Editing Lynch syndrome

== Background ==
* Also known as hereditary nonpolyposis colorectal carcinoma (HNPCC)

* Lynch syndrome preferred term since most patients will develop one or several adenomatous polyps

== Pathogenesis ==
*'''<span style="color:#ff0000">Caused by inactivation of 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
* '''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]

== 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.
** '''<span style="color:#ff0000">Associated malignancies (11):</span>'''
**#'''<span style="color:#ff0000">Colorectal (20-80%) (most common)</span>'''
**#'''<span style="color:#ff0000">Gynecologic</span>'''
**##'''<span style="color:#ff0000">Endometrial (15-60%) in females (second most common)</span>'''
**##'''<span style="color:#ff0000">Ovarian cancer (1-38%) in females</span>'''
**#'''<span style="color:#ff0000">Urologic</span>'''
**##'''<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">Other gastrointestinal</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 ==

* Recommended screening[https://pubmed.ncbi.nlm.nih.gov/25043945/]
** 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 ==

* [https://pubmed.ncbi.nlm.nih.gov/25043945/ 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.
* [https://pubmed.ncbi.nlm.nih.gov/30231390/ Yurgelun, Matthew B., and Heather Hampel. "Recent advances in lynch syndrome: diagnosis, treatment, and cancer prevention." ''American Society of Clinical Oncology Educational Book'' 38 (2018): 101-109.]