Dr'R'Talaie

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(No Transcript)
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COLORECTAL ADENOMAFAMILIAL POLYPOSIS

• Dr.R.Talaie
• Internist
• Gastroenterologist
• Shahid Beheshti medical university

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The adenoma-carcinoma sequence

•  Most human CRCs are thought to arise from
  adenomas (adenomatous polyps) that are dysplastic
  .
• Adenomatous polyps form in the colon when normal
  mechanisms regulating epithelial renewal are
  disrupted.

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Pathogenesis of colorectal cancer
adenoma-carcinoma sequence
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Risk of colon cancer associated with a family
history

• The highest risk is in people with multiple
  first-degree relatives or relatives who have
  developed colorectal cancer at a relatively young
  age.

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FAMILIAL POLYPOSIS

• Among the multiple cancer family syndromes,
  several are known to be associated with the
  development of colon cancer. These disorders may
  be diagnosed during evaluation of the index
  patient or during screening of family members who
  are at risk.
• Hereditary nonpolyposis colorectal cancer (HNPCC)
  
• Familial adenomatous polyposis (FAP)
• Attenuated Familial adenomatous polyposis (AFAP)
  
• MYH associated adenomatous polyposis (MAP)
• Peutz-Jeghers syndrome (PJS)
• Familial juvenile polyposis coli (FJP)

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INTRODUCTION

• Two inherited disorders, which are transmitted in
  an autosomal dominant fashion, are associated
  with the greatest risk of developing colon
  cancer
• familial adenomatous polyposis (FAP) and
• hereditary nonpolyposis colorectal cancer
  (HNPCC),
• which is much more common.
• An autosomal recessive polyposis syndrome, termed
  MYH associated polyposis (MAP), has also been
  described,

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DEFINITIONS 

•  Familial adenomatous polyposis (FAP) and its
  variants Turcot's syndrome (FAP associated with
  brain tumors), Gardner's syndrome (FAP with
  associated extraintestinal manifestations), and
  attenuated familial adenomatous polyposis (AFAP)
  
• autosomal dominant diseases caused by mutations
  in the adenomatous polyposis coli (APC) gene.
• FAP occurs in approximately 1/10,000 to 1/30,000
  live births, and accounts for less than 1 percent
  of the total colon cancer risk in the United
  States . It affects both sexes equally and has a
  worldwide distribution.

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GENETICS 

•  FAP is caused by germline mutations in the
  adenomatosis polyposis coli (APC) gene, which is
  located on chromosome 5q21-q22 .
• More than 800 mutations of the APC gene
  associated FAP have been described, most of which
  lead to frame shifts or premature stop codons,
  resulting in a truncated APC gene product .

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APC Gene Mutations
Nicola et al. Human Molecular Genetics. 2001.
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clinical phenotype

• As a general rule, mutations between codons 169
  to 1393 are associated with the classic form of
  FAP, which is characterized by the development of
  hundreds to thousands of colonic adenomas .
• while mutations that are more 3' or 5' are
  associated with the attenuated form of APC that
  has fewer adenomas.

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APC Mutation Phenotypes
Colored regions mutations / Grey areas
translated regions Nicola et al. Human Molecular
Genetics. 2001107.
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• Mutations between codons 1445 and 1578 have been
  associated with desmoid tumors in some reports ,
  although others have not found this association .
• Mutations downstream from codon 1051 have been
  associated with severe periampullary lesions .
• Mutations in the central part of the APC gene
  (codons 279 to 1309) correlate with the
  development of duodenal polyposis .

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• Almost all of the germ line mutations in APC
  causing FAP are truncating mutations that lead to
  the production of an incomplete APC protein that
  is not fully functional.

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Function of the APC gene product 

• The normal APC protein may prevent the
  accumulation of a cytosolic and nuclear protein
  (beta-catenin) by mediating its phosphorylation
  and resultant degradation.
• In the absence of normal APC function, beta
  catenin can bind to and activate a transcription
  factor (Tcf-4), which may have a role in the
  oncogenic activity due to APC loss.

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The APC gene, and possible pathogenetic
mechanisms in familial adenomatous polyposis

• The APC (adenomatous polyposis coli) gene
  modulates B-catenin, Tcf transcriptional
  activation, and Wnt signal transduction.
• (A) In the presence of wildtype APC or in the
  absence of Wnt ligand, B -catenin is localized to
  the adherens junction where it is associated with
  E-cadherin, B-catenin, p120cas, and indirectly
  with the cytoskeleton. GSK3 phosphorylates
  B-catenin in a complex that contains B-catenin,
  APC, and axin family members, and B-catenin is
  rapidly degraded by ubiquination at the
  proteosome.

