Familial Adenomatous Polyposis and Turcot and Peutz–Jeghers Syndromes




© Springer International Publishing Switzerland 2016
Debra G.B. Leonard (ed.)Molecular Pathology in Clinical Practice10.1007/978-3-319-19674-9_23


23. Familial Adenomatous Polyposis and Turcot and Peutz–Jeghers Syndromes



Kandelaria M. Rumilla 


(1)
Department of Laboratory Medicine and Pathology, Laboratory Genetics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

 



 

Kandelaria M. Rumilla



Abstract

To date the majority of colorectal cancers are thought to be sporadic. However, familial predisposition has been well recognized for years. Familial adenomatous polyposis coli, Turcot syndrome, Gardner syndrome, and Peutz–Jeghers syndrome are examples of hereditary syndromes that predispose individuals to colorectal adenocarcinoma as well as a host of other malignant, hamartomatous, and benign growths. While not comprehensive of all familial colorectal predisposition syndromes, a summary of these syndromes is provided in this chapter.


Keywords
Familial adenomatous polyposis coliFAP APC Turcot syndromeGardner syndromeAttenuated polyposisDesmoid tumorsEpidermoid cystDuodenal adenocarcinomaPapillary thyroid carcinomaCNS tumorsHepatoblastomaCHRPEPeutz-Jeghers syndrome STK11 Juvenile polyposisIntussusceptionPeutz-Jeghers polypsMucocutaneous pigmentation


To date the majority of colorectal cancer are thought to be sporadic. However, familial predisposition has been well recognized for years. Familial adenomatous polyposis coli, Turcot syndrome, Gardner syndrome, and Peutz–Jeghers syndrome are examples of hereditary syndromes that predispose individuals to colorectal adenocarcinoma as well as a host of other malignant, hamartomatous, and benign growths. While not comprehensive of all familial colorectal predisposition syndromes, a summary of these syndromes is provided in this chapter.


Familial Adenomatous Polyposis Coli


Familial adenomatous polyposis coli (FAP) is estimated to account for approximately 1 % of colorectal adenocarcinoma in the general population. The reported incidence ranges from 1 in 7,500 [1] to 1 in 30,000 [2] and the penetrance is approximately 100 % by age 40 [3]. Early references to this autosomal dominant disorder date back to the 1880s. By 1960, the association with epidermoid cysts, osteomas [4], and central nervous system tumors had been described [5]. The disease is caused by constitutional mutations in the adenomatous polyposis coli (APC ) gene identified in 1991 [6]. Variants of FAP also are described and include attenuated FAP (AFAP), Gardner syndrome, and Turcot syndrome.


Clinical Features



Familial Adenomatous Polyposis Coli


While the diagnostic criteria for FAP rests primarily in the number of adenomatous polyps that are identified in the distal colorectum at an early age (>100 colorectal adenomatous polyps), the true impact of this syndrome is seen in the risk for colorectal cancer and other neoplasms. If untreated, virtually 100 % of affected individuals will develop colorectal adenocarcinoma. The average age of diagnosis is 39 years in the classic presentation. The risk for malignant neoplasm is not limited to the colorectum. Individuals with this syndrome are also at increased risk of other malignancies compared to the general population. Adenocarcinomas from other gastrointestinal primary sites (small intestine, including duodenum and periampullary) occur in 4–12 % of patients, while pancreatic adenocarcinoma and papillary thyroid carcinoma (PTC) occur in approximately 2 % of FAP patients. Although this is a small percent of FAP patients, both pancreatic adenocarcinoma and PTC are much less common in the general population; there is 0.2 % incidence of PTC in the general population [7]. FAP is associated with a specific histologic subtype of PTC, the cribriform-morular variant [8], but is not pathognomonic [9]. Gastric adenocarcinoma and medulloblastoma [10] occur in less than 1 % of FAP patients, while hepatoblastoma occurs in approximately 1 of 150 FAP patients under the age of 5. Other malignant tumors arising from the bile duct or adrenal gland are associated with FAP, but are infrequent.

The clinical diagnosis rests on the identification of numerous pre-cancerous adenomatous polyps. Colonic adenomatous polyps can be identified in affected patients at young ages; polyps are present in 50 % of affected individuals by age 16 years, and in 95 % by age 35. Adenomatous polyps can be seen in the stomach of approximately 10 % of patients. Adenomatous polyps of the duodenum and ampulla of Vater can present as intussusception and obstructive pancreatitis, respectively.

