Hereditary and familial colorectal cancer Pathophysiology

Jump to navigation Jump to search

Genetics

Associated conditions

Approximately 5% of all the cases are associated with highly penetrant inherited mutations.

Lynch syndrome:

  • Endometrial cancer is the most common extra-colonic malignancy associated with this syndrome. (Lynch syndrome causes approximately 2% of all endometrial cancers)[1]
  • Other cancers associated with Lynch syndrome: gastric, ovarian, hepatobiliary tract, upper urinary tract, small bowel, brain (glioblastoma) and pancreatic [2] [3].
  • Other: keratoacanthomas, sebaceous adenomas/carcinomas.


Familial adenomatous polyposis (FAP)

  • Polyps of the Upper gastrointestinal tract.
    • Gastric fundic gland polyps: found in approximately 50% of individuals,and can be profuse [4]
    • Adenomatous polyps in the stomach: usually located in the antrum, less common than fundic gland polyps.
    • Dysplastic changes in fundic gland polyps: common, no concern unless dysplasia is severe[5]
    • Adenomatous polyps in the duodenum: found in approximately 50% of individuals, commonly found in the second and third portions of duodenum. (Duodenal cancer is the second most common malignancy in FAP or attenuated FAP [6].
  • Additional cancers: colon, duodenum, periampullary, stomach, thyroid, hepatoblastoma, medulloblastoma.
  • Other: osteomas (skull and mandible), congenital hypertrophy of the retinal pigment epithelium (CHRPE), epidermoid cysts, fibromas, dental abnormalities, and desmoids [7].


MUTYH-associated polyposis

  • Gastric and duodenal polyps (11% and 17% of patients)
  • Duodenal cancer
  • Other: ovarian, bladder, skin, sebaceous gland tumors and possibly breast cancer.


Hamartomatous polyposis conditions:

  • Peutz-Jeghers syndrome (PJS)
    • Cancer: Breast, colon, pancreas, stomach, ovary, lung, small bowel, uterine, cervix, testicle.
    • Other: mucocutaneous pigmentation, gastrointestinal hamartomatous polyps.
  • Juvenile polyposis syndrome (JPS)
    • Cancer: colon, stomach, pancreas, small bowel.
    • Other: gastrointestinal hamartomatous (juvenile) polyps, HHT, congenital defects.


Hyperplastic polyposis (HPP)

  • Cancer: colon
  • Other:Hyperplastic polyps, sessile serrated polyps, traditional serrated adenomas and mixed adenomas.


References

  1. ↑ Hampel H, Frankel W, Panescu J; et al. (2006). "Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients". Cancer Res. 66 (15): 7810–7. doi:10.1158/0008-5472.CAN-06-1114. PMID 16885385. Unknown parameter |month= ignored (help)
  2. ↑ Rustgi AK (2007). "The genetics of hereditary colon cancer". Genes Dev. 21 (20): 2525–38. doi:10.1101/gad.1593107. PMID 17938238. Unknown parameter |month= ignored (help)
  3. ↑ Kastrinos F, Mukherjee B, Tayob N; et al. (2009). "Risk of pancreatic cancer in families with Lynch syndrome". JAMA. 302 (16): 1790–5. doi:10.1001/jama.2009.1529. PMID 19861671. Unknown parameter |month= ignored (help)
  4. ↑ Burt RW (2003). "Gastric fundic gland polyps". Gastroenterology. 125 (5): 1462–9. PMID 14598262. Unknown parameter |month= ignored (help)
  5. ↑ Bianchi LK, Burke CA, Bennett AE, Lopez R, Hasson H, Church JM (2008). "Fundic gland polyp dysplasia is common in familial adenomatous polyposis". Clin. Gastroenterol. Hepatol. 6 (2): 180–5. doi:10.1016/j.cgh.2007.11.018. PMID 18237868. Unknown parameter |month= ignored (help)
  6. ↑ Bülow S, Björk J, Christensen IJ; et al. (2004). "Duodenal adenomatosis in familial adenomatous polyposis". Gut. 53 (3): 381–6. PMC 1773976. PMID 14960520. Unknown parameter |month= ignored (help)
  7. ↑ Speake D, Evans DG, Lalloo F, Scott NA, Hill J (2007). "Desmoid tumours in patients with familial adenomatous polyposis and desmoid region adenomatous polyposis coli mutations". Br J Surg. 94 (8): 1009–13. doi:10.1002/bjs.5633. PMID 17410559. Unknown parameter |month= ignored (help)

Template:WH Template:WS

Gross Pathology

Microscopic Pathology

Genetics

  • Lynch syndrome

Germline mutation in a class of genes involved in DNA MMR, including: hMSH2, hMLH1, hMSH6, and hPMS2.

