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis. We examined germline mutations of the APC gene and clinical features among eighty-seven individuals who consisted of thirty-nine FAP-patients, thirty-seven of their family members with a 1 in 2 risk of predisposition to this disease, and eleven normal persons. We accurately identified nine heterozygotes, among individuals with a 1 in 2 risk by genetic testing, without the uncertainty of the recurrence risk calculated by Bayes' theorem. Six of the nine heterozygotes were confirmed to have colorectal polyps by colonoscopic examination. Since they were diagnosed at 12.7 years-of-age on average, and were no more than 20 years old, they could be treated to prevent colorectal cancer. Based on the genotype-phenotype correlation, we concluded that the germline mutations responsible for the sparse polyps phenotype of FAP-patients tend to locate from codon 1055 in the proximal region of the APC gene, while those for the profuse type locate from codon 1102 in the distal region. Among the thirty-nine FAP-patients, we found that those with the germline mutations within codon 1055 and codon 1262 had colorectal carcinomas of an advanced stage, at a high rate (71.4%). Special attention and aggressive intervention is needed in these patients and relatives at risk. With reasonable and appropriate management, it should be possible to prolong and improve the quality of life of those family members both affected and at risk.     

Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines

BackgroundBi-allelic germline mutations of one of the DNA mismatch repair genes, so far predominantly found in PMS2, cause constitutional MMR-deficiency syndrome. This rare disorder is characterised by paediatric intestinal cancer and other malignancies. We report the clinical, immunohistochemical and genetic characterisation of four families with bi-allelic germline PMS2 mutations. We present an overview of the published gastrointestinal manifestations of CMMR-D syndrome and propose recommendations for gastro-intestinal screening.Methods and ResultsThe first proband developed a cerebral angiosarcoma at age 2 and two colorectal adenomas at age 7. Genetic testing identified a complete PMS2 gene deletion and a frameshift c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) mutation. In the second family, both the proband and her brother had multiple intestinal adenomas, initially wrongly diagnosed as familial adenomatous polyposis. A splice site c.2174+1G>A, and a missense c.137G>T (p.Ser46Ile) mutation in PMS2 were identified. The third patient was diagnosed with multiple colorectal adenomas at age 11; he developed a high-grade dysplastic colorectal adenocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband developed a cerebral anaplastic ganglioma at age 9 and a high-grade colerectal dysplastic adenoma at age 10 and carries a homozygous c.2174+1G>A mutation.Tumours of all patients showed microsatellite instability and/or loss of PMS2 expression.ConclusionsOur findings show the association between bi-allelic germline PMS2 mutations and severe childhood-onset gastrointestinal manifestations, and support the notion that patients with early-onset gastrointestinal adenomas and cancer should be investigated for CMMR-D syndrome. We recommend yearly follow-up with colonoscopy from age 6 and simultaneous video-capsule small bowel enteroscopy from age 8.     

A comparison of the phenotype and genotype in adenomatous polyposis patients with and without a family history

Objectives: Adenomatous polyposis of the colon is often secondary to an inherited mutation in adenomatous polyposis coli (APC) gene, however, approximately one third of patients have no family history of the disease. We studied the phenotype and genotype of adenomatous polyposis in patients without a family history. Methods: A cohort of 57 unrelated adenomatous polyposis patients were evaluated. Seventeen patients with no family history were compared with 40 patients who had a positive family history of the disease. Family history and medical records were collected and analyzed. Germline APC and Mut Y homologue (MYH) testing was undertaken. Results: Patients without a family history were diagnosed with polyposis at an older age (41 years vs. 32 years) and presenting more frequently with symptoms (76 vs 20, P < 0.05). The number of colonic polyps and frequency of extracolonic manifestation associated with adenomatous polyposis did not differ between the two groups. APC mutations were detected less frequently among patients without a family history of the disease (4 out of 17 vs 25 out of 40, P=0.007), even among those with greater than 100 colorectal adenomas (4 out of 12 versus 21 out of 29, P=0.03). One homozygous MYH mutation carrier (G382D) was detected among the six patients without a family history and without a germline APC mutation who were tested. Conclusions: Adenomatous polyposis patients without a family history are usually diagnosed with symptoms, and at a later age. Phenotypically, they are similar to those with a family history. However, germline APC mutations are detected far less frequently in patients without a family history. A small percentage of these cases may be secondary to biallelic germline MYH mutations.     