Desmoid tumors (proliferation of myofibroblasts) occur in 3.5–32 % of FAP patients. Although most common after surgery, desmoid tumors may occur in the absence of prior surgery and are the presenting symptom in approximately 16 % of FAP patients. Characteristic features, such as abdominal location, may help distinguish FAP-associated and non-FAP-associated desmoid tumors. Gender does not correlate between FAP and non-FAP cases as women have more desmoids than men in both the FAP and non-FAP groups [11].

Hamartomatous and benign lesions seen in FAP include gastric fundic gland polyps (50 % of FAP cases), lipomas, fibromas, sebaceous, and epidermoid cysts [12], osteomas usually affecting the long bones, mandible, or skull, nasal angiofibromas, dental abnormalities ranging from unerupted teeth to absent or supernumerary teeth (17 % of FAP cases). Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a benign finding which does not affect visual acuity but can be the presenting finding.


Attenuated Familial Adenomatous Polyposis Coli


AFAP is an important clinical phenotypic variant of FAP. AFAP has fewer polyps (from 30 to 100 polyps) which are located more proximal in the colon, and has a later age of onset [13]. The AFAP phenotype can overlap with other syndromes, including MYH-associated polyposis and Lynch syndrome (Hereditary Non-polyposis Colon Cancer, HNPCC). Several criteria have been proposed for clinical diagnosis of AFAP, with most including a lower number of polyps present at slightly older ages with family history, polyposis, or cancer. One example is less than 100 polys by 25 years and an autosomal dominant family history [14]. Most of these proposals do not include mutation status of the APC gene, exclusion of other predisposing syndromes, or consideration of other noncolonic manifestations, which likely limits the sensitivity of such diagnostic criteria in clinical practice.


Gardner Syndrome


Gardner syndrome is a clinical diagnosis that includes colorectal adenocarcinoma and colorectal polyposis as seen with FAP plus osteomas, fibromas, or epidermoid cysts within the individual or family.


Turcot Syndrome


Widely recognized as a subset of FAP and Lynch syndrome, Turcot syndrome is defined by the combination of primary colonic neoplasms with synchronous or metachronous malignant central nervous system tumors. As originally described, Turcot syndrome overlaps both FAP and DNA mismatch repair (MMR) defective tumor syndromes with APC gene mutations identified in approximately two-thirds of affected individuals. The type of cancer to which patients are predisposed depends in part on the affected gene. For example, the risk of medulloblastoma with an APC gene mutation is 92 times greater than for the general population, but the lifetime risk remains low (less than 1 %). APC mutations also are associated with astrocytomas and ependymomas. Individuals with mutations in a MMR gene (e.g., MLH1, MSH2, PMS2) are predisposed to glioblastoma.


Prevention and Surveillance



Familial Adenomatous Polyposis Coli


Prevention and surveillance target the detection of malignant and premalignant lesions characteristic of FAP. Evaluation of patients 18 years or younger identified that 68 % were already symptomatic, which led to the recommendation that colonoscopy screening begin at age 10 years [15]. Controversy remains regarding the use and frequency of some screening tests, such as for hepatoblastoma (alpha-fetoprotein and hepatic ultrasound). The mainstay of screening remains colonoscopy every 1–2 years prior to colectomy. Screening methods also continue to evolve; for example, more recent work done in screening for PTC suggests that ultrasound is more effective than palpation [7]. Other gastrointestinal manifestations also require screening, including esophagogastroduodenoscopy (EGD) for small bowel disease starting at about age 25 years, although the age to start and frequency of screening is not clear. Flexible sigmoidoscopy may be sufficient for initial diagnosis, but insufficient for surveillance in carriers who have not undergone colectomy. For prophylactic colectomy, the extent of resection also is debated [16]. For those who have not had molecular testing or do not have an identified mutation such that the diagnosis is based on clinical diagnosis alone, and first-degree relatives, the recommendation is to have regular colon/sigmoidoscopy from 10 years of age until multiple polyps are found or the patient reaches age 50 years, and then to follow routine population-based colon cancer screening recommendations [17].

