Classical Familial Adenomatous Polyposis Research Articles

Clinical and genetic characterization of classical forms of familial adenomatous polyposis: a Spanish population study

BackgroundClassical familial adenomatous polyposis (FAP) is characterized by the appearance of >100 colorectal adenomas. Patients and MethodsWe screened the APC and MUTYH genes for mutations and evaluated the genotype–phenotype correlation in 136 Spanish classical FAP families. ResultsAPC/MUTYH mutations were detected in 107 families. Sixty-four distinct APC point mutations were detected in 95 families of which all were truncating mutations. A significant proportion (39.6%) had not been previously reported. Mutations were spread over the entire coding region and great rearrangements were identified in six families. Another six families exhibited biallelic MUTYH mutations. No APC or MUTYH mutations were detected in 29 families. These APC/MUTYH-negative families showed clinical differences with the APC-positive families. A poor correlation between phenotype and mutation site was observed. ConclusionsOur results highlight that a broad approach in the genetic study must be considered for classical FAP due to involvement of both APC and MUTYH and the heterogeneous spectrum of APC mutations observed in this Spanish population. The scarcely consistent genotype–phenotype correlation does not allow making specific recommendations regarding screening and management. Differences observed in APC/MUTYH-negative families may reflect a genetic basis other than mutations in APC and MUTYH genes for FAP predisposition.

The Genetic Etiology of Familial and Nonfamilial Colorectal Cancer

Colorectal cancer (CRC) is the third most frequently diagnosed cancer in the US and the second leading cause of cancer death. CRCs arise from a multistep carcinogenic process, beginning with early changes from normal to hyperproliferative epithelium, then to the development of adenomas, which in turn are believed to be precursors of carcinomas. These histological changes are associated with the accumulation of genetic and epigenetic changes involving the activation of oncogenes and the inactivation of tumor suppressor genes. Approximately two thirds of new cases of CRC appear to be sporadic (i.e., occur without a family history of the disease), and the necessary genetic changes seem to arise de novo, fueled by etiologic agents that can include age, environmental exposures, and lifestyle factors. Nearly one third of cases, however, tend to cluster in families, so that first-degree relatives of patients with newly diagnosed adenomas or invasive CRCs are at increased risk. While many of these familial clusters may be linked to shared behaviors or environmental exposures among family members, some are associated with germline mutations in specific genes. Although specific genetic mutations have been identified for a wide variety of syndromes that may involve CRC, screening is normally directed at the most common of these: hereditary nonpolyposis CRC (HNPCC), also known as Lynch syndrome, and familial adenomatous polyposis (FAP). Lynch syndrome is the most common hereditary cancer syndrome predisposing to CRC, accounting for approximately 3% of all cases. It is associated with mutations in four DNA-mismatch repair (MMR) genes: MSH2, MLH1, MSH6, and PMS2. Individuals with a germline mutation in any of these genes have a significant lifetime risk of developing CRC (70% for men, 40% for women), as well as a heightened risk for the development of cancers at other sites, including the endometrium, ovary, stomach, small bowel, urinary tract, and pancreas. FAP, about one tenth as common as Lynch syndrome, is associated with mutations in the APC gene, which is classified as a tumor suppressor gene. Individuals with FAP may have hundreds of adenomas, making this syndrome relatively straightforward to detect. Because so many adenomas develop at an early age, classic FAP carries a lifetime risk of nearly 100% for the development of CRC. Additional hereditary CRC syndromes that are not routinely tested for include Peutz-Jeghers syndrome, familial juvenile polyposis, Cowden's disease, Bannayan-Ruvalcaba-Riley syndrome, and Li-Fraumeni syndrome. For both sporadic and familial CRC, a key early change is the development of genetic and epigenetic instability, which increases the rate at which further changes can be accumulated. At least three patterns of instability can contribute to the development of CRC; typically, one type will predominate in a specific cancer. One common pattern, prominent in at least 50% of CRCs, is chromosome instability (CIN), which can result in genetic deletions, duplications, and rearrangements. CRCs with CIN are characterized by aneuploid tumor cells. A second pattern is microsatellite instability (MSI), which occurs in about 15% of CRCs (Figure ​(Figure11). Microsatellites are simple repeat sequences 1 to 6 base pairs in length that occur thousands of times across the genome. MSI occurs through the inactivation of the DNA mismatch repair (MMR) system, resulting in sequences that accumulate errors and become abnormally long or short. In some instances, this creates a frameshift mutation in a gene, such as a tumor suppressor gene. Unlike CIN, most CRCs with MSI are diploid or near diploid. More than 90% of the CRCs attributable to Lynch syndrome are associated with MSI. Figure 1 Two molecular pathways to the development of colorectal cancer with microsatellite instability. From Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138(6):2073–2087.e3. Reprinted with permission from ... The third pattern seen in CRC is an epigenetic change that involves the methylation of promoters of human genes. This can lead to the silencing of certain tumor suppressor genes in CRC. About half of the promoters of human genes are embedded in CpG islands, so this phenotype in tumor DNA is called the CpG island methylator phenotype (CIMP). Overlap between MSI and CIMP occurs in about 12% of CRCs when the promoter of the MMR gene MLH1 is methylated (and inactivated), leading to MSI.

