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Οικογενής Πολυποδίαση : Γενετική και Screening

‘Υγεία’ Σεμινάριο Λαπαροσκοπικών Κολεκτομών. Οικογενής Πολυποδίαση : Γενετική και Screening. Νικόλαος Γ. Τσουκαλάς MD,MSc,PhD Παθολόγος-Ογκολόγος Ογκολογική Κλινική 401 ΓΣΝΑ Αθήνα 2 7 Σεπτεμβρίου 2013. Causes of Hereditary Susceptibility to CRC. Sporadic (65 %– 85%).

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Οικογενής Πολυποδίαση : Γενετική και Screening

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  1. ‘Υγεία’ Σεμινάριο Λαπαροσκοπικών Κολεκτομών Οικογενής Πολυποδίαση: Γενετική και Screening Νικόλαος Γ. Τσουκαλάς MD,MSc,PhD Παθολόγος-Ογκολόγος Ογκολογική Κλινική 401 ΓΣΝΑ Αθήνα 27 Σεπτεμβρίου 2013

  2. Causes of Hereditary Susceptibility to CRC Sporadic (65%–85%) Familial (10%–30%) Rare CRC syndromes (<0.1%) Hereditary nonpolyposis colorectal cancer (HNPCC) (5%) Familial adenomatous polyposis (FAP) (1%) Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996

  3. Familial Adenomatous Polyposis (FAP) • Familial adenomatous polyposis (FAP) is a genetic disease where affected individuals will develop hundreds to thousands of polypsthroughout their gastrointestinal (GI) tract beginning at a young age (usually as a teenager or young adult).

  4. Familial Adenomatous Polyposis (FAP) • These polyps are usually found in the large intestine (colon and rectum), but they can develop in the stomach and small intestine as well. • In the large intestine are known as adenomasand are considered to be precancerous. • Individuals with FAP may also develop other features outside of the gastrointestinal tract.

  5. Familial Adenomatous Polyposis (FAP) • Attenuated FAP (AFAP) is a milder form of FAP. • 5’ and 3’ APC gene mutations • 6% of FAP pedigrees • Oligopolyposis (<100 adenomas), R-sided • Heterogeneous phenotype • Later development of CRC (51 vs 39 y.o.)

  6. What causes FAP? • FAP is caused by an inheritedmutation in the Adenomatous Polyposis Coli (APC) gene. Located in chromosome 5q 21. • Autosomal dominant disease. • Tumor suppressor gene. • 300 different mutations identified. • APC protein - cell adhesion, signal transduction and transcription activation.

  7. What causes FAP? • Most of the time, FAP is passed on to a child from the parent who has the condition. • In about one-third (33%) of all cases, people develop FAP even though their parents do not have FAP. When this occurs, it is due to a new gene alteration, or mutation, and it occurs by chance.

  8. What are my chances of inheriting FAP? • If a parent has FAP, each child has a 50% (or, 1 in 2) chance of inheriting FAP. • FAP does not skip generations. • Both males and females are equally likely to be affected.

  9. Martin’s family Martin Suzanne 36 d. 34yrs (colectomy @ 25) Jamie 12 Sophie 9 Alex 5 Who is at risk?

  10. Martin’s family Martin Suzanne 36 d. 34yrs (colectomy @ 25) Jamie Sophie Alex 12 9 5 Who is at risk?

  11. What are the signs and symptoms of polyps? • Are rare with the early development of polyps. However, as polyps grow, multiply, and become cancerous over time, the following may occur: • • Bright red blood in the stool • • Thin stools • • Diarrhea and/or constipation that cannot be explained by diet or illness • • Abdominal pain, cramping, or bloating • • Continued weight loss • • Continued lack of energy • • Anemia

  12. Are there other signs or features of FAP? • Individuals with FAP and AFAP may develop polyps in other parts of the GI tract. • Almost all individuals with FAPwill develop polyps in the stomach called fundic gland polyps. The chance that a fundic gland polyp will develop into stomach cancer is very low.