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The APC gene, and possible pathogenetic
mechanisms in familial adenomatous polyposis
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• (B) When APC is mutated, B-catenin accumulates in
  the cytoplasm and the nucleus. Similarly, binding
  of Wnt ligand to its receptor, known as frizzled,
  inactivates the GSK3 kinase through dishevelled,
  generating a cytosolic pool of B-catenin.
• B -catenin is associated with members of the Tcf
  family of transcription factors and modulates the
  transcription of target genes with Tcf
  recognition sequences.
• In some instances, B-catenin increases
  transcription of target genes by competing for
  Tcf binding with corepressors, such as Groucho
  and CREB-binding protein (CBP), to relieve
  transcriptional repression.

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• In the majority of patients, the expression of
  the APC mutation involves an inherited mutation
  of one APC allele, with a "second hit" deletion
  of the other allele . However, in some patients,
  the second allele is mutated rather than deleted.
  
• Allelic loss is strongly associated with
  mutations near codon 1300. Inactivating mutations
  of both APC alleles is thought to be sufficient
  to cause the development of colorectal adenomas
  .

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CLINICAL MANIFESTATIONS 

• Polyposis typically develops in the second or
  third decade of life .In one report that combined
  two registries, the mean age was 16 years the
  youngest patient was 8 and the oldest was 34
• Other reports have documented adenomas in
  patients as young as four while microscopic
  adenomatous changes have been detected even
  earlier .

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• Its attenuated form carries a similarly high risk
  but with an older average age of cancer diagnosis
  of 54 years.
• When fully developed, patients with FAP have 100s
  to 1000s of adenomatous colonic polyps.

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FAP

• In addition to colorectal adenocarcinoma,
  patients with FAP are at risk for several
  extracolonic malignancies including
• Duodenal ampullary carcinoma
• Follicular or papillary thyroid cancer
• Childhood hepatoblastoma
• Gastric carcinoma
• CNS tumors (mostly medulloblastomas)

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• Adenomas may also occur rarely in the
  gallbladder, bile duct, and the small bowel,
  particularly the distal ileum, where both
  adenomas and adenocarcinoma can occur
  postoperatively .
• Some patients have congenital hypertrophy of the
  retinal pigment epithelium (CHRPE), the presence
  of which may provide a clue toward the diagnosis.
  
• The sensitivity of CHRPE in patients with known
  FAP was poor (only 40 percent), although
  specificity was 97

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FAP DIAGNOSIS

• The diagnosis of FAP is based upon the presence
  of more than 100 adenomatous colorectal polyps,
  except for patients with attenuated FAP who have
  fewer polyps

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• Endoscopic findings at multiple levels in a
  50-year-old man with familial adenomatous
  polyposis. Multiple polyps of various sizes are
  seen. At colectomy, some of these polyps had
  areas of dysplasia and early malignant
  transformation.

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ATTENUATED FAP

•  An attenuated form of FAP has been recognized.
  It was originally referred to as "attenuated
  adenomatous polyposis" and later renamed
  "attenuated familial adenomatous polyposis .
• Affected patients have fewer than 100 colorectal
  adenomas and a delayed onset of colorectal cancer
  (on average delayed by 12 years) compared to
  those with classic FAP . Attenuated FAP is
  phenotypically and genetically heterogeneous .

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Diagnostic Criteria for AFAP

• Leppert et al suggest a set of diagnostic
  criteria for the disease
• A positive family history of colorectal cancer
  with at least one of the following criteria
• CRC at any age
• gt 5 colorectal adenomas
• 2-4 adenomas and multiple gastric fundic polyps
• Leppert et al. N Engl J Med 1990 3229.
• Later studies suggest a fourth criteria
• Number of colorectal adenomas must be lt 100
• Knudsen et al. Familial Cancer. 2003243-55

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ATTENUATED FAP

• This variant is associated with mutations in
  FAP that are in the more 5' (5' to codon 158) and
  3' (3' to codon 1596) ends of the APC gene
  compared to classic FAP.
• Because of its variable presentation, attenuated
  FAP may be confused with sporadic colorectal
  cancer, Lynch syndrome, MYH associated polyposis
  and possibly other forms of colorectal cancer
  predisposition.

