Germline APC Research Articles

The tumor suppressor Apc controls planar cell polarities central to gut homeostasis

The stem cells (SCs) at the bottom of intestinal crypts tightly contact niche-supporting cells and fuel the extraordinary tissue renewal of intestinal epithelia. Their fate is regulated stochastically by populational asymmetry, yet whether asymmetrical fate as a mode of SC division is relevant and whether the SC niche contains committed progenitors of the specialized cell types are under debate. We demonstrate spindle alignments and planar cell polarities, which form a novel functional unit that, in SCs, can yield daughter cell anisotropic movement away from niche-supporting cells. We propose that this contributes to SC homeostasis. Importantly, we demonstrate that some SC divisions are asymmetric with respect to cell fate and provide data suggesting that, in some SCs, mNumb displays asymmetric segregation. Some of these processes were altered in apparently normal crypts and microadenomas of mice carrying germline Apc mutations, shedding new light on the first stages of progression toward colorectal cancer.

Genetic Testing by Cancer Site

Gastric cancer is a global public health concern, ranking as the fourth leading cause of cancer mortality, with a 5-year survival of only 20%. Approximately 10% of gastric cancers appear to have a familial predisposition, and about half of these can be attributed to hereditary germline mutations. We review the genetic syndromes and current standards for genetic counseling, testing, and medical management for screening and treatment of gastric cancer. Recently, germline mutations in the E-cadherin/CDH1 gene have been identified in families with an autosomal dominant inherited predisposition to gastric cancer of the diffuse type. The cumulative lifetime risk of developing gastric cancer in CDH1 mutation carriers is up to 80%, and women from these families also have an increased risk for developing lobular breast cancer. Prophylactic gastrectomies are recommended in unaffected CDH1 mutation carriers, because screening endoscopic examinations and blind biopsies have proven inadequate for surveillance. In addition to this syndrome, gastric cancer risk is elevated in Lynch syndrome associated with germline mutations in DNA mismatch repair genes and microsatellite instability, in hereditary breast and ovarian cancer syndrome due to germline BRCA1 and BRCA2 mutations, in familial adenomatous polyposis caused by germline APC mutations, in Li-Fraumeni syndrome due to germline p53 mutations, in Peutz-Jeghers syndrome associated with germline STK11 mutations, and in juvenile polyposis syndrome associated with germline mutations in the SMAD4 and BMPR1A genes. Guidelines for genetic testing, counseling, and management of individuals with hereditary diffuse gastric cancer are suggested. A raised awareness among the physician and genetic counseling communities regarding these syndromes may allow for increased detection and prevention of gastric cancers in these high-risk individuals.

Identification of Familial Adenomatous Polyposis carriers among children with desmoid tumours

ObjectiveDesmoid tumours are rare mesenchymal tumours with unpredictable progression and high recurrence risk. They can occur sporadically or in association with Familial Adenomatous Polyposis (FAP), which is caused by germline APC mutations. The Wnt/β-catenin pathway has a central role in the pathogenesis of desmoid tumours. These tumours can occur due to either a somatic CTNNB1 or APC mutation but can also be the first manifestation of FAP. Because germline APC analysis is not routinely performed in children with desmoid tumours, the diagnosis FAP may escape detection. The aim of this study is to form guidelines for the identification of possible APC germline mutation carriers among children with desmoid tumours, based on CTNNB1 mutation analysis and immunohistochemical analysis (IHC) for β-catenin. Patients and methodsWe performed IHC of β-catenin and mutation analysis of CTNNB1 and APC in 18 paediatric desmoid tumours, diagnosed between 1990 and 2009 in the Erasmus MC, Rotterdam. ResultsIn 11 tumours, IHC showed an abnormal nuclear β-catenin accumulation. In this group a CTNNB1 mutation was detected in seven tumours. In two tumours with an abnormal nuclear β-catenin accumulation and no CTNNB1 mutation, an APC mutation was identified, which appeared to be a germline mutation. ConclusionsAberrant staining of β-catenin in paediatric desmoids helps to identify children at risk for FAP. We recommend to screen paediatric desmoid tumours for nuclear localisation of β-catenin and consequently for CTNNB1 mutations. For patients with nuclear β-catenin expression and no CTNNB1 mutations, APC mutation analysis should be offered after genetic counselling.