When is a desmoid not a desmoid? Endometrial cancer as an extracolonic manifestation of MYH Associated Polyposis (MAP)

Background Desmoids are a recognized feature of the classical and attenuated forms of familial adenomatous polyposis (FAP), occurring in 15% of individuals with classic FAP. Case history A 68 year old Caucasian woman presented with a lump in her right groin and lower abdominal pain. No changes in bowel habit or other bowel symptoms were reported. Previous medical history included endometrial cancer diagnosed at age 57, treated by hysterectomy and bilateral salpingo-oophorectomy. The family history was negative for desmoids, colon polyps and cancer. By CT scan, a 4 x 3 cm soft tissue mass arising from the right rectus muscle and tethered to bowel loops was identified. It was felt to represent a desmoid. Before resecting this mass, due to bowel tethering, a colonoscopy was performed. The cecum was completely replaced by a carpeting villous adenoma. Two tubular adenomas and one tubulovillous adenoma, all with lowgrade dysplasia, were noted. During definitive surgery, the lesion arising from the sigmoid mesentery and suspected to be a desmoid, was shown to be a well-differentiated adenocarcinoma with endometrioid features. 28 tubulovillous adenomas and hyperplastic polyps, with no malignancy or dysplasia were identified in the subtotal colectomy. The clinical impression was that of attenuated polyposis and metastatic endometrial carcinoma. Results

Gene variants associated to malignant thyroid disease in familial adenomatous polyposis: A novel APC germline mutation

Familial adenomatous polyposis (FAP) is an autosomal inherited syndrome characterized by hundreds to thousands colorectal adenomatous polyps with oncological transformation lifetime risk of 100%. FAP is mainly associated with mutations in APC (autosomal dominant inheritance) or MUTYH (autosomal recessive inheritance) genes. Affected individuals are at increased risk of developing extra-intestinal tumors. Lifetime risk of developing thyroid carcinoma has been described in previous reports of about 2-12%, mainly in females, and the mean age is below 30 yr. About 95% of cancers are papillary thyroid carcinomas (PTC), mostly multifocal. The aim of this study was to evaluate the frequency of PTC among our series of FAP patients and to assess the type of gene mutation associated with the disease. Fifty-four subjects from 36 FAP families were selected (29 females/25 males) and the mean age (±SD) at diagnosis was 28.8±10.8 yr. All patients underwent blood examination for thyroid hormones and antibodies, germline mutational analysis of APC and/or MUTYH genes, thyroid ultrasound, and endocrinological evaluation. In 13/54 (24.1%) subjects, an eumetabolic thyroid disease was found: plurinodular disease in 7/54 (13.0%); single nodule in 4/54 (7.4%); in 2/54 patients (3.7%), we found a malignant nodule characterized after total thyroidectomy as a classical PTC. Both patients were female and showed a classic FAP phenotype. Mutational analysis revealed in the first patient the APC germline mutation 3183_87del ACAAA and in the second patient the del9-10 (del9080dup11) novel APC variant; the first mutation has been already reported in association with PTC; to our knowledge the second mutation has never been previously reported in association with FAP. In the population examined, the estimated prevalence of thyroid malignant diseases was 3.7%. In both patients, the identified APC gene pathogenetic variants mapped within the 5' region of the gene, previously reported as a PTC-associated mutational hot spot. Both patients had classic FAP phenotype and genetic analysis revealed two pathogenetic APC mutations: c.3183_87delACAAA, a recurrent pathogenetic variant and del9-10 (del9080dup11), a novel, not previously described genomic rearrangement. In agreement with previous studies, the morpho-functional surveillance of thyroid in FAP series should be recommended. A better insight into the overall genotype-phenotype correlation of APC gene mutations would be helpful for the identification of at-risk individuals.