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Attenuated FAP

• Attenuated FAP differs from classical FAP by
  typically having
• fewer colonic adenomas (20 to 100) ,
• later ages of diagnosis of colonic polyps
  (average 40 to 45 years of age) and cancer
  (average about 50 to 60 years of age) .
• There is a frequent involvement of proximal
  colon and an infrequent involvement of rectum.

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• The cumulative colon cancer risk by the age of 80
  is estimated to be 60 to 70 percent with about 75
  percent of tumors occurring in the proximal colon
  .

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• The mutations in APC associated AFAP have mainly
  been detected in three parts of the gene
• in the 5' end (the first five exons),
• in exon 9, and
• in the distal 3' end.
• There have been reports of individuals with AFAP
  mutations that have no adenomas as well as those
  that exceed 100 adenomas.

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• Colonoscopic and endoscopic screening have been
  recommended starting at the age of 20 to 25.
• Patients with colonoscopic findings consistent
  with AFAP may undergo polypectomy when feasible,
  followed by continued yearly surveillance.
• Patients with adenomas too numerous to clear
  endoscopically, or for whom endoscopic
  surveillance is not technically possible, should
  be considered for surgical management.

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• Patients with AFAP develop duodenal adenomas and
  periampullary carcinomas like in classic FAP and
  therefore should be managed for these risks by
  the management guidelines described for classic
  FAP.
• In some AFAP patients, extra-colonic features
  have been reported to be rare, but in other
  instances such as those with hereditary desmoid
  disease there is severe extra-colonic disease .

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• There is no consensus on screening for
  extracolonic features in AFAP and a conservative
  approach would be to manage these individuals as
  for classic FAP until there is a greater
  consensus of the risks

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• The phenotype of attenuated FAP resemble
  classical FAP in some cases but in others is
  difficult to distinguish from sporadic adenomas
  and CRC, underscoring the importance of genetic
  testing in at-risk patients

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An Explanation for Attenuation?

• 5 to codon 175
• Mutation in this region affect the homodimer
  forming domain of the APC gene (amino acids 6-57)
• Interactions between mutated and wild-type
  proteins are reduced
• 3 to codon 1596
• Gene product not detectable by Western blot
  analysis
• Suggests mRNA or protein degradation
• Exon 9
• Even wild-type allele undergoes significant
  physiological splicing in this region
• Alternate splicing pathways may skip over
  mutation

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Genetic Testing for AFAP

• Clinical criteria for AFAP
• Greater than 5 to 10 and less than 100 colorectal
  adenomas
• 2-4 adenomas and multiple gastric fundic polyps
• First-degree relatives of a person with a known
  APC mutation, regardless of polyp status
• A person with multiple adenomas who is a relative
  of a person with a known APC mutation
• Grady. Gastro. 200312415741594

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Role of MYH Testing in AFAP

• At this time, there are insufficient clinical
  data regarding the role of MYH mutations in
  people with adenomatous polyposis to make any
  recommendations regarding the use of MYH mutation
  analysis in the clinical management of these
  individuals.

Grady. Genetic Testing for High-Risk Colon
Cancer Patients. Gastro 200312415741594
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MYH defects and familial CRC

•  A small proportion of patients with multiple
  colorectal adenomas and a family history of CRC
  have germline mutations (often biallelic) in the
  base excision repair gene mutY homolog (MYH),
  sometimes in conjunction with somatic mutations
  in the APC gene .
• These mutations predispose patients to recessive
  inheritance of multiple colonic adenomas, and the
  phenotype of classic adenomatous polyposis,
  frequently referred to as MYH-associated
  polyposis (MAP).

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• In one series of 152 patients with multiple
  adenomas seen at one institution, 7.5 percent of
  those without a germline APC mutation were found
  to have two separate germline MYH mutations.
• These findings have implications for screening
  strategies in patients suspected of having FAP,
  which in most cases is inherited in an autosomal
  dominant pattern .

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• Perhaps more importantly, an increasing number of
  reports suggest that germline mutations in these
  MYH genes may account for a substantial fraction
  of familial colorectal cancers that occur in the
  absence of a dominantly inherited familial
  syndrome .
• MYH mutation carriers were significantly more
  likely to develop CRC, and were more likely to
  have first- or second-degree relatives with CRC.