As surveillance and prophylactic methods result in longer survival for affected individuals, such that other lesions (including nonmalignant lesions) are becoming more significant as their impact on morbidity and mortality grows. Most notably, 5–20 % of FAP patients who develop desmoid tumors, which can cause compression or obstruction, have significant morbidity or mortality [18]. Fortunately, nonsurgical options are available for treating desmoid tumors, including hormonal therapy, embolization, and chemotherapy, since surgery can trigger the growth of desmoids [19].


Attenuated Familial Adenomatous Polyposis Coli


Surveillance recommendations are similar to FAP with modifications for the lesser severity and later onset of the disease. AFAP surveillance includes colonoscopy every 2–3 years starting at age 18–20 years of age, and EGD by 25 years of age and every 1–3 years depending on extent of small bowel disease observed.


Gardner Syndrome


Appropriate surveillance is similar to FAP for gastrointestinal disease. Recommendations to address other manifestations of Gardner syndrome are less specific, but include physical examinations. Some patients come to clinical attention for cosmetic reasons related to superficial fibromas, or epidermoid cysts.


Turcot Syndrome


Appropriate surveillance is similar to FAP or HNPCC with additional screening and awareness of the increased risk for CNS tumors.


Genetics



Familial Adenomatous Polyposis Coli


Mutations located in the APC gene located at 5q21 cause FAP [6]. APC encodes a 2,843-amino acid protein, 75 % of which is encoded by the last exon historically numbered exon 15. Approximately 20 % of families with a clinical diagnosis do not have an identifiable mutation using current testing methods. Several possible explanations for this include mutations in regions of the gene not typically tested (introns for example); mutation in a different gene; and de novo mutations that are not represented in the bone marrow. One-third of affected individuals are thought to have a de novo mutation, and may have a more variable phenotype, lack a significant family history, and testing from peripheral blood may be negative or mosaic depending on the sensitivity of the method used for analysis. Genetic counseling is important due to the limitations of testing, and the medical implications of genetic testing. In general, genetic testing is considered standard of care [20]. Additionally, the fact that FAP includes childhood onset of tumors with recommendations for surveillance procedures to begin at 10–12 years of age, genetic screening prior to the age of 18 is medically and ethically supported.


Attenuated Familial Adenomatous Polyposis Coli


Less than 30 % of individuals with AFAP have a germline mutation identified in APC [21]. One likely reason for this lower detection rate is the greater degree of overlap in the phenotypic spectrum with other predisposing syndromes, including MUTYH-associated adenomatous polyposis syndrome.


Gardner Syndrome


Gardner syndrome is caused by mutations in the APC gene, as described above for FAP.


Turcot Syndrome


Turcot syndrome can be caused by APC mutations, but also may be caused by mutations in MMR genes. In addition, several different inheritance patterns have been reported, including autosomal dominant, autosomal recessive, and compound heterozygous changes involving APC and the MMR genes. Of Turcot syndrome families, 66–80 % have an identifiable mutation in APC and 20–33 % have a mutation in one of the MMR genes.


Molecular Mechanism



Familial Adenomatous Polyposis Coli/Attenuated Familial Adenomatous Polyposis Coli


APC functions as a classic tumor suppressor with a role in signal transduction and modulation of transcription factors, which in turn regulate a number of cellular processes including cell division and cell adhesion. The normal APC protein product interacts with a number of components of the Wnt signaling pathway. APC regulates cytoplasmic beta-catenin levels by ubiquitination and degradation, thereby reducing the beta-catenin available to localize to the nucleus and resulting in reduced activation of genes involved in promoting cell proliferation, including MYC and cyclin D1 (CCND1). Therefore, loss of APC function results in increased levels of beta-catenin by reducing its degradation rate and increased cell proliferation. The increased beta-catenin expression can be seen in the cytoplasm and nucleus by immunohistochemistry. This APC loss of function mechanism for FAP is consistent with the finding that the majority of germline mutations are truncating mutations or result in decreased expression of APC [24].


Genotype–Phenotype Correlation



Familial Adenomatous Polyposis Coli


Although genotype–phenotype correlations involving the locations of mutations in APC can be made, variation of the phenotype can be seen between and within families. While some correlations are useful clinically to focus screening procedures, the associations are not definitive. In classic FAP cases, the FAP phenotype is usually clear, but by young adulthood a spectrum that ranges from florid polyposis to a few adenomatous polyps can be seen [22, 23].