MUTYH‐associated polyposis – variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations

To further characterize 215 APC mutation-negative patients with colorectal neoplasias classified in classical, attenuated, or atypical familial adenomatous polyposis (FAP) coli we performed mutation screening in the Mut Y homologue (MUTYH) gene. The incidence was 15% for biallelic and 3.7% for monoallelic MUTYH mutations. We describe six novel MUTYH mutations in biallelic constellation and two novel monoallelic missense mutations. Of 33 MUTYH-associated polyposis coli (MAP) patients 57% were attenuated familial adenomatous polyposis (AFAP) patients, 10% display early-onset classical FAP and 18% had only few adenomas at higher age. Biallelic cases had a high incidence of extracolonic polyposis in 32% and colorectal cancer (CRC) in 33% of the cases. The clinical picture of MAP ranged from classical FAP or synchronous CRC at age 30 years to few adenomas at age 54 years without evidence of CRC, initially suspected for hereditary non-polyposis colorectal cancer (HNPCC). The mean age of onset was 43 years, with 11 (33%) patients being younger than 40 years of age, indicating that the clinical manifestation can be earlier than so far reported. Monoallelic MUTYH mutation carriers had a positive family history in seven of eight cases allowing the hypothesis of a disease-causing synergism of MUTYH mutations with other genes.

Abstract 2114: Deletions/Duplications detection by MLPA in Chilean families with hereditary colorectal cancer: Lynch syndrome and FAP

Abstract The main variants of colorectal cancer hereditary are Familial Adenomatous Polyposis (FAP) and Lynch Syndrome, which account for approximately 5% of total cases of colorectal cancer. Point mutations in APC and MMR genes are responsible of about 85% and 50% of Chilean FAP (classic phenotype) and Lynch Syndrome (Amsterdam criteria) families, respectively. Different molecular strategies are available for the detection of mutations in these genes. Studies in other populations have identified deletions and duplications of one or more consecutive exons account for around 50% and 10-20% of the total alterations in MMR and APC genes, respectively. The aim of our work was the detection of genomic deletion/duplication through Multiplex Ligation-Dependent Probe Amplification (MLPA) in Lynch Syndrome and FAP patients in Chile. In this study, we analized alterations in MLH1 and MSH2 in 26 Lynch Syndrome families (5 Amsterdam and 21 Bethesda families), and in APC in 10 FAP families (6 classic and 4 attenuated), all of them non carriers of point mutations in these genes. We identified 3 different alterations in the MLH1 in four Amsterdam families, all of them are 0.5 times deletion, which are located: exon 1 in one family, exon 19 in two families, and exons 14 and 15 in one family. In the MSH2, in one Amsterdam family we detected a 0.5 time deletion of exon 2. In the APC, we found 2 different alterations in three classic FAP families: in one family we detected a 0.5 times deletion of the whole gene including promoter region, and in two families we found a 1.5 time amplification of exons 1, 2 and 3. These alterations were confirmed in other relatives of these families and in two independent MLPA analysis. The deletion of exon 19 in MLH1 and the amplification of exons 1, 2 and 3 in APC have not been previously described in other populations. In conclusion, genomic deletions/duplications were only detected in 5 Lynch Syndrome families that fulfilled Amsterdam criteria, and in 3 FAP families with classic phenotype. The detection of different mutations involved in these syndromes, allows the development of prevention strategies of these diseases. Financed by Cleveland Clinic Foundation and Las Condes Clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2114.

