Inherited colorectal cancer — Information in the form of tweets
We all learn in different ways. Social media, especially Twitter, is a great place to learn new things. Here’s an example.
Professor Heather Hampel is an expert on hereditary CRC. Prof. Hampel’s Twitter profile is @HHampel1
She has been very creative in giving us bite-sized information about hereditary colorectal cancer all through March 2022. This blogpost is a collection of information adapted from her tweets during #ColorectalCancerAwarenessMonth, compiled with her permission. My notes are highlighted in yellow.
Thank you Prof. Hampel for all your efforts to educate patients & caregivers.
This year, an estimated 151,030 adults in the United States will be diagnosed with colorectal cancer. These numbers include 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer. 💙#ColorectalCancerAwarenessMonth
— Heather Hampel (@HHampel1) March 2, 2022
If you have a parent, sibling or child with colorectal cancer, you are at least 2-3 times more likely to get colorectal cancer yourself. Your risk may be higher if there is a hereditary cancer syndrome – more on that later this month. #ColorectalCancerAwarenessMonth
— Heather Hampel (@HHampel1) March 3, 2022
Overall, the lifetime risk of developing colorectal cancer is: about 1 in 23 (4.3%) for men and 1 in 25 (4.0%) for women. >>That means if your parent, sibling, or child has CRC, your risk lifetime risk is around 8-12%.<< #ColorectalCancerAwarenessMonth https://t.co/n3xV9p1UdL
— Heather Hampel (@HHampel1) March 3, 2022
The ACS recommends that people at average risk of CRC start regular screening at age 45. This can be done either with a test that looks for signs of cancer in a person’s stool, or with an exam that looks at the colon and rectum such as colonoscopy. #ColorectalCancerAwarenessMonth
— Heather Hampel (@HHampel1) March 4, 2022
The @NCCN guidelines recommend that anyone with a parent, sibling, or child with CRC start screening colonoscopy at age 40 or 10 years prior to their relative’s age at diagnosis and repeat it every 5 years.#ColorectalCancerAwarenessMonth
— Heather Hampel (@HHampel1) March 5, 2022
The NCCN CRC screening patient guidelines is a great resource if you want to learn more about screening for colorectal cancer.
— Heather Hampel (@HHampel1) March 6, 2022
15.5% of colorectal cancer patients have a pathogenic variant (mutation) in a cancer susceptibility gene; 3% have Lynch syndrome. https://t.co/RVeZBx7cLm #ColorectalCancerAwarenessMonth pic.twitter.com/Obnr7lUUYM
— Heather Hampel (@HHampel1) March 8, 2022
Lynch syndrome is the most common inherited cause of colorectal and endometrial cancer. It also causes increased risks for gastric, ovarian, small bowel, gastric, hepatobiliary, pancreatic, urothelial, brain and certain skin cancers. #ColorectalCancerAwarenessMonth
— Heather Hampel (@HHampel1) March 9, 2022
It is estimated that 1 in 279 of the general population have Lynch syndrome (MLH1 1 in 1,946, MSH2 1 in 2,841, MSH6 1 in 758, & PMS2 1 in 714). https://t.co/nceRW8z5kP
— Heather Hampel (@HHampel1) March 10, 2022
Lynch syndrome is caused by inherited mutations (pathogenic variants) in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2. It can also be caused by large deletions of the 3’ end of EPCAM which lead to inactivation of MSH2.#ColorectalCancerAwarenessMonth
— Heather Hampel (@HHampel1) March 11, 2022
MSH2
🧬 Pathogenic variants in MSH2 cause #LynchSyndrome
🧬 Lifetime #colorectalcancer risk is 33-52%
🧬 Colonoscopy every 1-2 years begins at age 20-25
🧬 Lifetime #EndometrialCancer risk is 21-57%
🧬 Hysterectomy considered after child-bearing#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 12, 2022
MLH1
🔬Pathogenic variants in MLH1 cause #LynchSyndrome
🔬Lifetime #colorectalcancer risk is 46-61%
🔬Colonoscopy every 1-2 years begins at age 20-25
🔬Lifetime #EndometrialCancer risk is 34-54%
🔬Hysterectomy considered after child-bearing#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 12, 2022
MSH6
⚕️Pathogenic variants in MSH6 cause #LynchSyndrome
⚕️Lifetime #colorectalcancer risk is 10-44%
⚕️Colonoscopy every 1-2 years begins at age 30-35
⚕️Lifetime #EndometrialCancer risk is 16-49%
⚕️Hysterectomy considered after child-bearing#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 13, 2022
PMS2
🏥Pathogenic variants in PMS2 cause #LynchSyndrome
🏥 Lifetime #colorectalcancer risk is 8.7-20%
🏥 Colonoscopy every 1-2 years begins at age 30-35
🏥 Lifetime #EndometrialCancer risk is 13-26%
🏥 Hysterectomy considered after child-bearing#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 14, 2022
🛰16% of colorectal cancers have microsatellite instability.
Of those:
🛰 57% have MLH1 promoter hypermethylation
🛰 26% have Lynch syndrome
🛰 15% have biallelic somatic MMR gene mutations
🛰 2% remain unexplained#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 16, 2022
Mismatch repair status can be assessed by MSI testing (by PCR or NGS) or by IHC staining for the four mismatch repair genes. If any of the MMR proteins are absent in the tumor on IHC, the tumor has defective mismatch repair and is likely MSI-high. #ColorectalCancerAwarenessMonth pic.twitter.com/FrxF8tCvqk
— Heather Hampel (@HHampel1) March 17, 2022
In the image above, you can see what an IHC (immunohistochemistry test) for mismatch repair looks like. The brown dots represent each of the corresponding proteins labeled present in the nucleus of normal cells. In each panel you can see spaces without the brown dots, which show cancer cells that lack each of these proteins.