Polyposis syndromes– what to do when genotyping seems not informative

identifiable. The new NHMRC guidelines out for public comment recommend follow up of patients: As multiplicity of adenomas is a strong determinant of risk of metachronous advanced and non advanced neoplasia, follow up should be at twelve months for those with five or more adenomas, and sooner in those with ten or more adenomas. The risk of colorectal cancer to relatives of patients with multiple adenomas is related to the number of adenomas in the proband – outside FAP and MYH. Therefore, as distinct from patients with small numbers of adenomas, relatives of patients with larger numbers (10 +) should be offered colonoscopy at an age relative to the age of presentation of the proband. The interval is not well defined but I would suggest 5 yearly. Hyperplastic polyposis HPS has no defined genetic basis as yet. These patients are at high risk of colorectal cancer, either through the serrated pathway or through their concurrent adenomas. Two yearly colonoscopy is advised. Although the mode of inheritance is also poorly defined, it is thought it may be recessive. Therefore siblings are offered surveillance, though usually not expected to be found with HPS themselves. There is however, a high risk of colorectal cancer in first degree relatives (siblings or parents) so colonoscopy should be offered to these relatives 5 yearly. Low level mosaicism, gonadal mosaicism, somatic mosaicism Somatic mosaicism is now well described in FAP, with respect to the APC gene; cases of multiple adenomatous polyposis may therefore be found with no germline (lymphocytic) APC mutati on. We have been searching for the same APC mutation in multiple polyps, and in

A De Novo Germline APC Mutation (3927del5) in a Patient with Familial Adenomatous Polyposis: Case Report and Literature Review

Introduction Characterized by the development of hundreds to thousands of colonic adenomas, classic familial adenomatous polyposis (FAP) is one of the most common hereditary syndromes associated with an increased risk of colorectal cancer. Several studies have attempted to correlate specific APC mutations with clinical phenotype.6 However, there is considerable variability in the expression of specific phenotypes within families and among individuals with identical mutations.7 Case presentation A 30 year-old Hispanic female presented to the emergency department with a 2-week history of persistent, worsening, left lower quadrant abdominal pain. She had no family history of malignancy. Sigmoidoscopy revealed innumerable polyps in the rectum and sigmoid colon and a large mass in the sigmoid colon. Biopsy of the mass revealed a moderately differentiated adenocarcinoma invading the subserosa. Endoscopy revealed innumerable polyps. Genetic testing of the patient via southern blot revealed a germline APC mutation 3927del5, resulting in a premature truncation of the APC protein at amino acid position 1312. Conclusion Genetic information has only recently started being incorporated into clinical care. More research and randomized clinical trials need to be conducted to definitively characterize random mutations. Once these mutations are further understood, FAP patients may be able to be risk stratified and this may ultimately improve the screening, diagnosis, and treatment of this rare condition.

Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis

The evolution of colorectal cancer suggests the involvement of many genes. We performed insertional mutagenesis with the Sleeping Beauty (SB) transposon system in mice carrying germline or somatic Apc mutation. Analysis of common insertion sites (CISs) isolated from 446 tumors revealed many hundreds of candidate cancer drivers. Comparison to human datasets suggested that 234 CIS genes are also deregulated in human colorectal cancers. 183 CIS genes are candidate Wnt targets, and 20 are shown to be novel modifiers of canonical Wnt signaling. We also identified gene mutations associated with a subset of tumors containing an expanded number of Paneth cells, a hallmark of deregulated Wnt signaling, and genes associated with more severe dysplasia included members of the FGF signaling cascade. Some 70 genes showed pairwise co-occurrence clustering into 38 sub-networks that may regulate tumor development.