Implication of Adenomatous Polyposis Coli and MUTYH Mutations in Familial Colorectal Polyposis

Familial adenomatous polyposis is an autosomal dominantly inherited syndrome characterized by hundreds or thousands of colorectal polyps and a high risk of colorectal cancer at a young age. Truncating germline mutations in the adenomatous polyposis coli gene are detected in approximately 80 percent of patients with classical familial adenomatous polyposis and in approximately 10 percent of the attenuated familial adenomatous polyposis patients. We investigated the adenomatous polyposis coli and MUTYH genes mutations in a well-characterized series of 25 unrelated Italian patients with familial adenomatous polyposis. We characterized the specific adenomatous polyposis coli gene mutation in 10 probands, and identified eight truncating mutations (4 novel and 4 known mutations) and two splicing mutations. One of these, a novel missense mutation in exon 15, activates an exonic splicing enhancer control sequence. Moreover, 11 MUTYH gene mutations have been identified in 7 patients without a dominant family history of polyposis. This study enlarges the genotype-phenotype correlations of familial adenomatous polyposis and suggests that messenger alterations could be responsible for a subset of familial adenomatous polyposis cases without germ-line adenomatous polyposis coli or MUTYH gene mutations. It also confirms that genotype-phenotype correlations in MUTYH-associated polyposis are very complex.

A large novel deletion in the APC promoter region causes gene silencing and leads to classical familial adenomatous polyposis in a Manitoba Mennonite kindred

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by the inheritance of germline mutations in the APC tumour suppressor gene. The vast majority of these are nonsense and frameshift mutations resulting in a truncated protein product and abnormal function. While APC promoter hypermethylation has been previously documented, promoter-specific deletion mutations have not been reported. In a large Canadian Mennonite polyposis kindred, we identified a large novel germline deletion in the APC promoter region by linkage analysis and MLPA. By RT-PCR and sequence analysis, this mutation was found to result in transcriptional silencing of the APC allele. A few genetic disorders have been characterized as over-represented in the Manitoba Mennonite population, however, the incidence of cancer has not been recognized as increased in this population as compared to other Manitoba ethnic groups. This study strengthens the likelihood that this novel APC promoter mutation is linked to this unique population as a founder mutation.

Detection of APC Gene Deletions Using Quantitative Multiplex PCR of Short Fluorescent Fragments

approximately 20% of classic familial adenomatous polyposis (FAP) cases and 70% to 80% of attenuated FAP (AFAP) cases are negative for the APC/MUTYH point mutation. Quantitative multiplex PCR of short fluorescent fragments (QMPSF), a technique for detecting copy number alterations, has been successfully applied to several cancer syndrome genes. We used QMPSF for the APC gene to screen FAP APC/MUTYH mutation-negative families to improve their diagnostic surveillance. we set up and validated APC-gene QMPSF using 23 negative and 1 positive control and examined 45 (13 FAP and 32 AFAP) unrelated members of APC/MUTYH mutation-negative families for copy number alterations. We confirmed the results using multiplex ligation-dependent probe amplification (MLPA). We used different approaches such as sequencing, quantitative real time-PCR (QRT-PCR), and fluorescence in situ hybridization (FISH) to further characterize the identified deletions. APC QMPSF was capable of detecting deletions with an acceptable variability, as shown by mean values (SD) of allele dosage for the deleted control obtained from intra- and interexperimental replicates [0.52 (0.05) and 0.45 (0.10)]. We detected 3 gross deletions in 13 (23%) of the classic FAP cases analyzed (1 complete gene deletion and 2 partial deletions encompassing exons 9 and 10 and exons 11-15, respectively). No rearrangements were detected in the 32 AFAP cases. QMPSF is able to detect rearrangements of the APC gene. Our findings highlight the importance of using a copy number alteration methodology as a first step in the routine genetic testing of FAP families in the clinical setting.