DNA MMR: necessary to maintain genomic stability by correcting single-base mistmatches and insertion-deletion loops that form during DNA replication.

Mutations in hMSH2 and hMLH1: 90% of Lynch syndrome cases

Mutations in hMSH6: 10% of Lynch syndrome cases

Mutations in hPMS2: rare [1] [2].

Other: germline deletions in the EpCAM (epithelial cell adhesion molecule) gene, also known as TACSTD1 [3] 19098912.



  • Familial adenomatous polyposis (FAP): FAP and attenuated FAP

Germline mutations in APC.

APC encodes a tumor suppressor that is part of the WNT signaling pathway.

APC mutations (New or de novo): 25% of FAP cases.

Somatic mosaicism: 20% of individuals with an apparent de novo APC mutation[4].



  • MUTYH-associated polyposis

MUTYH gene product: part of the base-excision repair pathway, involved in defending against oxidative DNA damage. (Helps to prevent G:C to T:A transversions caused by oxidative stress to highly mutagenic DNA bases). Genetic testing for MAP is warranted in individuals with greater than 10 colorectal adenomas but without an identifiable mutation in APC. Siblings of individuals with biallelic MUTYH mutations have a 25% chance of having MAP.



  • Hamartomatous polyposis conditions:

Peutz-Jeghers syndrome (PJS) Germline mutations in STK11 (LKB1) Disease-associated mutations: 70% of patients [5].


Juvenile polyposis syndrome (JPS) Mutations: SMAD4 or BMPR1A. Disease-associated mutations: 40% of patients.



  • Hyperplastic polyposis (HPP)

Mutations: BRAF mutations Methylation of CpG islands Familial cases of HPP have been reported [6], but are rare. The reported family frequency varies from 0 to 63% [7]. Evidence supporting inheritance of HPP is weak.


References

  1. ↑ Rustgi AK (2007). "The genetics of hereditary colon cancer". Genes Dev. 21 (20): 2525–38. doi:10.1101/gad.1593107. PMID 17938238. Unknown parameter |month= ignored (help)
  2. ↑ Peltomäki P, Vasen H (2004). "Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database". Dis. Markers. 20 (4–5): 269–76. PMID 15528792.
  3. ↑ Kovacs ME, Papp J, Szentirmay Z, Otto S, Olah E (2009). "Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome". Hum. Mutat. 30 (2): 197–203. doi:10.1002/humu.20942. PMID 19177550. Unknown parameter |month= ignored (help)
  4. ↑ Hes FJ, Nielsen M, Bik EC; et al. (2008). "Somatic APC mosaicism: an underestimated cause of polyposis coli". Gut. 57 (1): 71–6. doi:10.1136/gut.2006.117796. PMID 17604324. Unknown parameter |month= ignored (help)
  5. ↑ Volikos E, Robinson J, Aittomäki K; et al. (2006). "LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome". J. Med. Genet. 43 (5): e18. doi:10.1136/jmg.2005.039875. PMC 2564523. PMID 16648371. Unknown parameter |month= ignored (help)
  6. ↑ Yeoman A, Young J, Arnold J, Jass J, Parry S (2007). "Hyperplastic polyposis in the New Zealand population: a condition associated with increased colorectal cancer risk and European ancestry". N. Z. Med. J. 120 (1266): U2827. PMID 18264196.
  7. ↑ Chow E, Lipton L, Lynch E; et al. (2006). "Hyperplastic polyposis syndrome: phenotypic presentations and the role of MBD4 and MYH". Gastroenterology. 131 (1): 30–9. doi:10.1053/j.gastro.2006.03.046. PMID 16831587. Unknown parameter |month= ignored (help)

Template:WH Template:WS

References

Template:WH Template:WS

Retrieved from "https://www.wikidoc.org/index.php?title=Hereditary_and_familial_colorectal_cancer_Pathophysiology&oldid=860944"