Hereditary Colon/GI Cancer Syndromes

when to suspect hereditary colon cancer syndromes

cancer in 2 or more close relatives

early age at diagnosis

bilateral or multiple primary tumors

rare cancers

multiple colon polyps (>10)

constellation of tumors consistent with specific syndrome

hyperplastic polyps

benign & common polyps

tubular adenoma polyps

most common adenomatous polyps

villous adenomas

cauliflower-like shape polyps

higher risk of becoming cancerous

tubulovillous adenomas

mixed growth pattern polyps

serrated polyps

polyps with a sawtooth appearance

can be precancerous

inflammatory polyps

polyps that are a reaction to inflammation in the colon

hamartomatous polyps

generally noncancerous polyps associated with a genetic syndrome

lynch syndrome tumor site

ascending colon primarily

lynch syndrome extracolonic cancers

endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors

Muir Torre Syndrome genes

MSH2 or MLH1

muir-torres syndrome features

HNPCC

sebaceous gland tumors

Keratoacanthomas

lynch syndrome personal history criteria

CRC, EC, or gastric cancer, or any LS-related cancer diagnosed <50

EC >50

CRC >50

GC >50

LS related cancer and 1 relative with LS related cancer <50

LS related cancer and 2 relatives with LS related cancer

lynch syndrome family history criteria

1 first degree relative with CRC, EC, or GC diagnosed <50

1 first or second degree relative with synchronous LS related cancer

2 first or second degree relatives with LS related cancer, 1 <50

3 first or second degree relatives with LS related cancer

Amsterdam II & Bethesda Guidelines

previous criteria used for lynch syndrome

lynch syndrome genes (MMR genes)

MLH1, MSH2, MSH6, PMS2, EPCAM

MMR gene mutations

cause microsatellite instability

MLH1 cancer risks

colorectal

endometrial

ovarian

small bowelML

MLH1 surveillance

colonoscopy 20-25

total hysterectomy 40

BSO

EGD 30-40

pancreatic MRI 50

PMS2 cancer risks

colorectal

endometrial

EPCAM

mutations silence MSH2 causing lynch syndrome

EPCAM & MSH2 cancer risks

colorectal

endometrial

ovarian

renal

bladder

small bowel

prostate

3% of colorectal cancers

amount of colorectal cancers caused by lynch syndrome

universal screening

all colorectal and endometrial cancers undergo IHC to assess for lynch syndrome

normal MMR complexes

MSH2 with MSH6/MSH3

MLHL with PMS2/PMS1

BRAF

methylation/mutations silence MLH1

MLH1 & MSH2 stability

MMR genes stable on their own

MSH6 & PMS2 stability

MMR genes unstable on their own

microsatellite instability

repetitive sequences increase in length due to MMR gene failure

constitutional mismatch repair deficiency syndrome cancers

childhood cancers

hematologic malignancies

brain/CNS

colorectal tumors

embryonic tumors

cafe au lait spots

CMMRD cause

biallelic mutations in lynch syndrome genes

RPS20

rare gene with LOF variants with CRC risk

turcot syndrome type 1

multiple adenomatous polyps & glial tumors

MMR mutations

turcot syndrome type 2

multiple adenomatous polyps & meduloblastoma

APC mutations

polyposis syndrome considered

10 or more cumulative adenomatous polyps

2 hamartomatous polyps

5 or more serrated polyps

25-30% de novo rate

FAP de novo rate

APC mutations

cause FAP

familial adenomatous polyposis features

hundred to thousands of adenomatous polyps in colon

extracolonic tumors (upper GI, desmoid, thyroid)

gardner syndrome

FAP with extraintestinal lesions

desmoid tumors, osteomas, CHRPE, soft tissue skin tumors, extra teeth

FAP cancer risks

colon

rectal

duodenal

gastric

desmoid

thyroid

FAP management

colonoscopy 10-15

colectomy once polyp rate is too high

attenuated FAP

fewer adenomatous polyps

polyps in ascending colon

CRC dx 50s

not associated with CHRPE/desmoids

gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)

mutations in promoter 1B of APC

numerous stomach polyps (fundic)

APC I1307K

colon cancer risk mutation in 10% ashkenazi jewish individuals

5-10% lifetime risk of colon cancer

4% risk

average colon cancer risk

MUTYH associated polyposis (MAP) features

10-100s colorectal adenomas

no or minimal risk in monoallelic carriers

hereditary mixed polyposis syndrome

increases risk of developing polyps in colon and rectum

very rare, 10-25% risk

GREM1 mutations

causes hereditary mixed polyposis syndrome

polymerase proofreading associated polyposis

30-100 adenomatous polyps

colon cancer risk >20%

POLE/POLD1 mutations

causes polymerase proofreading associated polyposis

recessive polyposis genes

MBD4, MSH3, MLH3, NTHL1, MUTYH

hamartoma syndromes

juvenile polyposis syndrome

peutz-jeghers syndrome

cowden syndrome

SMAD4 or BMPR1A mutations

causes juvenile polyposis syndrome

juvenile polyposis syndrome

predisposition for hamartomatous polyps in stomach, small intestine, colon & rectum

immature appearance of tissue

hereditary hemorrhagic telangiectasia

blood disorder that causes abnormal connections between arteries and veins

fragile blood vessels

associated with SMAD4 mutations

PTEN hamartoma tumor syndrome/Cowden

high risk for benign and malignant tumors of thyroid, breast, endometrium, CRC

macrocephaly

papillomatous papules

STK11 mutations

causes Peutz-Jeghers syndrome

Peutz-Jeghers syndrome

gastrointestinal polyposis, mucocutaneous pigmentation

hamartomatous polyps common in small intestine

female risks of peutz-jeghers syndrome

ovarian sex cord tumors with annular tubules

male risk with peutz-jeghers syndrome

large calcifying sertoli cell tumors

serrated polyposis syndrome

elevated CRC risk

multiple large serrated lesions/polyps

RNF43 & biallelic MUTYH

hereditary diffuse gastric cancer syndrome

signet ring cells in stomach

CDH1 & CTNNA1

hereditary diffuse gastric cancer syndrome management

gastrectomy

endoscopic surveillance

esophageal cancer risks

RHBDF2

Fanconi anemia genes (AR)