Nomenclature of the APC gene located on 5q21 can be confusing as there are multiple transcripts with varying numbers of exons. The more common transcript has 15 translated exons that produce a 2,843 amino acid protein [22]. The protein has a number of functional domains including binding sites for beta-catenin, DNA, axin, and microtubules, as well as a nuclear export motif. Two “hot spot” germline mutations occur at codons 1061 and 1309 which together represent approximately 28 % of FAP [17, 24]. Two other important variants in the APC gene are p.I1307K and p.E1317Q. Testing for p.I1307K in the Ashkenazi Jewish population has been controversial. The APC p.I1307K mutation increases the lifetime risk of colorectal carcinoma to 10–20 %, with an odds ratio of 1.85. The p.I1307K mutation is found in approximately 6 % of the Ashkenazi Jewish population but has been reported in up to 28 % of patients with a family history of colorectal cancer. It is important to note that this mutation is not sufficient to cause a polyposis phenotype and does not alter clinical management of carriers, as many carriers would already be undergoing increased screening due to their family history. Since p.I1307K does not result in a nonfunctional protein, the theorized mechanism by which this mutation results in increased cancer risk is different than typical FAP. The p.I1307K change is thought to create a hypermutable site in APC which leads to loss of protein function mutations [25]. Whether or not the p.E1317Q variant confers an increased risk of colorectal carcinoma is not as well established, and the clinical significance remains debatable.

The classic FAP phenotype is associated with mutations involving codons 168–1600, while severe expression of the disease based on number of polyps is associated with mutations in codons 1350–1464. Other associated lesions have also been correlated with the location of the mutation in the APC gene, including extra colonic manifestations such as CHRPE which has been associated with mutations in codons 1403–1578 and codons 463 and 1387. Osteomas and desmoids appear to have the highest association with mutations in codons 1395 and 1560. In general, mutations at either end of the APC gene, before codon 400 and after codon 1500, and whole gene deletions, have been associated with the attenuated phenotype and have more variable expressivity [24, 26]. Somatic mutations also are common in APC but the location of these mutations is more restricted, with about 80 % occurring between codons 1284 and 1580, a region designated as the mutation cluster region [24].


Attenuated Familial Adenomatous Polyposis Coli


AFAP is associated with mutations in different regions of the gene, including: (1) 5′ to codon 157 in exon 4; (2) alternative splice in exon 9; (3) 3′ to codon 1595 in exon 15; and (4) some in-frame deletions [27].


Gardner Syndrome


Desmoid tumors are more strongly associated with APC mutations between codons 1444 and 1580 than with mutations either 5′ or 3′ of this region [28].


Turcot Syndrome


Although APC mutations between codons 457–1309 have been associated with brain tumors [23], specific genotype–phenotype correlations within the APC gene are not widely used. Importantly, medulloblastomas are associated with APC mutations and glioblastomas are associated with MMR gene mutations (Lynch syndrome).


Clinical Testing and Laboratory Issues


The methods used for clinical testing of the APC gene have changed over the years with direct germline sequencing of the entire coding region becoming more common than targeted testing for specific mutations. Unlike screening assays, sequencing can detect changes in the coding region, flanking sequences and intron/exon boundaries, and can identify novel mutations. Depending on the sequencing method and platform used, there are various pitfalls including inability to detect large deletions and duplications and the interpretation of novel nontruncating alterations that are likely to be classified as variants of unknown significance (VUS). While Sanger sequencing is still commonly used for testing this is being quickly replaced by next-generation sequencing (NGS) and will likely continue to gain momentum as bioinformatics improves and larger insertions/deletions (indels) and copy number variants can be detected by NGS. Large deletion/duplication analysis is routinely performed using multiplex ligation dependent probe amplification assays (MLPA) or array comparative genomic hybridization (aCGH) technologies.

The protein truncation test (PTT) is a screening method that is still used in some clinical laboratories for several reasons. PTT allows for higher throughput mutation screening for the large last exon of APC where many mutations are located. Since PTT detects truncated protein products, the underlying mutations are almost certainly deleterious. PTT does have drawbacks, however. For example, missense alterations that have an effect on protein function will likely not be detected, and several gene regions will not be well covered in terms of mutation detection, including alterations outside of the coding regions and mutations that are located at the 5′ or 3′ ends of the segments. Additionally, follow-up sequencing is required to identify the exact sequence change detected by PTT.

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Oct 29, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Familial Adenomatous Polyposis and Turcot and Peutz–Jeghers Syndromes

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