Molecular characterization of parathyroid tumors from two patients with hereditary colorectal cancer syndromes

The tumor suppressor adenomatous polyposis coli (APC) has recently been implicated in parathyroid development. We here report clinical, histopathological and molecular investigations in parathyroid tumors arising in two patients; one familial adenomatous polyposis (FAP) syndrome patient carrying a constitutional APC mutation, and one Lynch syndrome patient demonstrating a germline MLH1 mutation as well as a non-classified, missense alteration of the APC gene. We sequenced the entire APC gene in tumor and constitutional DNA from both cases, assessed the levels of APC promoter 1A and 1B methylation by bisulfite Pyrosequencing analysis and performed immunohistochemistry for APC and parafibromin. In addition, copy number analysis regarding the APC gene on chromosome 5q21-22 was performed using qRT-PCR. Histopathological workup confirmed both tumors as parathyroid adenomas without signs of malignancy or atypia. No somatic mutations or copy number changes for the APC gene were discovered in the tumors; however, in both cases, the APC promoter 1A was hypermethylated while the APC promoter 1B was unmethylated. APC promoter 1B-specific mRNA and total APC mRNA levels were higher than in normal parathyroid samples. Immunohistochemical analyses revealed strong APC protein immunoreactivity and positive parafibromin expression in both parathyroid tumors. Absence of additional somatic APC mutations and copy number changes in addition to the positive APC immunoreactivity obtained suggest that the tumors arose without biallelic inactivation of the APC tumor suppressor gene. The finding of an unmethylated APC promoter 1B and high APC 1B mRNA levels could explain the maintained APC protein expression. Moreover, the findings of positive parafibromin and APC immunoreactivity as well as a low MIB-1 proliferation index and absence of histopathological features of malignancy/atypical adenoma indicate that the parathyroid adenomas arising in these patients did not harbor malignant potential.     

Mutation analysis of <Emphasis Type="Italic">MUTYH</Emphasis> in Japanese colorectal adenomatous polyposis patients

Germline MUTYH mutations were investigated in 14 Japanese colorectal polyposis patients without germ line adenomatous polyposis coli (APC) gene mutations. Three patients had a heterozygous IVS10-2A>G MUTYH mutation. The onset of MUTYH-associated polyposis (MAP) occurs later than that of familial adenomatous polyposis with germline APC mutation. Thus, we compared the carrier frequency of MUTYH IVS10-2A>G heterozygote in the APC mutation negative cases with that in 115 controls over 70 years of age who showed no apparent clinical manifestations of cancer and claimed that they had no history of cancer at the time of enrollment. The frequency of IVS10-2A>G heterozygote in APC germline mutation negative polyposis patients was significantly higher than control subject (p = 0.012, Chi square test). Although the sample size is still too small to conclude, the IVS10-2A>G MUTYH heterozygote might add to the risk of developing germline APC mutation negative polyposis.     