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MYH Mutation and AFAP

• In a recent study, Wang et al analyzed 984
  patients with high risk for genetic mutation
• 313 patients with 1-3 adenomatous polyps on
  colonoscopy
• 444 patients with history of CRC
• 140 patients referred for probable FAP
• 18 patients with biallelic mutations were
  identified
• 2 patients with colorectal cancer at age gt 51
• 16 patients with 20 - 500 adenomatous polyps
• No patients with polyp counts lt 20 had a
  biallelic MYH mutaition
• Wang et al. Gastro.

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MUTYH ASSOCIATED POLYPOSIS

•   MUTYH associated polyposis is an autosomal
  recessive polyposis syndrome caused by biallelic
  mutations in the MYH gene.
• The highest frequency of biallelic mutations have
  been found in individuals with 15 to 100 adenomas
  but individuals with classic FAP phenotype who
  have biallelic MYH mutations have also been
  reported .

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• Others have found equal representation of MYH
  mutations in those with 10 to 100 polyps and
  those with 100 to 1000 polyps.
• There have even been cases of MYH biallelic
  mutations found in young individuals diagnosed
  with colon cancer (under 50 years old) with no
  polyps detected on colonoscopy .
• Monoallelic carriers did not appear to be at
  increased risk for colorectal cancer.

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• One of the largest studies suggested that the
  presence of more than 15 synchronous colorectal
  adenomas or colorectal cancer diagnosed before
  the age of 50 were the most effective criteria
  for identifying biallelic MYH carriers .

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MAP

• Extracolonic features have also been described
  including gastroduodenal polyps,
• duodenal carcinoma,
• osteomas,
• breast cancer in female
  carriers,
• congenital hypertrophy of the
  retinal pigment
• epithelium (CHERPE),
• dental cysts, and
• Muir Torre phenotype with sebaceous gland
  tumors.
• Breast cancer risk in women with biallelic
  mutations appears to be higher than that of the
  general population

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Screening 

•  There are currently no widely accepted screening
  guidelines for MUTYH associated polyposis.
• Some recommend colonoscopy starting at age 18 for
  biallelic carriers or those that do not choose to
  pursue genetic testing .
• Others recommend both upper and lower endoscopy
  starting at age 25 to 30 years of age.

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Screening 

• Women with biallelic MYH mutations may consider
  high risk breast cancer screening with two annual
  clinical breast examinations in addition to
  annual mammograms and monthly self breast exams.
• As in AFAP surgical therapy should depend up on
  clinical and endoscopic findings rather than on
  mutation analysis.

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Comparison of Hereditary Colorectal Diseases
Adapted from Grady. Gastro. 200312415741594
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HEREDITARY NONPOLYPOSIS COLORECTAL CANCER 

• Hereditary nonpolyposis colorectal cancer
  (HNPCC), also called Lynch syndrome, is an
  autosomal dominant disorder with high penetrance
  of cancer in mutation carriers (approximately 80
  percent).
• Lynch syndrome accounts for 1 to 3 percent of
  all colonic adenocarcinomas . It is caused by
  germline mutations in one of several DNA mismatch
  repair (MMR) genes..

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• Mismatch repair genes  Mismatch repair (MMR)
  genes are responsible for correcting the
  ubiquitous nucleotide base mispairings and small
  insertions or deletions that occur during DNA
  replication.
• Several of these genes exist, including hMSH2
  (human mutS homolog 2), hMLH1 (human mutL homolog
  1), hPMS1 and hPMS2 (human postmeiotic
  segregation 1 and 2), hMSH6 (human mutS homolog
  6), and hMLH3, a mismatch-repair gene that
  interacts with MLH1.

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HNPCC

• Germline mutations in one of the MMR genes appear
  to be the underlying genetic defect in most
  kindreds with hereditary nonpolyposis colorectal
  cancer (HNPCC), and loss of expression of MMR
  genes can also be found in approximately 15
  percent of sporadic colorectal cancers (CRCs) .
• However, sporadic tumors with defective
  expression of MMR genes do not contain MMR gene
  mutations instead, they have epigenetic changes
  that silence gene expression .

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• Cells with MMR deficiency accumulate DNA errors
  throughout the genome . The biologic "footprint"
  of an MMR defect is the accumulation of
  abnormalities in short sequences of nucleotide
  bases (microsatellites ).
• As abnormalities in the microsatellites are
  common
• with MMR deficiency, this phenomenon is
  termed
• microsatellite instability (MSI).