Different phenotypic consequences of simultaneous versus stepwise Apc loss

APC is considered a gatekeeper for colorectal cancer (CRC). Cells with heterozygous APC mutations have altered expression profiles suggesting that the first APC hit may help set the stage for subsequent transformation. Therefore, we measured transformation efficiency following what we have designated as “simultaneous” versus “stepwise” Apc loss. We combined a conditional Apc allele (ApcCKO) with a Cre reporter gene and an out-of-frame Cre allele (Pms2cre) that stochastically becomes functional by a frameshift mutation in single cells. Loss of one Apc allele (ApcCKO/+) had little consequence, whereas simultaneous loss of both Apc alleles (ApcCKO/CKO) resulted in increased clonal expansion (crypt fission), consistent with the gatekeeper function of Apc. Interestingly, our analyses showed that most of the Apc-deficient crypts in ApcCKO/CKO mice appeared normal, with morphologic transformation, including β-catenin deregulation, occurring in only 17% of such crypts. To determine whether transformation efficiency was different following stepwise Apc loss, we combined ApcCKO with a germline mutant allele, either ApcMin or Apc1638N. Transformation efficiency following stepwise Apc loss (ApcMin/CKO or Apc1638N/CKO) was increased 5-fold and essentially all of the Apc-deficient cells were dysplastic. In summary, our data suggest that the gatekeeper function of Apc consists of two roles, clonal expansion and morphologic transformation, because simultaneous Apc loss frequently leads to occult clonal expansion without morphologic transformation, whereas stepwise Apc loss more often results in visible neoplasia. Finally, that Apc-deficient cells in certain scenarios can retain a normal phenotype is unexpected and may have clinical implications for surveillance strategies to prevent CRC.

Coincident APC point mutation and germline rearrangement in an Iranian polyposis family with an unusually severe phenotype

Coincident APC point mutation and germline rearrangement in an Iranian polyposis family with an unusually severe phenotype

Abstract 5564: Lack of efficacy of metformin in several standard prevention models: Methylnitrosourea rat mammary (ER+), MMTV-Neu/p53 mouse mammary (ER−) and the Min mouse colon

Abstract Metformin, an anti-diabetic drug, activates AMP-activated protein kinase (AMPK), and has generated considerable interest as a potential preventive agent for a variety of cancers. This interest is based both on epidemiologic studies showing that diabetics treated with metformin have a lower incidence of a variety of cancers, and on mechanistic considerations arguing that activation of AMPK is likely to be relevant to cancer treatment and prevention. The preventive efficacy of metformin was examined in three commonly employed in rodent prevention models of breast and intestinal cancers. Treatment of female Sprague-Dawley rats at 50 days of age with a single dose of MNU (75 mg/kg BW) resulted in the development of multiple ER+ mammary cancers. This model has been highly responsive to a wide variety of agents or hormonal alterations that affect ER+ tumors in humans (SERMs, aromatase inhibitors, pregnancy, and ovariectomy). Metformin was administered by gavage (7x/week) at either 150 or 50 mg/kg BW/day; beginning seven days after MNU treatment and continuing for the duration of the study. Metformin failed to decrease mammary cancer incidence and, in fact, increased tumor multiplicity in this model by approximately 35%. In addition, the ability of metformin to inhibit mammary cancer in MMTV-Neu/p53 KO mice (which spontaneously develop ER− cancers) was evaluated. In this study, metformin was administered in the diet at a dose level of 1500 mg/kg diet. Initial supplementation of the diet with this agent began when the mice were 60 days of age, and continued for 10 months. This study similarly showed no efficacy of metformin (average tumors/mouse: 2.7 in both controls and metformin-treated mice). Finally the effect of metformin was examined in the Min model of intestinal neoplasia, in which mice have a germline APC mutation. Again, we failed to observe any efficacy of metformin. In contrast, naproxen (a non-specific NSAID) was highly effective in this model when used as a positive control. Thus, these initial studies failed to detect any chemopreventive efficacy of metformin in three commonly employed prevention models. One major caveat to these studies is that the animals were not diabetic nor were they administered an altered diet containing high fat or carbohydrates. Supported by NCI contract number HHSN261200433001C. 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 5564. doi:10.1158/1538-7445.AM2011-5564

Differential Expression of MicroRNAs in Tumors from Chronically Inflamed or Genetic (APCMin/+) Models of Colon Cancer