  13. Are there other signs or features of FAP? • Individuals with FAPcan develop polyps in the small intestine, particularly in the duodenum. Sometimes the polyps can occur on the ampulla of Vater. • These polyps are called adenomas and are considered to be precancerous because they have a small chance (about 4-12%) to develop into cancer.

  14. Clinical Course of FAP Puberty - polyps appear 15 y.o. - average age onset of polyps 33 y.o. - symptoms appear 36 y.o. - average age of diagnosis 39 y.o. - average age of colorectal cancer diagnosis 42 y.o. - death from colorectal cancer

  15. Are there other signs or features of FAP? • People with FAP may have other signs of FAP. These include lumps or bumps on the skull and jaw (osteomas); cysts on the skin (epidermoid cysts); dental changes (extra teeth); non-cancerous tumors most often found in the abdomen (desmoid tumors); and freckle-like spots on the inside of the eye (CHRPE). • Previously, individuals with FAP who had these other features were considered to have Gardner’s syndrome.

  16. Are there other signs or features of FAP? • Individuals with FAP do have an increased chance of developing certain other cancers. These include thyroid cancer, brain cancer (medulloblastoma), and liver cancer in children (hepatoblastoma). • However, most of these cancers are rare even in FAP and most people with FAP will not develop them.

  17. How is FAP diagnosed? • Diagnostic tests includeflexible sigmoidoscopy, colonoscopy and genetic testing. • If a parent has FAP or AFAP, it is not safe to wait for symptoms to occur in his/her children before having them checked for FAP by a doctor.

  18. How is FAP diagnosed? • Individuals with a family history of FAP should begin annual colon evaluation at 10-12 years of age. • People with a family history of AFAP should begin colon evaluation by 18 years of age, or earlier based on family history.

  19. How is FAP diagnosed? • Genetic testingcan be used to help diagnose FAP. A small blood sample is takenand is sent to a special laboratory that studies the APC gene. • Genetic testing is useful in confirming a diagnosis of FAP in those rare cases where there is some doubt about the diagnosis. • Once an individual is confirmed to have an APC gene mutation, genetic testing can help identify whether or not family members have FAP.

  20. How is FAP diagnosed? • Genetic testing is recommended beginning at 10-12 years of age in families with FAP, which is also the age when screening for FAP should start. • In families with AFAP, genetic testing is recommended beginning at 18 years of age, or earlier based on family history, which is also the age when screening for AFAP should start. • It is necessary and helpful to meet with a genetic counselor to talk about genetic testing.

  21. Indications for APC Gene Testing • Molecular diagnosis of FAP in patients who present with: • polyposis (>100 adenomas) • attenuated FAP • Predictive testing for FAP in blood relatives of persons with FAP or known APC mutations Giardiello FM et al. N Engl J Med, 336:823, 1997

  22. How is FAP diagnosed? • A flexible sigmoidoscopy is an examination of the rectum and the lower colon. • A colonoscopy is an examination of the large intestine (colon and rectum).

  23. Why is early diagnosis important? • Early diagnosis of FAP is important for early detection and prevention of cancer. • People who are diagnosed with FAP are at high risk for developing colon cancer.

  24. How is FAP managed? • Surveillance • Surgery

  25. Surveillance (Colon Polyps and Colorectal Cancer) • A surveillance examination at regular intervals is very important. Beginning at age 10-12 years a flexible sigmoidoscopy is recommended every year for individuals with FAP. • Once colon polyps are found, or by age 20-25 years, colonoscopyshould be completed every year. • Individuals with AFAP are recommended to undergo a colonoscopy beginning at age 18 years, or earlier based on family history, and repeated every year.

  26. Surveillance (Upper Intestinal Polyps and Cancer ) • Surveillance of the upper GI tract is also very important for people with FAP or AFAP. • Upper GI endoscopy exam should be performed every 1-3 years for monitoring of fundic gland (stomach) polyps and duodenal adenomas. • Most individuals are recommended to start having upper GI endoscopy at age 20-25 years, or just prior to colorectal surgery.

