hereditary colorectal cancer

What are the risk factors for CRC?

Age-> avg. dx 72y

Phx adenomas or CRC

High-fat, low-fiber diet

Inflammatory bowel disease

Fhx CRC

What % of CRC is hereditary? what are breakdowns according to genes/syndromes?

5-10% of CRC is hereditary. 32% is familial

Lynch syndrome 3-5% of all CRC

FAP 1% of all CRC

MAP 1% of all CRC

Rare syndromes (Peutz-Jeghers syndrome, juvenile polyposis syndrome, etc.) 4% of all CRC

What is the risk for CRC based on:

general population

Phx of CRC

inflammatory bowel dz

Lynch syndrome

FAP?

What is the risk for CRC based on:

general population- 4% or 1/25

Phx of CRC- 15-20%

inflammatory bowel dz 15-40%

Lynch syndrome: depends on gene, can be 10-80%

FAP: classic is >95% and attenuated is 80%

What are the three types of polyps?

Adenoma:

- 70% of polyps and most common

- precancerous polyp takes roughly 5 years to become cancer (1-3yrs if lynch) and chance of malignancy depends on subtype but ranges 2-35%

Hyperplastic:

- normal cells but organized mass in wrong place

- very rarely malignant BUT EXCEPTION FOR sessile serrated adenoma

Hamartoma:

- normal cells in disorganized mass

- low likelihood of malignancy but can reflect malignancy somewhere else in body

- juvenile polyp and Peutz-Jegher polyps

95% of colonic polyps are hyperplastic or adenomatous

How common are polyps? how often does CRC arise from polyps? likelihood of malignancy?

- by 50y 1/4 ppl have at least one polyp

- 95% of CRC comes from polyps

- only 5-10% polyps become malignant

What does Non-polyposis means? what percentage of CRC is it? what are genes associated with it?

category that is not characterized by excessive polyps, but they can still have polyps

3-6% of all CRC

Lynch aka HNPCC hereditary nonpolyposis colorectal cancer(MLH1, MSH2, MSH6, PMS2, EPCAM

What does polyposis means? what percentage of CRC is it? what are genes/conditions associated with it?

category characterized by excess polyps

roughly 6% of all CRC

Subsections:

Adenomatous polyposis

-> FAP/AFAP (APC genes)

-> MAP (MUTYH gene)

-> Polymerase Proofreading-Associated Polyposis syndrome (POLE/POLD gene)

Hamartomatous polyposis

-> Juvenile polyposis (BMPR1A and ENG gene)

-> Peutz-Jeghers (STK11 gene)

-> Cowden syndrome (PTEN gene)

What is the rate of Lynch syndrome?

1/500

Lynch syndrome: how of CRC and uterine cancer does it account for? What is the lifetime cancer risk- for male or women?

roughly 3% CRC and 2-5% of uterine cancer

Lifetime cancer: 90% in men, 70% in women

What extra-colonic tumors are present in Lynch and what are the chances?

Colon: 10-60%

Uterine 13-57%

Ovarian 4-24%

Stomach 6-13%

Urinary tract: 1-4%

Pancreas 1-6%

Small bowel 3-6%

Bile ducts 1-4%

special note: these syndromes were named before genetic causes identified

- sebaceous skin tumors 1-9% + CRC is Muir-Torre syndrome. largely known to be MSH2 mutations

- brain tumors, usually gliomas/glioblastomas 1-3% +CRC is Turcot syndrome.

What genetic mutations are in Lynch? What amount do they contribute to Lynch? What's the name of the category?

Mismatch repair genes (MMR):

MLH1 and MSH2: 35-80% of Lynch and high penetrant

MSH6: 12-35% of Lynch and low penetrant

PMS2: 5-15% of Lynch and low penetrant

Mut type

-> Sequence variants, deletion, rearrangements, and promotor methylation (which is rare)

->MSH2 has Boland inversion which is Inversion of exons 1-7 . AD inheritance reported and not detected by sequencing

EPCAM (not MMR gene) deletions can methylate MSH2 which causes LOF: <10%. EPCAM is at 3' end of MSH2

What is the percentage of CRC for Lynch based on mutation type? think also avg dx age.

MLH1: 46-61%, avg dx 44y

MSH2/EPCAM: 33-52%, avg dx 44y

MSH6: 10-44%, avg dx 42-69y

PMS2: 9-10%, avg dx 61-66y

whats the typical CRC histology for lynch? where are they often located?

2/3 cases are right sided tumors

Histology: signet ring or cribiform, mucinous, tumor-infiltrating lymphocytes, poor differentiation

What is the percentage of endometrial cancer for Lynch based on mutation type? think also avg dx age.