Concordance between MSI and IHC for the MMR proteins is very high in colorectal cancer. However, MSI fails more often then IHC due to insufficient tumor. #ColorectalCancerAwarenessMonth pic.twitter.com/qsUIxFJMKP
— Heather Hampel (@HHampel1) March 18, 2022
MMR IHC results are concordant between primary colorectal cancers & metastases.
🗣50 CRC with abnormal IHC & metastases identified
🗣IHC performed on the metastatic tumor
🗣100% correlation with IHC result on primary tumor
PMID: 26666765#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 19, 2022
MSI-high cancers produce frameshift peptides. These peptides are the target of the vaccines being developed to prevent cancer development in individuals with Lynch syndrome. #ColorectalCancerAwarenessMonth
— Heather Hampel (@HHampel1) March 19, 2022
Precancerous polyps can also be a sign of an ⬆️ risk for CRC. If you have a parent, sibling, or child with an advanced adenoma (>=1cm, villous features, or high grade dysplasia), you should start colonoscopy at age 40 and repeat it every 5-10y. #ColorectalCancerAwarenessMonth
— Heather Hampel (@HHampel1) March 20, 2022
If you or a close relative has had >=10 precancerous colon polyps (adenomas) or >=2 hamartomatous polyps, you should consider seeing cancer genetics to be evaluated for a hereditary polyposis condition. 🍄#ColorectalCancerAwarenessMonth
— Heather Hampel (@HHampel1) March 22, 2022
There are at least 4 autosomal dominant genes for adenomatous polyposis: APC, POLE, POLD1, & AXIN2. GREM1 is an autosomal dominant gene that can cause hereditary mixed polyposis.#ColorectalCancerAwarenessMonth
— Heather Hampel (@HHampel1) March 22, 2022
On Lynch Syndrome Awareness Day, I always like to take a moment to remember Henry Lynch, the father of cancer genetics, and to be grateful that he brought awareness to Lynch syndrome back when no one believed cancer could be hereditary. #ColorectalCancerAwarenessMonth pic.twitter.com/lSeb4RQIgY
— Heather Hampel (@HHampel1) March 22, 2022
Familial Adenomatous Polyposis (FAP): >100 adenomas
Usually requires colectomy to prevent CRC
Attenuated FAP: 30-100 adenomas
Can sometimes be managed w/frequent colonoscopy
Caused by mutations in the APC gene
25% of APC mutations are de novo #ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 23, 2022
Germline pathogenic variants in the POLE & POLD1 genes cause Polymerase Proofreading-Associated Polyposis (PPAP).
🔒Autosomal dominant
🔒30-100 adenomas
🔒Possible increased risks for brain & endometrial cancers
🔒Ultrahypermutated tumors#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 24, 2022
Individuals with AXIN2 mutations have:
🦷 >30 colorectal adenomas,
🦷 an increased risk for colorectal cancer, and
🦷 oligodontia (at least 6 adult teeth that did not come in at all although this can be variable). #ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 25, 2022
GREM1 pathogenic variants cause Hereditary Mixed Polyposis syndrome
🍄Autosomal dominant
🍄40 kb dup in 5’ regulatory region is an Ashkenazi Jewish founder mutation
🍄A few other dups found in non-Jewish individuals
🍄Multiple polyp types#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 26, 2022
There are at least 5 genes that can cause autosomal recessive adenomatous polyposis (usually 30-100):
👀 MUTYH
👀 MLH3
👀 MSH3
👀 NTHL1
👀 MBD4#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 27, 2022
MUTYH-Associated Polyposis
▪️Biallelic mutations cause ⬆️ risk for adenomas & CRC
▪️Base-excision repair gene
▪️Tumors have mutational signature 36
▪️~1/100 carrier rate in Caucasians
▪️Carriers may have slight ⬆️ risk for CRC#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 28, 2022
NTHL1 is a multi-tumor syndrome that also causes attenuated polyposis.
🎯Autosomal recessive
🎯 ⬆️ risks for colon, breast, brain & other cancers
🎯Tumors have mutation signature 30
🎯Link to nice paper below#ColorectalCancerAwarenessMonth
https://t.co/o5SJUcGQsG pic.twitter.com/p8AL8eaITL— Heather Hampel (@HHampel1) March 29, 2022
MLH3-Associated Polyposis
🗝1st reported in 2019 in 4 individuals with unexplained polyposis
🗝Age of onset of #polyposis was 48-52
🗝Adenomas were MSS
🗝Autosomal recessive
🗝Founder mutation p.Ser1188Ter in Finland
🗝PMID: 30573798#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 31, 2022
MSH3-Associated Polyposis
🧰1st reported in 2016 in 2 families each w/2 affected siblings
🧰Colorectal & duodenal adenomas, colorectal cancer, gastric cancer, & an early-onset astrocytoma
🧰IHC absence of MSH3
🧰Tumors had eMAST
🧰PMID: 27476653#ColorectalCancerAwarenessMonth— Heather Hampel (@HHampel1) March 31, 2022
If you found this useful, don’t forget to follow Prof. Hampel (@HHampel1) on Twitter.
I will be back soon with more information on colorectal cancer. Until then, take care!