Efficacy of methotrexate + vinblastine in intra-abdominal desmoid (mesenteric aggressive fibromatosis): Retrospective analysis of 29 patients from a single institution

10567 Background: Desmoid tumors (DT) are rare neoplasms characterized by clonal proliferation of myofibroblasts, that do not metastasize but exhibit an infiltrative pattern, producing tissue destruction and significant functional impairment. Although sporadic desmoids are rare, these tumors are common in patients (pts) with familial adenomatous polyposis (FAP): 3.5 to 32% of the pts are diagnosed with diffuse mesenteric desmoid, which is the second reported lethal complication of FAP. The combination of methotrexate (MTX) + vinblastine (VNB) is known to be active in extraabdominal desmoids. Methods: The dataset of the Istituto Nazionale Tumori, Milan (1,115 Classical FAP) was analyzed. Overall, 167 (14.9%) were diagnosed with DT arising in FAP. 104/167 were females, and age ranged from 29 to 70 years. 96/167 pts received surgery. In this case series analysis, we retrospectively reviewed clinical efficacy of weekly MTX at the dose of 30 mg/m2 + VBL at the dose of 6 mg/m2 in 29 consecutive pts, all of whom but 2 have concluded their therapy. As an external control, we retrospectively evaluated also 43 pts treated with other approaches (hormone therapy, NSAIDs, etc.) in the same period. Tumor response was assessed by RECIST criteria after the first 2 months of treatment and then every other month. Results: As of December 2007, 21 pts (72%) had PR or SD exceeding 6 months. Of pts treated with other approaches, 23 (53%) are still on treatment with PR or SD exceeding 6 months. Overall, 32/167 pts died, 14 of intra-abdominal DT (8.4%), 10 of Colorectal cancer, 6 of extracolonic cancer, and 2 of other causes. Conclusions: The MTX and VBL regimen seems to active also in intra-abdominal DT, as shown in sporadic DT, and may be considered among the medical options available for the advanced stages of this disease. No significant financial relationships to disclose.

Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families

BackgroundThe dominantly inherited condition familial adenomatous polyposis (FAP) is caused by germline mutations in the APC gene. Finding the causative mutations has great implications for the families. Correlating the genotypes to the phenotypes could help to improve the diagnosis and follow-up of patients.MethodsMutation screening of APC and the clinical characterization of 96 unrelated FAP patients from the Swedish Polyposis Registry was performed. In addition to generally used mutation screening methods, analyses of splicing-affecting mutations and investigations of the presence of low-frequency mutation alleles, indicating mosaics, have been performed, as well as quantitative real-time polymerase chain reaction to detect lowered expression of APC.ResultsSixty-one different APC mutations in 81 of the 96 families were identified and 27 of those are novel. We have previously shown that 6 of the 96 patients carried biallelic MUTYH mutations. The 9 mutation-negative cases all display an attenuated or atypical phenotype. Probands with a genotype (codon 1250–1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11–49) years compared with 34.4 (range, 14–57) years among those with mutations outside this region (P < 0.017). Dense polyposis (> 1000) occurred in 75% of the probands with a severe phenotype compared with 30% in those with mutations outside this region. The morbidity in colorectal cancer among probands was 25% at a mean age of 37.5 years and 29% at a mean age of 46.6 years.ConclusionUsing a variety of mutation-detection techniques, we have achieved a 100% detection frequency in classical FAP. Probands with APC mutations outside codon 1250–1464, although exhibiting a less-severe phenotype, are at high risk of having a colorectal cancer at diagnosis indicating that age at diagnosis is as important as the severity of the disease for colorectal cancer morbidity.