MLH1: 34-54%, avg dx 49y

MSH2/EPCAM: 21-57%, avg dx 48y

MSH6: 16-49%, avg dx 54y

PMS2: 13-26%, avg dx 50y

What is important to note for endometrial vs uterine cancer in Lynch?

Tend to use uterine and endometrial as interchangable BUT endometrial is a type of uterine cancer.

What often presents first in women with Lynch? CRC or endometrial cancer?

many women have endometrial cancer before CRC

What type of tumor testing is appropriate for endometrial tumors? is there a significance for this?

IHC and MSI are appropriate, not validated for other Lynch-related tumors (beside CRC)

Give specifics for the other cancer types in Lynch. for ex. small bowel cancer but located where?

Ovarian: mean dx age 42, roughly 30% are dx <35yrs. WHICH IS EARLY ONSET COMPARED TO BRCA

Stomach: mean dx 56y, often intestinal-type adenocarcinoma but 20% can be diffuse

Urinary tract: transitional carcinomas of ureter and renal pelvis. also for bladder cancer

Pancreas: mildly elevated, largely MLH1 up to 6%

Small bowel: jejunum and duodenum most commonly, 50% are in reach of upper endoscopy, majority adenocarcinomas

Skin: Sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratocanthomas

CNS: most common Glioblastoma

What is constitutional mismatch repair deficiency (CMMRD)? what are the most common cancers?

Biallelic MMR mutations

Cancers:

CNS tumors most common

Colon or small bowel cancer often prior to teenage years, >10 polyps is common

Blood cancers

Cafe-au-lait macules typically >6y and can have other manifestations of NF like freckling

What are the problems with CMMRD diagnosing?

May be mistaken for NF1 due to cafe-au-lait macules or freckling

Often lack of fhx suggestive of Lynch on either side

-> studies show up to 85% absent fhx

-> mutations are low penetrant so decreases fhx sx

CMMRD mutations are not commonly reported. and lots of provider misinformation

What type of testing is used for Lynch?

tumor testing:

- MSI +/- IHC

-> tumor tissue polyps are less likely to yield abnormal results

-> polyp testing only rec when tumor not available and polyp is large, and strong fhx

- Bethesda criteria vs universal screening vs modification of either

GT:

-> NCCN rec 2022 that germline multigene panel should be offered to all CRC <50y and considered for all others especially with evidence of mismatch repair in tumor or suggestive fhx

-> panel test standard of care

-> single gene based on IHC results (older)

-> MSH2 inversion testing commonly exons 1-7 (may or may not be included in seq/panel)

Predictive models

-> PREMM1,2,6

-> MMRpredict

-> MMRpro

What is the Amsterdam II criteria? what does the criteria consist of?

made in 1991 attempt to standarize dx criteria for Lynch families for multi-center studies and revised in 1998 for identifying who should be offered GT

3 or + w Lynch-associated tumor, one must be FDR

2 or + generations

1 must be dx <50y

FAP must be excluded

tumors have been verified histologically

note: up to 80% of lynch families fail to meet guidelines, failure doesn't exclude Lynch

What is the Bethesda criteria? what does the criteria consist of?

created in 1996 for people who should have tumor testing for Lynch and was revised in 2002

Only have to meet one:

CRC dx <50y

synchronous or metachronous CRCs or Lynch-associated extra-colonic ca at any age

CRC w MSI-H histology <60y

CRC in 1 or + FDR w Lynch-related tumor, w at least 1 dx <50y

CRC in 2 or + FDR or SDR w Lynch-related tumors, at any age

Lynch-related tumors in this case DO NOT include CNS

What are the Universal screening criteria for Lynch? What does the criteria consist of?

25% of ppl w Lynch didnt meet Amsterdam or bethesda criteria so made a new screening method

Perform IHC and/or MSI on ALL newly dx CRC and endometrial ca REGARDLESS of fhx

OR

test all tumors dx <70 and those >70y who meet Bethesda criteria

Cost effectiveness was worthwhile, but a study in 2021 showed it missed nearly 40% of hereditary syndromes

What is Immunohistochemistry done for in Lynch? What is important to note about IHC

Shows presence or absence of particular proteins

Screens for Lynch b/c in Lynch-related tumors there is an ABSENCE of the involved protein

imp to note:

Proteins can be absent b/c methylation or acquired mutations

Proteins can be present even w germline mut like certain missense or splice site mutations. like making a protein but w wrong function

NOT A QUANTITATIVE STUDY

What does a positive vs negative IHC result mean?

negative stain means protein absent-> suggests a mutation

Positive stain means protein present-> argues against mutation

patient w a hetero germline PMS2 nonsense mutation ex. p.K738X would have absent PMS2 staining on what tissues?

