Lynch syndrome: Difference between revisions
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== Pathogenesis == | == Pathogenesis == | ||
*Caused by inactivation of one of several DNA mismatch repair (MMR) | *'''Caused by inactivation of one of several DNA genes responsible for mismatch repair (MMR)''' | ||
** MMR genes (4): | ** MMR genes (4): | ||
***MLH1 | ***MLH1 | ||
| Line 11: | Line 11: | ||
***MSH6 | ***MSH6 | ||
***PMS2 | ***PMS2 | ||
*** Mutations in MLH1 and MSH2 account for up to 90% of LS cases | **** '''Mutations in MLH1 and MSH2 account for up to 90% of LS cases''' | ||
* Autosomal dominant | *****Alterations affecting the normal function of these genes results in an accumulation of DNA errors and increases the potential for cancer development | ||
* '''Autosomal dominant''' | |||
** NCI definition: autosomal dominant inheritance is a way a genetic trait or condition can be passed down from parent to child. One copy of a mutated (changed) gene from one parent can cause the genetic condition. A child who has a parent with the mutated gene has a 50% chance of inheriting that mutated gene.[https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/autosomal-dominant-inheritance] | ** NCI definition: autosomal dominant inheritance is a way a genetic trait or condition can be passed down from parent to child. One copy of a mutated (changed) gene from one parent can cause the genetic condition. A child who has a parent with the mutated gene has a 50% chance of inheriting that mutated gene.[https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/autosomal-dominant-inheritance] | ||
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** LS cancers form only after a second hit (by one of several genetic damage mechanisms) occurs within somatic tissue, which causes loss of function to the normal (wild-type) allele inherited from the unaffected parent | ** LS cancers form only after a second hit (by one of several genetic damage mechanisms) occurs within somatic tissue, which causes loss of function to the normal (wild-type) allele inherited from the unaffected parent | ||
*** This results in total loss of DNA MMR activity in that cell and subsequent microsatellite instability. | *** This results in total loss of DNA MMR activity in that cell and subsequent microsatellite instability. | ||
** Associated malignancies: | ** '''<span style="color:#ff0000">Associated malignancies (11):</span>''' | ||
** | **#'''<span style="color:#ff0000">Colorectal (20-80%) (most common)</span>''' | ||
** | **#'''<span style="color:#ff0000">Endometrial (15-60%) in females (second most common)</span>''' | ||
*** Urologic ( | **#'''<span style="color:#ff0000">Ovarian cancer (1-38%) in females</span>''' | ||
*** | **#'''<span style="color:#ff0000">Urologic</span>''' | ||
*** Inconsistent: Pancreas, | **##'''<span style="color:#ff0000">Urothelial (1-18%), includes upper urinary tract and bladder</span>''' | ||
**##'''<span style="color:#ff0000">Prostate</span>''' | |||
**##'''<span style="color:#ff0000">Adrenal[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739861/ §]</span>''' | |||
**#'''<span style="color:#ff0000">Gastric cancers (1-13%)</span>''' | |||
**#'''<span style="color:#ff0000">Hepatobiliary</span>''' | |||
**#'''<span style="color:#ff0000">Small bowel</span>''' | |||
**#'''<span style="color:#ff0000">Skin</span>''' | |||
**#*Sebaceous adenoma, sebaceous epithelioma, sebaceous adenocarcinoma, keratoacanthoma, and squamous cell carcinoma[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423888/] | |||
**#'''<span style="color:#ff0000">Brain</span>''' | |||
**#Inconsistent: Pancreas, breast, (prostate) | |||
== Diagnosis and Evaluation == | |||
*Clinical criteria: Amsterdam II criteria, Revised Bethesda Guidelines | |||
*Models | |||
*Tumour testing: microsatellite instability, immunohistochemistry | |||
== Screening == | == Screening == | ||
Revision as of 06:46, 16 March 2024
Background
- Also known as hereditary nonpolyposis colorectal carcinoma (HNPCC)
- Lynch syndrome preferred term since most patients will develop one or several adenomatous polyps
Pathogenesis
- Caused by inactivation of one of several DNA genes responsible for mismatch repair (MMR)
- MMR genes (4):
- MLH1
- MSH2
- MSH6
- PMS2
- Mutations in MLH1 and MSH2 account for up to 90% of LS cases
- Alterations affecting the normal function of these genes results in an accumulation of DNA errors and increases the potential for cancer development
- Mutations in MLH1 and MSH2 account for up to 90% of LS cases
- MMR genes (4):
- Autosomal dominant
- NCI definition: autosomal dominant inheritance is a way a genetic trait or condition can be passed down from parent to child. One copy of a mutated (changed) gene from one parent can cause the genetic condition. A child who has a parent with the mutated gene has a 50% chance of inheriting that mutated gene.[1]
Phenotype
- Increased risk of cancer
- LS cancers form only after a second hit (by one of several genetic damage mechanisms) occurs within somatic tissue, which causes loss of function to the normal (wild-type) allele inherited from the unaffected parent
- This results in total loss of DNA MMR activity in that cell and subsequent microsatellite instability.
- Associated malignancies (11):
- Colorectal (20-80%) (most common)
- Endometrial (15-60%) in females (second most common)
- Ovarian cancer (1-38%) in females
- Urologic
- Urothelial (1-18%), includes upper urinary tract and bladder
- Prostate
- Adrenal§
- Gastric cancers (1-13%)
- Hepatobiliary
- Small bowel
- Skin
- Sebaceous adenoma, sebaceous epithelioma, sebaceous adenocarcinoma, keratoacanthoma, and squamous cell carcinoma[2]
- Brain
- Inconsistent: Pancreas, breast, (prostate)
- LS cancers form only after a second hit (by one of several genetic damage mechanisms) occurs within somatic tissue, which causes loss of function to the normal (wild-type) allele inherited from the unaffected parent
Diagnosis and Evaluation
- Clinical criteria: Amsterdam II criteria, Revised Bethesda Guidelines
- Models
- Tumour testing: microsatellite instability, immunohistochemistry
Screening
- Recommended screening[3]
- Colonoscopy
- Pelvic exam with endometrial sampling
- Transvaginal ultrasound (ovarian)
- Esophagogastroduodenoscopy with biopsy of the gastric antrum
- Urinalysis
- Limited data to support urinary screening
- Routine screening of the prostate and breast cancer is not recommended beyond what is advised for the general population
References
Giardiello, Francis M., et al. "Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer." Gastroenterology 147.2 (2014): 502-526.