Genotype–phenotype correlations in 19 Dutch cases with APC gene deletions and a literature review

Partial and whole gene deletions represent a large proportion (4-33%) of the APC mutations found in polyposis patients, who previously had negative test results. The genotype-phenotype correlations for these APC deletions have not been studied in detail. We aimed to assess the number of germ line APC deletions in Dutch polyposis patients, to describe the clinical phenotype(s), and to review the current literature. We screened 296 index patients with polyposis, who previously had negative test results for APC or MUTYH mutations, for germ line APC gene deletions using Multiplex Ligation-dependent Probe Amplification. APC deletions were identified in 19 polyposis patients; seven had a whole gene deletion, nine had a deletion involving two or more exons, and three had single exon deletions. Most of the deletion families (83%) displayed a classic familial adenomatous polyposis (FAP) phenotype (100-2000 adenomas). We saw no patients with APC deletions and a severe phenotype (ie >2000 polyps); on the contrary, two families carrying a deletion of exons 7-13 and one family with a deletion of exons 1-5 showed a distinctly attenuated FAP phenotype. APC deletions were found in a considerable proportion of polyposis patients previously tested negative for APC or MUTYH (6%, 19/296) and represent 8% of all APC mutations found at our clinics (19/242). Methods to identify such deletions should therefore be included in routine germ line APC mutation analysis. While most total and partial APC deletions lead to a classic FAP phenotype, specific (in-frame) deletions may lead to an attenuated polyposis phenotype.

Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects

BackgroundGermline mutations in the adenomatous polyposis gene (APC) result in familial adenomatous polyposis (FAP). FAP is an autosomal dominantly inherited disorder predisposing to colorectal cancer. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extracolonic manifestations. An attenuated form of polyposis (AFAP) is characterized by less than 100 adenomas and later onset of the disease.MethodsHere, we analyzed the APC gene for germline mutations in 59 Czech and 15 Slovak FAP patients. In addition, 50 apparently APC mutation negative Czech probands and 3 probands of Slovak origin were screened for large deletions encompassing the APC gene. Mutation screening was performed using denaturing gradient gel electrophoresis and/or protein truncation test. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. Screening for large deletions was performed by multiplex ligation dependent probe amplification. The extent of deletions was analyzed using following microsatellite markers: D5S299, D5S82, D5S134 and D5S346.ResultsIn the set of Czech and Slovak patients, we identified 46 germline mutations among 74 unrelated probands. Total mutation capture is 62,2% including large deletions. Thirty seven mutations were detected in 49 patients presenting a classical FAP phenotype (75,5%) and 9 mutations in 25 patients with attenuated FAP (36%). We report 20 novel germline APC mutations and 3 large deletions (6%) encompassing the whole-gene deletions and/or exon 14 deletion. In the patients with novel mutations, correlations of the mutation localization are discussed in context of the classical and/or attenuated phenotype of the disease.ConclusionThe results of the molecular genetic testing are used both in the establishment of the predictive diagnosis and in the clinical management of patients. In some cases this study has also shown the difficulty to classify clinically between the classical and the attenuated form of FAP according to the established criteria. Interfamilial and/or intrafamilial phenotype variability was also confirmed in some cases which did not fit well with predicted genotype-phenotype correlation. All these findings have to be taken into consideration both in the genetic counselling and in the patient care.

Attitudes Toward Prenatal Genetic Testing in Patients With Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome with >95% risk of colorectal cancer without prophylactic colectomy. Classic FAP is commonly associated with adenomatous polyposis coli (APC) gene mutations. If a mutation is identified, prenatal testing can reveal whether an embryo or fetus is affected. We conducted a pilot study to assess FAP patients' attitudes toward prenatal testing. Twenty individuals with FAP completed a 40-item survey on personal and family history related to FAP, demographics, and attitudes toward prenatal tests including amniocentesis, chorionic villous sampling (CVS), and preimplantation genetic diagnosis (PGD). Thirteen women and seven men participated. Ninety-five percent (19/20) would consider undergoing prenatal testing for FAP: 90% would consider PGD, 75% would consider amniocentesis or CVS. Having an affected child and experiencing a first-degree relative's (FDR) death secondary to FAP were associated with greater willingness to consider prenatal testing. Personal history of cancer or FAP-associated tumors did not influence the decision to consider prenatal testing. One hundred percent said it was ethical to provide prenatal testing for FAP and four of five subjects who self-reported strong religious backgrounds would consider prenatal testing for FAP. Early reassurance of having an unaffected child was the most important advantage of PGD and avoiding pregnancy termination was important for 64% and 71% of women and men, respectively. Patients with FAP are willing to consider prenatal testing to prevent transmission of disease to their children. Physicians caring for FAP patients should discuss available prenatal diagnostic options with patients of childbearing age.