Tumor only

Tumor and blood

Blood only

Tumor only

Blood would have a presence of PMS2

Patient w CMMRD due to homozygous germline PMS2 nonsense mutation ex. p.K738X would have absent PMS2 staining on what tissues?

Tumor and skin

Tumor only

skin only

Tumor and skin b/c homozygote

How do MMR dimers impact Lynch syndrome?

MLH1 binds with PMS2

MSH2 binds with MSH6

MLH1 and MSH2 are the KEY proteins, aka main character-> they can function w/o their normal co-proteins, but PMS2 and MSH6 cannot exist w/o them

What is macrosatellite instability (MSI)? What are the categories of results?

MSI is the expansion or reduction in length of repetitive DNA sequences.

Testing for MSI assess how well MMR proteins function

Poss results:

MSI-S=Stable, H= high instability >30% markers, L=low instability <30%

NOTE: PRESENCE of MSI DOES NOT absolutely mean Lynch. Results must be correlated with clinical findings, fhx, and other test results.

What MSI results indicate or imply Lynch?

roughly 15% of all CRCs are MSI-H but only 3-5% of CRC is due to Lynch

- Remaining 10-12% are sporadic-> 70% have MLH1 promoter methylation b/c of somatic BRAF V600E mutation which shows MLH1 and PMS2 loss by IHC

- almost always BRAF V600E mutations don't have Lynch

Nearly all MLH1 and MSH2-related tumors are MSI-H

MSH6 and PMS2-related tumors may be MSI-L

What is familial colon cancer type X?

not a syndrome b/c no recognizable gene but name of clinical dx

- fam meeting Amsterdam-I criteria but no evidence of defective MMR by tumor testing (MSI/IHC)

- substantially lower lifetime risk of ca than lynch, like 2-3x inc risk of general pop

- age of onset slightly older than lynch, 50-60y

- no/few extracolonic cancers

- believed to be multifactorial

What causes Familial Adenomatous Polyposis (FAP)?

Mutations in APC gene

-> 25-30% mutations are de novo

-> most proteins are truncating

-> roughly 10% deletions of 1+ exons or entire gene

->large deletions of 5q22 cause FAP and ID

->good genotype-phenotype correlation

Whats the estimated incidence of Familial Adenomatous Polyposis (FAP)?

1/10,000

Where is FAP likely located? how long for carcinoma to form?

generally left-sided tumors

normal time from tumor initiation to carcinoma 5-10y

what is the polyp count for Classic Familial Adenomatous Polyposis (FAP)? onset? lifetime risk for cancer?

- >100 adenomatous polyps to thousands

- polyps present throughout colon

-> w avg 16y onset of polyposis

-> 95% have polyposis by 35 years

- 100% lifetime risk for cancer

-> avg onset 39

-> screening inadequate so prophylactic colectomy is only prevention

Are there extra-colonic tumors in FAP? if so where?

Duodenal & periampullary 4-12%

thyroid 1-2% (non-medullary)

pancreas 1% (islet cell tumor)

hepatoblastoma (up to age 5/childhood ) 2%

Gastric <1% (polyps more frequent like adenomas and fundic gland hamartomatous polyps)

CNS <1% (most often medulloblastoma)

desmoid tumors

-> benign but aggressive fibrous tumors

-> often abdomenal

-> affect 10-30% w/ FAP

-> cause significant probs in 5%

Osteomas (benign bony tumors in skull/mandible)

Soft tissue tumors

-> epidermal cysts and fibromas

CHRPE (congenital hypertrophy of retinal pigmented epithelium)

-> no clinical problem

Dental abnormalities

-> supernumerary teeth, unerupted teeth, congenital absence of teeth, dentigerous cysts

What are some FAP variants?

Gardener syndome

-> FAP w soft tissue tumors and osteomas

Turcot syndrome

-> CRC and brain tumors (usually medulloblastoma)

Attenuated FAP

-> 10-99 polyps w avg 30y

->later age of onset of CRC

-> generally right sided tumors (like lynch)

-> lifetime CRC risk 70-80%

->no/RARE CHRPE

->mut often in 5' or 3' ends of APC

-> may affect more than 1/10,000

What population has a founder mutation for APC? What is the exact mutation?

I1307K mutation in APC is a Ashkenazi Jewish founder mutation

moderate inc in CRC (2x)-> rec colonoscopy at 40y

Phenotype of sporadic CRC

present in 6% of unselected AJ, 10% of unselected AJ w CRC, 28% of AJ w CRC and fhx of CRC

Not rec to test for only this mutation if APCtesting is indicated

what is MYH-associated polyposis aka MUTYH (MAP)

similar to (A)FAP phenotype b/c involved in repairing somatic APC mutations

- mult adenomas

- extra-colonic manifestations ->gastric, small intestine, endometrial, liver, thyroid, and skin

some evidence for breast

-> CHRPE and duodenal polyps less frequent with MAP

- Early-onset colon cancer

- MSI-S tumors

- mostly left sided tumors

Mostly adenomatous polyps can be some serrated adenomas or hyperplastic polyps

What are some founder mutations for MAP?