MYH biallelic mutation can inactivate the two genetic pathways of colorectal cancer by APC or MLH1 transversions

MYH associated polyposis is a hereditary syndrome responsible for early colorectal cancer with a distinct genetic pathway from the Familial Adenomatous Polyposis or the Hereditary Non Polyposis Colorectal Cancer syndrome. We have studied a family with three members bearing a biallelic mutation in MYH at c.1185_1186dup. One patient who developed colon cancer had loss of expression of MLH1 on tumoral tissue and microsatellite instability (MSI) phenotype. Analysis of MLH1 based on his blood sample revealed no germline mutation or large genomic deletion. No methylation of the promoter was identified in tumoral DNA. No transversion mutations were identified in APC or KRAS in tumor DNA of this patient. Loss of expression of MLH1 was due to a transversion in intron 7 at position +5 (c.588 + 5G > T) leading to a complete deletion of exon 7 at the RNA level. This observation demonstrates that MLH1 can be a target of MYH transversions leading to MSI phenotype.     

Mutation analysis of the APC gene in unrelated Korean patients with FAP: four novel mutations with unusual phenotype

Germline mutations within the adenomatous polyposis coli (APC) gene are responsible for most cases of familial adenomatous polyposis (FAP), an autosomal dominantly inherited predisposition to colorectal cancer. To date more than 900 different APC germline mutations have been characterized worldwide demonstrating allelic heterogeneity. Here, we analyzed the APC gene in 23 DNA samples from unrelated Korean patients with the typical clinical symptoms of FAP by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing. We identified 20 different APC sequence variants, including 9 truncating mutations, 1 missense mutation, 7 polymorphisms, and 3 intronic variants. Nine different truncating mutations, including four novel mutations (p.Leu180TyrfsX5, p.Gly567X, p.Ser1275PhefsX13, p.Leu1280CysfsX8), were detected. The most common mutation was a 5 bp deletion at codon 1,309 (p.Glu1309AspfsX4) as in Western studies. The next most common mutation was p.Ser1275PhefsX13 with a severe form of FAP with many extracolonic manifestations; this was a novel mutation identified in our study and may represent the second hot-spot mutation in a Korean population. Novel mutations are of particular interest because of the unusual phenotypic features shown by patients. In present study, we found new positions associated with thyroid cancer (codon 180) and desmoid tumor (codon 1,280), which have not been previously reported. The results of this molecular study have revealed the existence of novel pathogenic mutations in Korean patients with FAP. In addition to allowing phenotype–genotype correlations to be performed, these results are currently being used in genetic counseling and in patient care.     

Familial Adenomatous Polyposis: Experience from a Study of 1164 Unrelated German Polyposis Patients

The autosomal-dominant precancerous condition familial adenomatous polyposis (FAP) is caused by germline mutations in the tumour suppressor gene APC. Consistent correlations between the site of mutations in the gene and clinical phenotype have been published for different patient groups. We report our experiences of APC mutation analysis and genotype-phenotype correlations in 1166 unrelated polyposis families and discuss our results in the light of literature data. We show that the mutation detection rates largely depend on the family history and clinical course of the disease. We present a list of 315 different point mutations and 37 large deletions detected in 634 of the 1166 index patients. Our results confirm previously published genotype-phenotype correlations with respect to the colorectal phenotype and extracolonic manifestations. However, 'exceptions to the rule' are also observed, and possible explanations for this are discussed. The discovery of autosomal-recessive MUTYH-associated polyposis (MAP) as a differential diagnosis to FAP implies that some results have to be reinterpreted and surveillance guidelines in the families have to be reevaluated.     

A Very Large Villous Adenoma with an Adjacent Cancer of the Rectum: An Informative Case for Testing the Proposed Molecular Basis of Colorectal Tumorigenesis