The genetics of FAP and FAP-like syndromes

The presence of multiple adenomatous polyps in the large bowel confers a high lifetime risk of colorectal cancer. Although many cases of classical familial adenomatous polyposis (> 100 polyps) can be accounted for by mutations in the adenomatous polyposis coli (APC) gene, a large group of patients remains with multiple (5-100) adenomas and in whom there is no detectable APC mutation. Recently two new genetic variants have been found to be associated with multiple colorectal adenomas and cancer, MYH/MUTYH on chromosome 1p and the HMPS/CRAC1 locus on chromosome 15q13-q14. New information also continues to emerge regarding the less common hamartomatous polyposis conditions, Peutz-Jeghers syndrome and Juvenile Polyposis syndrome. In approximately half to two thirds of these families, germline genetic variants can now be uncovered. In this review we draw together some of the most recent information pertinent to the molecular pathogenesis of colorectal polyposis.

Detection of APC gene deletion by double competitive polymerase chain reaction in patients with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant familial cancer syndrome caused by germline mutations of the tumor suppressor adenomatous polyposis coli (APC) gene. Heterozygous apc mutations have been identified in the majority of classical FAP patients who develop more than 100 colorectal adenomas. However, classical FAP patients often fail to display germline APC mutations detectable by routine mutation analysis. These apparently mutation-negative cases may be caused by heterozygous large genomic deletions. In the present study, FAP patients who showed no APC germline mutation detectable by the protein truncation assay and direct sequencing of protein coding exons were screened for APC gene deletion by a gene dose assay based on double competitive polymerase chain reaction. Gene dosage measurements within exon 15 of the APC gene identified two patients with gene deletion and one with possible gene duplication among 41 apparently mutation-negative patients. The deleted sequences in the two patients were determined by fine gene dose mapping around the APC gene and nucleotide sequencing of the deletion breakpoints. They were approximately 435-kilobase pair (kb) and 737-kb regions including the whole APC gene and flanked by a 4-base pair repeat and LINE-1 repetitive sequences, respectively. The chimeric LINE-1 element created at the breakpoint in the latter case also contained a short sequence derived from another LINE-1 element, suggesting a complex unequal homologous recombination event. These findings indicate that this gene dose assay is a useful technique to detect large gene deletions of the APC gene and to determine their genomic breakpoints.

Prevalence of MYH germline mutations in Swiss APC mutation‐negative polyposis patients

In 10-30% of patients with classical familial adenomatous polyposis (FAP) and up to 90% of those with attenuated (<100 colorectal adenomas; AFAP) polyposis, no pathogenic germline mutation in the adenomatous polyposis coli (APC) gene can be identified (APC mutation-negative). Recently, biallelic mutations in the base excision repair gene MYH have been shown to predispose to a multiple adenoma and carcinoma phenotype. This study aimed to (i) assess the MYH mutation carrier frequency among Swiss APC mutation-negative patients and (ii) identify phenotypic differences between MYH mutation carriers and APC/MYH mutation-negative polyposis patients. Seventy-nine unrelated APC mutation-negative Swiss patients with either classical (n=18) or attenuated (n=61) polyposis were screened for germline mutations in MYH by dHPLC and direct genomic DNA sequencing. Overall, 7 (8.9%) biallelic and 9 (11.4%) monoallelic MYH germline mutation carriers were identified. Among patients with a family history compatible with autosomal recessive inheritance (n=45), 1 (10.0%) out of 10 classical polyposis and 6 (17.1%) out of 35 attenuated polyposis patients carried biallelic MYH alterations, 2 of which represent novel gene variants (p.R171Q and p.R231H). Colorectal cancer was significantly (p<0.007) more frequent in biallelic mutation carriers (71.4%) compared with that of monoallelic and MYH mutation-negative polyposis patients (0 and 13.8%, respectively). On the basis of our findings and earlier reports, MYH mutation screening should be considered if all of the following criteria are fulfilled: (i) presence of classical or attenuated polyposis coli, (ii) absence of a pathogenic APC mutation, and (iii) a family history compatible with an autosomal recessive mode of inheritance.