Y165C and G382D make up 85% mutations in NE caucasians

Y90X- Pakistanis

E446X- East Indians

Is there any implications for MAP carriers?

- 1-2% of population

- carrier state is thought to be MODERATE risk allele

-> 6-7% irrespective to fhx

-> 10-13% w affected FDR

- screening only rec if fhx w a cscope every 5y

- no clear risk for other cancers ( so no extra-colonic screening)

When should you consider MAP?

clinical dx of FAP/ AFAP but NO APC mutation detected

multiple polyps but no AD fhx of CRC or fhx consistent w AR

Early onset CRC with MSS tumors

What is Polypmerase proofreading associated polyposis syndrome (PPAP)? What genes are associated?

A polyposis hereditary cancer syndrome.

Genes are POLE and POLD which occur in exonuclease domain for DNA polymerase

AD and high penetrance

This is VERY new

What are Polymerase proofreading associated polyposis syndrome (PPAP) heterozygotes at risk of?

High penetrance: Adenomatous polyps and colorectal cancer -> some studies suggest 50-90% risk as early as 14

Possible inc risk for endometrial, ovarian, gastroduodenal (mostly duodenal) adenomas and malignancies

Is there any concerns for biallelic POLE Polypmerase proofreading associated polyposis syndrome (PPAP) mutations?

Biallelic POLE mutations cause AR facial dysmorphism, immunodefiency, livedo, and short stature known as FILS syndrome and in rarer cases (due to a recurrent intronic variant) IMAGe syndrome

What is Colonic (adenomatous) polyposis of unknown etiology (CPUE)? When is this a concern for patients?

A colorectal cancer diagnosis that appears like CRC type X but with polyps

This is brought up for patients with multiple adenomatous polyps but no mutation in recognized gene -> NCCN says 10-20 polyps but literature ranges from 10-100 polyps

What is the the colonic (adenomatous) polyposis of unknown etiology (CPUE) risk for cancer?

low overall risk of CRC compared to FAP and other polyposis syndromes

lower rate of adenoma growth

Older population

What is juvenile polyposis syndrome (JPS)? what does penetrance look like and polyps in families?

Most common hamartomatous polyp syndrome: 1/15,000-1/100,000 individuals

AD with 25% de novo.

90% penetrance

polyps vary signficantly even within families-> most have polyps by 20y. ranges from 4-5 polyps to >100 in a lifetime

What types of polyps are in juvenile polyposis syndrome (JPS)? What does the cancer risk look like?

Hamartomatous polyps

Juvenile polyp is a type of polyp but not age of onset. Sporadic juvenile polyps are mostly seen in children (thus the name)

Most are benign but can cause bleeding and anemia if untreated

RIsk of GI cancer is 9-50%

-> CRC

->pancreatic

-> gastric

-> upper GI tract

-> small intestine

What is needed for a JPS clinical dx?

AT LEAST 1 OF FOLLOWING:

minimum 5 juvenile colon/rectum polyps

mult juvenile polyps on GI tract

any number of polyps + fhx

What genes are present in JPS?

BMPRIA - 25%

SMAD4 - 25% (SMAD4 can also have hereditary hemorrhagic telangiectasia which is NOT a cancer syndrome

mutations in ENG were reported in 2 individuals with JPS and had very early onset but unsure if true correlation

How does juvenile polyposis syndrome present in infants?

polyps develops in first few years of life

accompanied by hypoproteinemia, protein-losing enteropathy, diarrhea, anemia, anasarca, and FTT

What is serrated polyposis syndrome (SPS)? is there a previous name known?

a polyposis syndrome with increased risk for early onset CRC

previously known as hyperplastic polyposis syndrome

How does serrated polyposis syndrome present? what genes are associated with it?

highly variable but risk estimate ranges from 7-70% but likely 40-50% forr CRC and 20% for gastric cancer

typical age of onset is 50-60y

No identified genetic cause but recent studies showed that 30% had FDR with CRC and 5% had FDR with SPS

Whats the diagnostic criteria for serrated polyposis syndrome? (per WHO 2000)

at least 5 confirmed hyperplastic polyps proximal to the sigmoid colon, two of which are greater than 10mm diameter

OR

any # of hyperplastic polyps occurring proximal to sigmoid colon with a FDR with hyperplastic polyp

OR

>30 hyperplastic polyps of any size but distributed throughout out the colon

BUT many ppl w/ HPS dont fit that criteria