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• Microsatellite instability  
• expansion or contraction of short repeated
  DNA sequences that are caused by the insertion or
  deletion of repeated units.
• MSI has been observed in more than 90 percent of
  tumor tissue from patients with HNPCC .

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• The presence of MSI in tumor tissue suggests that
  a defect in a DNA mismatch repair gene may be
  present but the specificity of MSI for HNPCC is
  low because MSI is also found in up to 15 percent
  of tumors from patients with sporadic colorectal
  cancer .

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• In this latter group, the MSI is typically due to
  methylation of the promoter region of the hMLH1
  gene, an epigenetic mechanism of gene silencing.
  Patients whose tumors demonstrate MSI appear to
  have improved stage-specific survival and may
  derive less benefit from adjuvant 5-FU-based
  chemotherapy, although this is a controversial
  area

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• Epigenetic alterations affecting MMR genes  
  mutations and allelic loss of one of the MMR
  genes are responsible for the MSI phenotype in
  most cases of HNPCC.
• In contrast, methylation of the promoter region
  of some MMR genes and/or loss of imprinting (ie,
  silencing of gene expression) is thought to
  underlie cases of sporadic CRC that display the
  MSI phenotype .

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• Consensus recommendations from panels of experts
  have suggested that analysis for MSI in tumor or
  adenoma tissue can be used as an initial
  screening test in patients suspected of having
  HNPCC (ie, those who fulfill the Bethesda
  guidelines).
• The results of MSI testing are reported as
  "MSI-high, MSI-low, or MSS (microsatellite
  stable) based upon definitions proposed in an
  international guideline .

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THE REVISED BETHESDA GUIDELINES for testing
colorectal tumors for microsatellite instability
(MSI)

• Tumors from individuals should be tested for MSI
  in the following situations
• 1. Colorectal cancer diagnosed in a patient who
  is less than 50 years of age.
• 2. Presence of synchronous, metachronous
  colorectal, or other HNPCC-associated tumors,
  regardless of age.
• 3. Colorectal cancer with the MSI-H-like
  histology diagnosed in a patient who is less than
  60 years of age.
• 4. Colorectal cancer diagnosed in a patient with
  one or more first-degree relatives with an
  HNPCC-related tumor, with one of the cancers
  being diagnosed under age 50 years.
• 5. Colorectal cancer diagnosed in a patient with
  two or more first- or second-degree relatives
  with HNPCC-related tumors, regardless of age.

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Revised Amsterdam criteria by the International
Collaborative Group on HNPCC

• There should be at least three relatives with an
  HNPCC-associated cancer (colorectal cancer,
  cancer of the endometrium, small bowel, ureter,
  or renal pelvis)
• One should be a first degree relative of the
  other two
• At least two successive generations should be
  affected
• At least 1 should be diagnosed before age 50
• Familial adenomatous polyposis should be excluded
  in the colorectal cancer case(s)
• Tumors should be verified by pathological
  examination

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• Evaluation for MMR mutations can be suspended in
  those classified as MSI-low or MSS since a
  germline mutation in MMR is unlikely to be found.

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• If MSI is considered in tumors or adenomas
  classified as being MSI-high,such patients should
  undergo specific testing for mutations of MMR
  genes, which is commercially available.
• If this gene testing is negative, testing for
  other DNA repair genes such as hMSH6 and PMS 2
  can be considered.

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• Many but not all tumors that contain MMR
  mutations can be identified by the presence of
  MSI. Most laboratories use a panel of several
  microsatellite loci when testing for MSI .
• In general, there are two phenotypic variants of
  MSI MSI low (MSI-L), and MSI high (MSI-H),
  depending upon the number of loci in the panel
  that demonstrate instability .
• The majority of patients with HNPCC have MSI-H
  tumors. Most sporadic CRCs with MSI are MSI-L.

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HNPCC

• In contrast to microsatellite-stable CRCs,
  sporadic tumors with MSI have characteristic
  clinicopathologic features.
• They tend to occur in the proximal colon,
  have a greater
• mucinous component, contain lymphocytic
  infiltration, and are
• more often poorly differentiated.
• Although tumors in HNPCC tend to be poorly
  differentiated, the presence of MSI has been
  associated with longer survival in both HNPCC and
  sporadic cases. Why this occurs is not known.

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Genetic counseling

• Informed consent 
•  Prior to genetic testing, practitioners must
  ensure that the patient or guardian has received
  appropriate counseling and has provided written
  informed consent .
• Informed consent should include a general
  description of the test, its purpose, the
  disorder to be tested for, the meaning of
  positive and negative results, and the level of
  certainty that a positive or negative test has as
  a predictor of disease.

