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Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is the most common inherited colorectal cancer syndrome. It is characterized by early-onset colorectal cancer, usually right-sided, and increased risk for various extracolonic malignancies—especially of the endometrium, ovaries, and upper urinary tract.
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https://www.youtube.com/watch?v=YGZmPdKxU90
Genetic basis:
https://doi.org/10.1007/s11912-021-01085-z
http://dx.doi.org/10.3748/wjg.v21.i31.9253
https://doi.org/10.1016/j.critrevonc.2021.103338
https://doi.org/10.3390/jcm9061954
https://doi.org/10.3390/genes13122326
| Feature | Details |
|---|---|
| Genes involved | DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS2, and EPCAM (deletion upstream of MSH2) |
| Mutation effect | Loss of MMR → microsatellite instability (MSI) |
| Inheritance | Autosomal dominant |
| Penetrance | High, but variable by gene and cancer type |
![Nonpolyposis colorectal cancer (CRC) [25,26,27]. Abbreviations are as follows: HNPCC—hereditary nonpolyposis colorectal cancer; IHC—immunohistochemistry; LLS—Lynch-like syndrome; LS—Lynch syndrome; MMR—mismatch repair; MSI—microsatellite instability.
Hryhorowicz S, Kaczmarek-Ryś M, Lis-Tanaś E, Porowski J, Szuman M, Grot N, Kryszczyńska A, Paszkowski J, Banasiewicz T, Pławski A. Strong Hereditary Predispositions to Colorectal Cancer. Genes. 2022; 13(12):2326. https://doi.org/10.3390/genes13122326](attachment:c0b777e1-e737-4c1b-bcd6-2374d770e37f:genes-13-02326-g002.png)
Nonpolyposis colorectal cancer (CRC) [25,26,27]. Abbreviations are as follows: HNPCC—hereditary nonpolyposis colorectal cancer; IHC—immunohistochemistry; LLS—Lynch-like syndrome; LS—Lynch syndrome; MMR—mismatch repair; MSI—microsatellite instability.
Hryhorowicz S, Kaczmarek-Ryś M, Lis-Tanaś E, Porowski J, Szuman M, Grot N, Kryszczyńska A, Paszkowski J, Banasiewicz T, Pławski A. Strong Hereditary Predispositions to Colorectal Cancer. Genes. 2022; 13(12):2326. https://doi.org/10.3390/genes13122326
Schematic representation of colorectal cancer predisposing syndromes, causal genes, and affected molecular pathways. Genes shaded in grey correspond to the most promising proposed candidate genes. Abbreviations: BER, base excision repair; DSB, double strand breaks; meth, promoter hypermethylation; MMR, DNA mismatch repair; SAC, spindle assembly checkpoint.
Terradas M, Capellá G, Valle L. Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes. Journal of Clinical Medicine. 2020; 9(6):1954. https://doi.org/10.3390/jcm9061954
| Domain | Manifestations |
|---|---|
| Colorectal cancer | Often right-sided, early onset (<50 yrs), multiple primaries |
| Endometrial cancer | Common in women with Lynch; may precede CRC |
| Other cancers | Ovarian, gastric, small bowel, ureter/renal pelvis, hepatobiliary, brain (glioblastoma – Turcot variant), and skin (Muir–Torre syndrome) |
Examples of Colorectal Tumors Arising in FAP and HNPCC Patients The left panel is a small portion of the colon from an FAP patient as viewed through the colonoscope, illustrating the multiple benign tumors (adenomas) characteristic of FAP (arrows). The right panel shows a single cancer from an HNPCC patient after surgical resection.
Kinzler KW, Vogelstein B. Lessons from Hereditary Colorectal Cancer. Cell. 1996;87(2):159-170. doi:https://doi.org/10.1016/s0092-8674(00)81333-1
Associated syndromes:
| Syndrome | Distinct Features |
|---|---|
| ‣ | Lynch syndrome + sebaceous skin tumors (adenomas, carcinomas, keratoacanthomas) |
| ‣ (Lynch variant) | Lynch + glioblastoma multiforme (MMR gene mutations) |