Colon Cancer (Polyps and No Polyps)

Familial Adenomatous Polyposis (FAP)

- APC (AD; 30% dnv)
- Cancer risks = Colorectal/duodenal polyps (untreated = 100% risk of CRC, carpeted polyps in colon range from 100s-1000s with 95% risk of polyps by 35yo), small bowel, papillary thyroid, hepatoblastoma, pancreatic, medulloblastoma - poylps + medulloblastoma = Turcot
- Polyps + soft tissue/bone cancers = Gardner
- Other = CHRPE (see eye doctor), missing/extra teeth, jaw osteomas (see dentist), desmoid tumors (GAPPs)
- Attenuated FAP = 10-100 polyps with later onset with CRC avg onset between 50-55yo and 70% with CRC by 80yo.

MUTYH-associated Polyposis (MAP)

- MUTYH (AR)
- Cancer risks = 10s-1002 of adenomatous polyps (leads to CRC), serrated polyps, can develop CRC w/o CRC (50% risk for CRC by 60yo), and increased risks for duodenal, bladder, and ovarian cancers.

Juvenile Polyposis Syndrome (JPS)

- SMAD4 or BMPR1A (AD)
- Features:
- 1 juvenile polyps (the type of polyp---not the age) where most are benign but can become malignant
- most w/ polyps by 20yo
- rectal bleeding/prolapse of rectal polyp
- OTHER = SMAD4 associated with HHT***

Peutz-Jeghers Syndrome (PJS)

- STK11 (AD)
- Cancer risk = hamartomatous polyps in GI tract, CRC, and breast
- Other = mucocutaneous pigmentation, hyperpigmented macules (lips, nose, fingers, and toes), (M) gynecomastia, (F) ovarian sex cord tumors, and (M) large calcifying sertoli cell tumors

Lynch Syndrome (LS)
- Genes and Cancer Risks

- MLH1, MSH2, MSH6, PMS2, EPCAM (AD
- EPCAM is NOT an MMR gene.
- Risks = CRC (right sided w/ NO polyps), endometrial, others include ovarian, stomach, small bowel, GUI, brain (glioblastoma), skin (sebaceous neoplasms), prostate, and some variants have shown associations with breast cancer.

What are suggestive findings/ criteria for LS?

- Increased microsatellite instability (MSI)
- Amsterdam II Criteria (for testing)
- Immunohistochemistry (IHC)

What is MSI?

- repeated DNA sequences, MSI is high when DNA MMR are not working
- use when microsatellites in tumor have many differences from normal tissues.
- MRI used based on Bethseda Guidelines

What is the Amsterdam II Criteria?

- (1)+ LS cancer dx before 50yo
- (2) consecutive affected generations
- (3)+ relatives with LS-related cancer (affected individuals must be first-degree relatives with one another)

What is IHC?

- looks at proteins present when MMR genes are appropriately expressed and the absent suggestive of LS.

What MMRs form heterodimers?

- MLH1 and PMS2 (MLH1 >> PMS2 so when MLH1 is absent, so is PMS2; not vice versa)

- MSH2 and MSH6 (MSH2 >> MSH6 so when MSH2 is absent, so is MSH6; not vice versa)

What might the loss of MLH1 and PMS2 indicate?

- Germline MLH1 or somatic promoter MLH1 promoter hypermethylation.

What should you do to determine if LS germline or somatic when MLH1 and PMS2 are absent on IHC?

Use BRAF variant analysis to clarify. If BRAF is present (+) this means origins are likely somatic (MLH1 promoter hypermethylation)

MLH1 + PMS2 absent means variant in? MSH2 + MSH6 absent means variant in?

MLH1; MSH2

If PMS2 is absent only and or MSH6 is absent only, this means there is a variant in what?

PMS2; MSH6, respectively.

What are the related conditions to LS?

Constitutional Mismatch Repair Deficiency (CMMRD) and Muire-Torre Syndrome (MTS).

What is CMMRD?

- biallelic variants in MMR genes (AR)
- cancer risks = childhood cancers, CRC, brain, and blood (lymphoma/leukemia) with 100% by 18yo and 20-40% of 2nd primary cancer.
- Other features = Cafe au Laits (CALs), freckling or hypopigmentation.

What is Muire Torre Syndrome (MTS)?

Subtype of LS with skin findings such as sebaceous gland tumors and keratocanthomas

When you have a patient with a fhx of CRC what things should you pay attention to and why?

- age (if dx is later than 35yo it is unlikely FAP)
- if no other fhx of CRC (think MUTYH b/c AR)
- If no polyps (r/o polyposis syndromes!)

What is the average colon cancer risk?

4-5%

What part of the colon is furthest from the rectum?

cecum

What type of polyps are associated with juvenile polyposis?

inflammatory

What are the AR colon cancer genes?

MUTYH, NTHL1, and MSH3

Who can be offered APC pathogenic testing?

children and adults

what is the standard MMR deficiency treatment?

immunotherapy

What is intussusception?

intestines folds on itself (obstruction/blockage)

What types of cancer for CDH1?

diffuse gastric and lobular breast

What is PJS associated with? What are the gene(S)

hamartomata's polyps, breast, GI, pancreatic, and ovarian cancers, intussception, mucocutaneous hyperpigmentation (mouth/lips/ fingers. toes)
- STK11 (aka LKB1)