What's New in Hereditary Colorectal Cancer?

Precancerous polyposes other than classic familial adenomatous polyposis and the condition hereditary nonpolyposis colorectal cancer, or Lynch syndrome, continue to present major diagnostic challenges for the anatomic pathologist. This editorial highlights the practical significance of novel insights and clinical guidelines in the recent literature, as well as in 4 contributions to this edition of the Archives of Pathology & Laboratory Medicine. The first section will address attenuated familial adenomatous polyposis and a newly recognized type of autosomal-recessive adenomatous polyposis associated with the DNA repair gene MYH. The remainder of the editorial discusses the role of the revised Bethesda guidelines in the diagnosis of hereditary nonpolyposis colorectal cancer and concludes with the recently identified serrated pathway syndrome.

Inherited Polyposis Syndromes: Molecular Mechanisms, Clinicopathology, and Genetic Testing

The inherited polyposis syndromes are a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gastrointestinal tract, most exhibit an increased risk of colon cancer. Benign and malignant extraintestinal tumors might also be observed. Recent elucidation of the underlying gene mutations has contributed to our understanding of the cell biology and molecular mechanisms associated with gastrointestinal tumorigenesis. Developments have also allowed genetic testing to become an integral component in accurate diagnosis, categorization, and management of inherited polyposis syndromes. In this review, we will focus on familial adenomatous polyposis, mutY human homologue-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. It is essential that both physician and patient understand the benefits and limitations of genetic testing before submission of samples to the laboratory. There are many issues accompanying molecular diagnosis of cancer syndromes, and genetic counseling is an essential prelude to genetic testing.

Is prophylactic colectomy indicated in patients with MYH‐associated polyposis?

The MYH gene has recently been associated with multiple colorectal tumours. It participates in the DNA base-excision-repair, avoiding mutations in other genes, namely the APC and Ki-ras. Recently, biallelic MYH mutations have been described in patients with attenuated polyposis and in 7.5% with classic polyposis and no detectable APC mutation. The aim of this study was to analyse the incidence of germ-line MYH mutations in selected Portuguese families recorded in a hereditary tumour registry and to evaluate the risk of colorectal cancer in this syndrome. Nineteen APC mutation negative patients, 13 presenting attenuated polyposis and 6 with classic familial adenomatous polyposis (> 100 adenomas), were screened for germline biallelic MYH mutations. Biallelic germline mutations in MYH were identified in 9 of the attenuated polyposis and in one of the classic polyposis patients. The mean age at the clinical diagnosis was 50.6 years (from 35 to 69 years); six were men and four women. Five patients belonged to families with affected siblings; three showed evidence for vertical transmission and two had no evidence for familial transmission of the disease. No extra-colonic manifestations were reported. All patients had surgical resections: five total colectomies, four reconstructive proctocolectomies and one left hemicolectomy. Eight patients had associated malignant degeneration: three T3N+, four T3N0 and one T1N+. In the follow-up two patients died due to tumour recurrence. A large frequency of biallelic MYH mutations (69%) was found in APC mutation negative patients belonging to families with attenuated polyposis; the highest percentage was observed in families presenting evidence for horizontal transmission of the disease. The high percentage of degeneration found in these patients suggests that colonoscopy with polypectomies is not sufficient and prophylactic colectomy is recommended. The identification of MYH associated polyposis is important to evaluate the level of risk, particularly for the siblings.