BackgroundChronic inflammation associated with ulcerative colitis predisposes individuals to increased colon cancer risk. The aim of these studies was to identify microRNAs that are aberrantly regulated during inflammation and may participate in transformation of colonic epithelial cells in the inflammatory setting.Methodology/Principal FindingsWe have use quantitative PCR arrays to compare microRNA (miRNA) expression in tumors and control colonic epithelial cells isolated from distal colons of chronically inflamed mice and APCMin/+ mice. Rank order statistics was utilized to identify differentially regulated miRNAs in tumors that arose due to chronic inflammation and/or to germline APC mutation. Eight high priority miRNAs were identified: miR-215, miR-137, miR-708, miR-31, and miR-135b were differentially expressed in APC tumors and miR-215, miR-133a, miR-467d, miR-218, miR-708, miR-31, and miR-135b in colitis-associated tumors. Four of these (miR-215, miR-708, miR-31, and miR-135b) were common to both tumors types, and dysregulation of these miRNAs was confirmed in an independent sample set. Target prediction and pathway analysis suggests that these microRNAs, in the aggregate, regulate signaling pathways related to MAPK, PI3K, WNT, and TGF-β, all of which are known to be involved in transformation.Conclusions/SignificanceWe conclude that these four miRNAs are dysregulated at some very early stage in transformation of colonic epithelial cells. This response is not dependent on the mechanism of initiation of transformation (inflammation versus germline mutation), suggesting that the miRNAs that we have identified are likely to regulate critical signaling pathways that are central to early events in transformation of colonic epithelial cells.

Identification of 5 novel germline APC mutations and characterization of clinical phenotypes in Japanese patients with classical and attenuated familial adenomatous polyposis

BackgroundFamilial adenomatous polyposis (FAP) is an autosomal dominant hereditary disease characterized by multiple colorectal adenomatous polyps and frequent extracolonic manifestations. An attenuated form of FAP (AFAP) is diagnosed based on a milder colorectal phenotype, and the colorectal phenotype of (A)FAP has been linked to germline APC mutations. The relationships between the spectrum of mutations and extracolonic manifestations are quite well known, but they need to be further defined.FindingsNine germline APC mutations, but no large deletions, were identified in the APC locus of 8 (A)FAP patients, and 5 of the mutations, c.446A > T (p.Asp149Val), c.448A > T (p.Lys150X), c.454_457insAGAA (p.Glu152ArgfsX17), c.497insA (p.Thr166AsnfsX2), and c.1958G > C (p.Arg653Ser), were novel mutations. In one patient the p.Asp149Val mutation and p.Lys150X mutation were detected in the same APC allele. The c.1958G > C mutation was located in the last nucleotide of exon 14, and RT-PCR analysis revealed that the mutation resulted in abnormal splicing. The above findings meant that a nonsense mutation, a frameshift mutation, or an exonic mutation leading to abnormal splicing was found in every patient. The following phenotypes, especially extracolonic manifestations, were observed in our (A)FAP patients: (1) multiple gastroduodenal adenomas and early-onset gastric carcinoma in AFAP patients with an exon 4 mutation; (2) a desmoid tumor in two FAP patients with a germline APC mutation outside the region between codons 1403 and 1578, which was previously reported to be associated with the development of desmoid tumors in FAP patients; (3) multiple myeloma in an AFAP patient with an exon 4 mutation.ConclusionsNine germline APC mutations, 5 of them were novel, were identified in 8 Japanese (A)FAP patients, and some associations between germline APC mutations and extracolonic manifestations were demonstrated. These findings should contribute to establishing relationships between germline APC mutations and the extracolonic manifestations of (A)FAP patients in the future.

Inactivation of theAPCGene Is Constant in Adrenocortical Tumors from Patients with Familial Adenomatous Polyposis but Not Frequent in Sporadic Adrenocortical Cancers