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GENETIC TESTING

• Evaluation of individuals at risk for FAP should
  begin by first testing a known affected family
  member to determine if there is a detectable
  mutation.
• If a mutation is found in an affected family
  member, then genetic testing of all relatives at
  risk can provide a true positive or negative
  result.
• If a mutation is not identified in an affected
  family member, testing at-risk relatives is
  useless since the results will be inconclusive.

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• FAP GENETIC TESTING

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GENETIC TESTING

• Other genetic mutations causing such cases are
  continuing to be uncovered.
• One of these is an autosomal recessive syndrome
  due to bi-allelic germ-line mutations in a base
  excision repair gene called mutY homolog (MYH).
• The syndrome is called MYH associated polyposis.
  It produces a clinical phenotype similar to
  attenuated or classic FAP but typically without
  either parent having the syndrome .

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GENETIC TESTING

• Testing for MYH mutations should be offered to
  patients with a family history compatible with
  recessive inheritance who have a phenotype
  similar to those with classic or attenuated FAP,
  particularly those who have 15 or more adenomas
  and those with colorectal cancer occurring at an
  early age .
• When an affected family member is not available
  for evaluation, genetic testing on at-risk family
  members can provide only positive or inconclusive
  results.

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GENETIC TESTING

• Testing for mutations in mismatch repair genes 
•  A number of methods for testing for mismatch
  repair gene abnormalities have been described.
  Commercial testing is available for hMSH2 and
  hMLH1 and testing is available on request for
  hMSH6 and hPMS2.
• The available assays have sensitivities gt95
  percent.

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GENETIC TEST (HNPCC)

• 1. The optimal approach to evaluation is
  microsatellite instability (MSI) or
  immunohistochemical (IHC) analysis of tumors,
  followed by germline MSH2/MLH1 testing in
  patients with MSI-H tumors or tumors with a loss
  of expression of one of the mismatch repair
  genes.
• 2. After the mutation is identified, at-risk
  relatives should be referred for genetic
  counseling and tested if they wish.
• 3. An alternative approach, if tissue testing is
  not feasible, is to proceed directly to germline
  analysis of the MSH2/MLH1 genes.

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• 4. If no mismatch repair gene mutation is found
  in a proband with an MSI-H tumor and/or clinical
  history of hereditary nonpolyposis colorectal
  cancer (HNPCC), the genetic test result is
  non-informative.
• The patients and the at-risk individuals (ie,
  relatives) should be counseled as if HNPCC was
  confirmed and high-risk surveillance should be
  undertaken.

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• For families with a strong suspicion of HNPCC,
• germline testing should be considered, even
  when the MSI/IHC results indicate MSI-L,
  microsatellite stable, or normal expression.
• The likelihood of finding a germline mutation
  in the MLH1/MSH2 genes of patients with
  colorectal cancer tumors that are not MSI-H is
  expected to be low

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Management 

•  Once colonic polyposis is established in a gene
  carrier or an at-risk member of an FAP family, a
  full colonoscopy should be performed to evaluate
  the extent of the colonic polyposis.
• An initial upper endoscopic exam should also be
  performed and a consultation should be arranged
  to discuss the timing of a colectomy.
• The number, size, and worst histology of the
  colonic adenomas determine the optimal timing of
  colectomy.

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MANAGEMENT

• Colectomy at the time of initial diagnosis is
  strongly recommended in patients with multiple
  large (gt1 cm) adenomas or adenomas with villous
  histology and/or high-grade dysplasia and is the
  safest approach of all those with profuse
  polyposis at initial diagnosis.

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MANAGEMENT

• Patients in the second decade of life with only
  sparse, small (lt5 mm) adenomas can usually be
  followed endoscopically with surgery scheduled to
  accommodate school and work schedules.

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• The preferred operation in children is a total
  proctocolectomy with ileoanal anastomosis.
• A subtotal colectomy with ongoing surveillance
  or a total colectomy is reasonable in patients
  with attenuated adenomatous polyposis who have
  little rectal involvement.

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• The risk of colon adenocarcinoma in classic FAP
  approaches 100 percent by age 45.
• Colonoscopy is not effective for identifying
  polyps with advanced pathology or in detecting
  early cancers, because the presence of multiple
  polyps precludes adequate sampling.

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