It is currently accepted that colorectal tumorigenesis resultsfrom accumulation of multiple mutations in certain genes. Thisconcept prompted us to search for possible mutations in theAPC, k-ras, and p53 genes in an advanced cancer coexisting witha large villous adenoma of the rectum in a 54-year-old patientwith no family history of colorectal cancer. Genomic DNA extractedfrom multiple subregions of the tumor and surrounding normalmucosa was studied by polymerase chain reaction (PCR) followedby single-strand conformation polymorphism (SSCP) analysis anddirect sequencing. Both the adenoma and carcinoma had abnormalPCR-SSCP for APC (exon 11) and k-ras, irrespective of the locationwithin the tumors. However, p53 abnormality (exon 7) was detectedonly in samples taken from the carcinoma. Subsequent sequencingrevealed a TTC to TAG mutation at codon 479 of APC, a GGT toGAT mutation at codon 12 of k-ras in both the adenoma and carcinoma,and a CGG to TGG mutation at codon 248 of p53 (exon 7) in thecarcinoma. These findings were in accord with the current conceptof colorectal tumor progression whereby genetic alteration ofAPC and k-ras occurs relatively early while that of p53 is ratherlate and is possibly a decisive event in relation to malignancy.     

Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in <Emphasis Type="Italic">APC</Emphasis> mutation carriers

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05–2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03–2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.     

Adenomatous Polyposis Syndromes: Familial Adenomatous Polyposis and <Emphasis Type="Italic">MutYH</Emphasis>-Associated Polyposis

The purpose of this review is to provide an overview of the etiology, diagnosis, and clinical management of the two most common polyposis; change adenomatous to polyposis hereditary colorectal cancer syndromes, familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). The syndromes are caused by inherited genetic variants in the APC and MutYH genes, respectively. Both syndromes carry significant increased risk of colorectal and extracolonic cancers. Intense surveillance is required to reduce this risk, and colectomy or proctocolectomy is frequently the ultimate form of colorectal cancer risk reduction. The colorectal phenotype and extracolonic manifestations continue to evolve as more is learned about the natural history of the diseases, particularly MAP.     

Wild-type APC Is Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer

BackgroundThe prognostic implication of wild‐type APC (APC‐WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined.Materials and Methods APC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC).ResultsIn comparison with the APC‐mutant (APC‐MT) population (n = 255), APC‐WT patients (n = 86) tended to be younger (59% of age < 40 vs. 26% of age > 50), right‐sided (41.7% vs. 27%), BRAF ^V600E mutated (23.3% vs. 0.8%), and KRAS wild type (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1, were over‐represented in the APC‐WT versus APC‐MT population (7% vs. 0.4% and 4.7% vs. 0.4%, respectively). APC‐WT patients had a worse overall survival (OS) than APC‐MT patients (22.6 vs. 45.6 months, p < .0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC‐WT was predictive of poor survival (APC‐MT vs. APC‐WT, hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44–0.86, p = .0037). The prognostic implication of APC‐WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database (APC‐MT vs. APC‐WT, HR, 0.63, 95% CI, 0.49–0.81, p < .0001).Conclusion APC‐WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC‐MT mCRC tumors, APC‐WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1. Our data suggest alternative therapy needs to be investigated in APC‐WT patients.Implications for PracticePatients with microsatellite stable metastatic colorectal cancer with wild‐type APC had a worse overall survival than patients with mutated APC regardless of RAS/RAF status. APC status should be considered as a stratification factor in prospective trials, and novel therapeutic strategies need to be developed for this subgroup of patients.     

Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients.

Recently we have isolated the adenomatous polyposis coli (APC) gene which causes familial adenomatous polyposis (FAP), and its germ-line mutations in a substantial number of FAP patients have been identified. On the basis of this information, we compared the location of germ-line mutations in the APC gene in 22 unrelated patients (12 of whom have been reported previously) with the number of colorectal polyps developed in FAP patients; 17 were sparse types and five were profuse types. All but one of the mutations were considered to cause truncation of the gene product by frame-shift due to deletion (14 cases) or nonsense mutation (seven cases). The location of the germ-line mutations seems to correlate with the two clinical types; germ-line mutations in five FAP patients with profuse polyps were observed between codon 1250 and codon 1464, whereas mutations in 17 FAP patients with fewer polyps were observed in the other regions of the APC gene. The result suggests that the number of colorectal polyps in FAP patients may be associated with a difference in the stability or biological function of the truncated APC protein.