In adrenocortical tumors (ACT), Wnt/β-catenin pathway activation can be explained by β-catenin somatic mutations only in a subset of tumors. ACT is observed in patients with familial adenomatous polyposis (FAP) with germline APC mutations, as well as in patients with Beckwith-Wiedemann syndrome with Wilms' tumors reported to have WTX somatic mutations. Both APC and WTX are involved in Wnt/β-catenin pathway regulation and may play a role in ACT tumorigenesis. The aim of this study was to report if APC and WTX may be associated with FAP-associated and sporadic ACT. ACTs from patients with FAP and sporadic adrenocortical carcinomas (ACC) with abnormal β-catenin localization on immunohistochemistry but no somatic β-catenin mutations were studied. APC was analyzed by denaturing high-performance liquid chromatography followed by direct sequencing and by multiplex ligation-dependent probe amplification when allelic loss was suspected. WTX was studied by direct sequencing. Four ACTs were observed in three patients with FAP and were ACC, adrenocortical adenoma, and bilateral macronodular adrenocortical hyperplasia, all with abnormal β-catenin localization. Biallelic inactivation of APC was strongly suggested by the simultaneous existence of somatic and germline alterations in all ACTs. In the 20 sporadic ACCs, a silent heterozygous somatic mutation as well as a rare heterozygous polymorphism in APC was found. No WTX mutations were observed. ACT should be considered a FAP tumor. Biallelic APC inactivation mediates activation of the Wnt/β-catenin pathway in the ACTs of patients with FAP. In contrast, APC and WTX genetic alterations do not play a significant role in sporadic ACC.

Ashkenazim with APC*I1307K: Why Do Some Carriers Form Colon Neoplasms While Others Do Not?

Purpose: The germline APC*I1307K mutation is a genetic risk factor for the development of colorectal neoplasms in Ashkenazi Jews. We compared risk factors, family history and specific genetic markers of carriers with and without known colorectal lesions in an attempt to understand why certain carriers of the APC*I1307K mutation develop lesions and other carriers do not. Methods: Available information included social history (cigarette, NSAID, and HRT use), family history, colonoscopic findings, and the histologic information about the lesions. Standard PCR based assays were performed on tissue or blood DNA for the germline mutations BLMash, MSH2*1906G>C, CRAC-1, MLH1*D132H and APC genotypes. Results: Nineteen (20.9%) of 91 APC*I1307K carriers did not have a colonic lesion despite one or more colonoscopies. Seventy-two (79.1%) of the 91 carriers had one or more adenomas and/or colorectal cancer based on history and pathology reports. The age of the APC*I1307K carriers with and without lesions at the time of first colonoscopy was 59.6 and 57.6 years, respectively. The average number of colonoscopies at the time of study-entry for patients with and without lesions was 3.1 and 2.2, respectively. Additionally, the average age when the first lesion was found in the group with lesions was 62.1 years. Both groups of patients carried only wild type for the BLMAsh, MSH2*1906G>C, CRAC-1, and MLH1*D132H gene variants, and there were no differences in the genotypes for the APC markers. There was a suggestion that a family history of colorectal neoplasm was more prevalent with those individuals with lesions than those without lesions. This difference did not reach statistical significance; however, the group without the lesions was quite small. Conclusion: It is not fully apparent why some carriers of the APC*I1307K mutation develop colorectal neoplasms and others do not. We have eliminated common risk factors and several other known germline risk mutations as contributory. There is a suggestion, nonetheless, that family history of colorectal lesions is a marker for such development. This, in turn could well be the result of additional unknown germline mutations, although common environmental factors or diet cannot be excluded.Table 1: Family history and risk factors for developing lesions in APC*I1307 K carriers with and without lesions

Aggressive Fibromatosis (Desmoid Tumor) Is Derived from Mesenchymal Progenitor Cells

The cellular origins from which most tumors arise are poorly defined, especially in mesenchymal neoplasms. Aggressive fibromatosis, also known as desmoid tumor, is a locally invasive soft tissue tumor that has mesenchymal characteristics. We found that aggressive fibromatosis tumors express genes and cell surface markers characteristic of mesenchymal stem cells (MSC). In mice that are genetically predisposed to develop aggressive fibromatosis tumors (Apc(wt/1638N)), we found that the number of tumors formed was proportional to the number of MSCs present. Sca-1(-/-) mice, which develop fewer MSCs, were crossed with Apc(wt/1638N) mice. Doubly mutant mice deficient in Sca-1 developed substantially fewer aggressive fibromatosis tumors than wild-type (WT) littermates, but Sca-1 deficiency had no effect on the formation of epithelial-derived intestinal polyps. MSCs isolated from Apc(wt/1638N) mice (or mice expressing a stabilized form of β-catenin) induced aberrant cellular growth reminiscent of aggressive fibromatosis tumors after engraftment to immunocompromised mice, but WT cells and mature fibroblasts from the same animals did not. Taken together, our findings indicate that aggressive fibromatosis is derived from MSCs, and that β-catenin supports tumorigenesis by maintaining mesenchymal progenitor cells in a less differentiated state. Protecting this progenitor cell population might prevent tumor formation in patients harboring a germline APC mutation, where fibromatosis is currently the leading cause of mortality.

Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP

Heterozygous APC germline alteration is responsible for familial adenomatous polyposis, a colon cancer predisposition with almost complete penetrance. Point mutations generally lead to truncated proteins or no protein at all....

Location in the large bowel influences the APC mutations observed in FAP adenomas

The right colon differs from the left, in embryological origin, luminal environment, and function. In both sporadic colorectal cancer and Familial Adenomatous Polyposis (FAP), polyp density and cancer susceptibility vary markedly by colonic site. Adenomas in FAP have a different mutational spectrum in small intestine versus colon. This study aimed to investigate whether colonic location also influences the APC mutation spectrum in FAP. 127 1-2 mm mildly dysplastic adenomas from 5 patients with a codon 1309 germline mutation, and 41 from 3 patients with mutations proximal to codon 1265, were analysed to assess the frequency of loss of heterozygosity (LOH). We chose polyps from different locations in the colon. Immunohistochemistry for beta-catenin, caspase-3 and Ki-67 was performed to assess Wnt pathway activation, apoptosis and proliferation. In polyps from patients with a 1309 mutation, the frequency of LOH showed a gradient from rectum (highest) to caecum/ascending colon (lowest), but this was not present in patients with proximal germline APC mutations. Crypt-by-crypt analysis confirmed the LOH findings from whole polyps. Beta-catenin and caspase-3 expression showed no significant variation by colonic region, but Ki-67 expression decreased from ascending colon to rectum in tumours and normal tissue. Colonic site alters the mutational spectrum of APC, and crypt cell proliferation. The higher frequency of LOH in rectal polyps from patients with codon 1309 mutations may help to explain their increased polyp burden at this site compared with patients who have other germline APC mutations.

Congenital Hypertrophy Retinal Pigment Epithelium as a Manifestation of Colon Cancer

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

Evaluating Lynch syndrome in very early onset colorectal cancer probands without apparent polyposis

To characterize the frequency of germline mutations associated with Lynch syndrome and review the potential expanded differential diagnoses in very early onset colorectal cancer (CRC) cases without apparent polyposis. Retrospectively reviewed medical records of 96 probands with CRC diagnosed prior to age 36 from three cancer centers. Determined the frequency of germline mutations in probands meeting different clinical criteria used to identify Lynch syndrome. Three of 46 (6.5%) single case indicators (probands without additional personal or family history suspicious for Lynch syndrome) were identified to carry a deleterious or suspected deleterious mismatch repair (MMR) mutation compared with 10 of 19 (52.6%) in the cases meeting at least one additional revised Bethesda guideline, and 11 of 15 (73.3%) in the cases meeting Amsterdam criteria. Two families without MMR mutations were documented to have a germline APC or TP53 mutation after additional clinical features were identified. Our results suggest that single cases of CRC (those without additional personal or family history suspicious of Lynch syndrome) diagnosed prior to age 36 infrequently have identifiable MMR mutations, especially when compared to cases meeting additional criteria. Careful attention to evolving or additional clinical features is warranted and may lead to an alternate genetic diagnosis in families with early onset CRC.

Multiple Neoplasia in a 15-year-old Girl With Familial Adenomatous Polyposis

A 15-year-old girl with adenomatous polyposis coli gene (APC) mutation and brain tumor-polyposis syndrome developed an unusual succession of cervicocephalic tumors (medulloblastoma, meningeal low-grade myxoid tumor, and papillary thyroid carcinoma), at the age of 5, 9, and 15 years, respectively. We discuss the genetic profile of the thyroid tumor in which a large somatic deletion of APC gene was found and the physiopathology of thyroid carcinoma in patients with germline APC mutation. We also point out the uncommon phenotype in this young girl with early multiple neoplasias and the difficulties of management of such familial adenomatous polyposis patients with occurrence of extracolonic cancers that require the use of potential trigger agents as radiotherapy or chemotherapy.

Familial adenomatous polyposis

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