  27. Additional Surveillance for FAP • • Annual complete physical exam to monitor for extra-intestinal features of FAP. • • Annual thyroid examination. • • Some families may also consider screening of young children, from birth to age 5 years, forhepatoblastomawhich includes annual physical exam and/or abdominal ultrasound exam and measurement of AFP. • • An abdominal ultrasound or CT scan is recommended prior to abdominal surgery to evaluate for desmoid tumors.

  28. Surgery • Since individuals with FAP develop too many precancerous colon polyps to remove them one by one, colon surgery is recommended to help prevent the development of cancer. • The timing of surgery can vary among family members who have FAP or AFAP. • The choice of procedure depends on various factors including, but not limited to: the number of rectal polyps, presence or absence of colorectal cancer, age of the patient, history of desmoids tumors, and patient preference.

  29. Surgery • Colectomy with Ileorectostomy (Ileorectal Anastomasis) • Restorative Proctocolectomy (Ileal Pouch Anal Anastomosis) • Total Proctocolectomy With Ileostomy

  30. After Surgery • After the first surgery for FAP, the following check-ups are recommended: • • Complete physical exam yearly. • • Flexible sigmoidoscopy: − Every 6-12 monthsfor a patient whose rectum has not been removed for the first few years. If the rectum remains relatively free of polyps, patients may be recommended to come back every 1-2 years. − Every 1-2 yearsfor patients with an ileoanal pouch, and patients whose polyps do not return.

  31. After Surgery • • Ileostomy surveillance: • − Every 1-3 yearsfor patients with an ileostomy. It is important that the stomabe looked at closely. • • Upper endoscopy (EGD) with side-viewing scope every 1-3 years.

  32. Familial Adenomatous Polyposis • Autosomal dominant disease • Mutation of APC gene • Hundreds of adenomas in colorectum • Presence/absence extracolonic lesions • Colorectal cancer inevitable

  33. Risk of Colorectal Cancer (CRC) 5% General population Personal history of colorectal neoplasia 15%–20% Inflammatory bowel disease 15%–40% 70%–80% HNPCC mutation >95% FAP 0 20 40 60 80 100 Lifetime risk (%)

  34. ΕΥΧΑΡΙΣΤΩ

  35. Are there other ways of treating FAP? • After surgery, polyps can occur in the remaining portion of the rectum. To treat these polyps, patients will have regular endoscopic examinations of the rectum or the ileal pouch and may receive a prescription for medications that will help reduce the risk of polyps returning. • These anti-inflammatory medications, or nonsteroidal anti-inflammatory drugs (NSAIDs), include Sulindac (Clinoril) or Celecoxib (Celebrex). • However, treatment with these medications will not replace endoscopy or surgery if it is needed.

  36. Μοντέλο της πολυσταδιακής φύσης της ανάπτυξης κληρονομικής αδενωματώδους πολυποδίασης (FAP), μιας μορφής καρκίνου του παχέος εντέρου. Διακρίνονται τα κρίσιμα γονίδια που μεταλλάσσονται σε κάθε στάδιο.

  37. Let’s put this together to form a picture of normal colon biology and how it is perturbed by APC mutations As cells migrate Away from the crypt, they differentiate Cells that receive them Become stem cells Stromal cells send Wnt signals

  38. Surveillance for FAP Annual sigmoidoscopies from age 10 to 12. Colonoscopies once polyps detected. Surveillance of remaining gut following colectomy. http://www.nice.org.uk/nicemedia/pdf/CSGCCfullguidance.pdf Is there an alternative? Genetic testing

  39. Screening • At-risk persons (1st degree relatives) • Sigmoidoscopy q yr. starting age 12, then q 2 yrs after age 25, then q 3 yrs after age 35, then average risk guidelines after age 50

  40. APC Gene Test Result • Positive - FAP- sigmoidoscopy yearly • Negative - No FAP- sigmoidoscopy age 25

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