Editing Lynch syndrome


Most common form of hereditary colon cancer


Previously also called hereditary non-polyposis colorectal cancer (HNPCC) - however this is a misnomer, because patients can develop many non-CRC cancers

* Some say HNPCC can be applied to patients who have not yet had a specific germline mutation identified

== '''Genetics''' ==

* Autosomal dominant
* Mutation in one of the DNA mismatch repair genes (''MLH1, MSH2, MSH6, PMS2, EpCAM'')
** Lynch syndrome CRCs are characterised by microsatellite instability - ubiquitous mutations at simple repetitive sequences (microsatellites) are found in the tumour DNA
** Also, they demonstrate loss of expression of MMR protein
** MLH1 chromosome 3, MSH 2 chromosome 2, MSH6 chromosome 2, PMS2 chromosome 7, epCAM chromosome 2
* These MSI regions can be tested for, since >90% of cancers in Lynch syndrome patients have them, and diagnose Lynch syndrome that way
* If ''BRAF'' mutations are present, probably not Lynch syndrome

== '''When to suspect''' ==

* Amsterdam II criteria below, or:
* Synchronous or metachronous CRC
* CRC or endometrial cancer <50yo
* Multiple Lynch-associated cancers
* Familial clustering of Lynch-associated cancers
* dMMR CRC

== '''Diagnosis''' ==

* Either germline sequencing of MMR genes, or identified to be high-risk via prediction tools
* MMRpredict tool (<nowiki>https://webapps.igc.ed.ac.uk/world/research/hnpccpredict/</nowiki>) performs better than either of the below tools (sp 91%; se 94%)
* Amsterdam II criteria (to identify individuals at risk of carrying the mutation)
** '''THREE''' or more relatives on the same side of the family with HNPCC-associated cancers (CRC, endometrial, small bowel, ureter, renal pelvis)
*** Plus all of the following
** '''TWO''' or more generations involved with HNPCC-associated cancers
** '''ONE''' or more cancers diagnosed before age 50
** FAP must be excluded and invasive cancer must be confirmed in the patient too.
* Revised Bethesda criteria for identifying which tumours should be tested for MSI
** Specificity 77%; sensitivity 82%
** Relevance declined significantly since universal IHC screening for dMMR was implemented
** betHESDA
*** H istopathological characteristics of an MSI-unstable cancer
*** E xtra HNPCC cancers - metachronous or synchronous
*** S ingle person in the family with CRC or uterine cancer diagnosed <50yo
*** D ouble (two or more) first-degree relatives with an HNPCC-associated cancer
*** A ge - diagnosed CRC <50yo in this patient
*

== '''Risks''' ==

* CRC
** Accounts for 3-5% of all CRC, and 10-19% of CRC diagnosed before age 50
** Lifetime CRC risk 70% for men and 40% for women
** Mean age of diagnosis 44-61yo
** Predilection for right-sided cancers, but other sites are also common
** If first cancer treated by segmentectomy, 16% risk of a second cancer at 10 years, 41% at 20 years, and 62% at 30 years
** Don't develop as many adenomas as FAP (usually <3 by 50yo), but these adenomas do tend to progress to cancer faster than normal
** Single-agent 5-FU is less beneficial for Lynch cancers, so FOLFOX should be used instead. 
*** As of 2025 immunotherapy and FOLFOX/FOLFIRINOX have not been directly compared, but the NEJM trial in 2024 showed pathological major response of 95% when used as neoadjuvant therapy
** Immunotherapy with an immune checkpoint inhibitor targeting PD-1 pathway is effective (and also true for many other Lynch cancers). Often use nivolumab/ipilimumab.
* Gastric cancer
* Endometrial adenocarcinoma
** Lifetime risk 32-45%
* Ovarian
* Small bowel
* Urinary tract
* Brain
* Pancreas - 8x increased risk
* Prostate cancer risk could be up to 30%, although lack of evidence
* Sebaceous adenomas/carcinomas of skin
** Seen in Muir-Torre variant of Lynch syndrome
* Muir-Torre Syndrome - Lynch-associated colon, genitourinary and skin cancers

== '''Screening''' ==

* Colonoscopy every 1-2 years, beginning at 25yo for MLH1/MSH2 or 35yo for MSH6/PMS2 (or earlier if there is earlier family history of CRC)
** Persons at risk: first-degree relatives of known MMR gene mutation carriers who have not had genetic testing
** Known Lynch syndrome - in this case, annual colonoscopy is preferred
* No gynae screening, but early referral if symptoms develop
* Gastroscopy with biopsy of antrum at 30yo, with subsequent surveillance every 2 years considered based on individual patient risk factors
* No annual urinalysis
* No prostate cancer surveillance

== '''Medical''' ==

* Recommend 100mg aspirin daily after starting colonoscopy screening to reduce risk of CRC

== '''Surgery''' ==

* If no previous cancer and endoscopically normal, no need for prophylactic colectomy
** However, patients who have a segmental colectomy for cancer have a 22% chance of having another cancer, and so it may be reasonable to opt for a subtotal colectomy and ileorectal anastomosis
** If having rectal cancer treated, it should be treated based on standard principles, with consideration of completion colectomy
* Hysterectomy and bilateral salpingo-oophorectomy at 40yo or after child-bearing complete (at 50yo in PMS2)

[[Category:Oncology]]