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Cancer genetics > Week 5: Hereditary colon cancer syndromes > Flashcards

Week 5: Hereditary colon cancer syndromes Flashcards

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1
Q

Differentiate polyposis from nonpolyposis

A

-Polyposis: 100s-1000s of polyps, ex: MUTYH, APC
-Nonpolyposis: colon cancer with few polyps, ex: Lynch

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2
Q

Prevalence and inheritance for Lynch syndrome?

A

-Prevalence: 1/300
-AD inheritance
-Mutations in MMR genes

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3
Q

Which syndrome is the most common cause of hereditary endometrial cancer?

A

Lynch syndrome

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4
Q

Lynch syndrome increases risk for developing what types of cancer?

A

Primarily:
-Colorectal
-Endometrial
-Ovarian

Other cancers include:
-Stomach
-Small bowel
-Kidney
-CNS
-Biliary tract
-Prostate
-Skin

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5
Q

What genes cause Lynch syndrome?

A

MLH1
MSH2
MSH6
PMS2
EPCAM (not MMR gene)

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6
Q

What is unique about EPCAM’s role in Lynch syndrome?

A

-EPCAM is immediately upstream of MSH2 gene
-Deletions of the stop codon of the EPCAM gene results in epigenetic silencing of MSH2
-There is no mutation present in the MSH2 gene, but the alteration in EPCAM is heritable somatic inactivation of MSH2 in all tissues that express EPCAM

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7
Q

Why is knowing which gene is mutated for Lynch syndrome relevant?

A

Because there are gene-specific cancer risks that differ for cancer types and between the different genes.

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8
Q

How does the lifetime risk for CRC and endometrial cancer for those with Lynch syndrome compare to general population/sporadic cases?

A

CRC
-General pop: 5%
-Lynch: 80%

Endometrial
-General pop: 3%
-Lynch: 60%

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9
Q

What are the cardinal features of Lynch syndrome?

A

-Early age of onset: ~45yr (vs general pop 63yr)
-Associated with right sided colon cancer
-Accelerated carcinogenesis: shorter time from adenoma to develop carcinoma
-High risk of second CRC: 25-30% of pts with Lynch will have second primary in 10 years

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10
Q

What are the two historical names of Lynch syndrome variants?

A

-Muir-Torre syndrome: sebaceous neoplasms and CRC, MLH1, MSH2, MSH6
-Turcot syndrome: historical term for individuals with CRC and tumors of CNS, caused by MMR genes or APC PVs

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11
Q

What two tests are used to screen for Lynch syndrome?

A

-IHC and MSI
-Used to determine if it is more or less likely that pt has Lynch syndrome
-Helps to direct genetic testing (specifically IHC patterns)

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12
Q

What does IHC test for for Lynch syndrome? What are some limitations of this?

A

-Tests for MLH1, PMS2, MSH2, MSH6
-These proteins are expected to be present in normal colon cells

Limitations:
-Some PVs will not result in the absence of detectable protein product
-Less reliable when performed on small tissue samples, less reliable if performed on adenomatous colon polyp vs colon cancers

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13
Q

What is the most common implication if IHC staining reveals loss of MLH1 and PMS2?

A

Sporadic BRAF pathogenic variant

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14
Q

What is the most common implication if IHC staining reveals loss of PMS2?

A

Usually PMS2 pathogenic variant

Could also be MLH1 pathogenic variant

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15
Q

What is the most common implication if IHC staining reveals loss of MSH2 and MSH6?

A

Usually MSH2 pathogenic variant

Could also be EPCAM pathogenic variant

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16
Q

What is the most common implication if IHC staining reveals loss of MSH6?

A

Usually MSH6 pathogenic variant

Could be MSH2/EPCAM

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17
Q

What are microsatellites?

A

Regions of repeated DNA that change in length (show instability) when MMR is not working correctly

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18
Q

How is microsatellite instability (MSI) analyzed for cancer and what can it tell us?

A

-MSI by PCR testing: looks at length of specific DNA microsatellites from tumor sample to see if they have gotten longer or shorter as measure of “instability”
-Abnormal result is MSI-H (MMR deficient): high amount of instability
-Normal result is MSS (microsatellite stable)

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19
Q

In regards to Lynch syndrome management, when are colonoscopies generally started?

A

Typically about 25yr and performing them every 1-2yrs

Guidelines are now gene specific and based on varying levels of cancer risk between genes

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20
Q

What is constitutional MMR deficiency (CMMRD)?

A

-Rare childhood cancer syndrome due to biallelic pathogenic variants in MLH1, MSH2, MSH6 or PMS2 genes
-High risk for CRC and cancer of small intestines
-Includes cutaneous NF1-like phenotype with cafe au lait spots
-Other cancers: hematologic and brain tumors

21
Q

3 clues that your patient might have Lynch syndrome?

A

-Diagnosed with colon cancer <50yr
-Colon cancer is MSI-high, abnormal IHC staining
-Family hx of Lynch related cancers- endometrial, small bowel, ovarian, stomach

22
Q

BRAF variants for colon cancer are associated with what form of inheritance?

A

Sporadic

23
Q

What three syndromes are caused by variants in APC gene?

A
  1. Familial adenomatous polyposis (FAP)
  2. Attenuated FAP
  3. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)
24
Q

Describe the characteristics and inheritance of FAP?

A

-AD
-Characterized yb development of hundreds to thousands precancerous polyps
-Essentially 100% chance of colon cancer without colectomy
-Polyps develop adolescence or early adulthood

25
Q

What is the average age of colon cancer diagnosis for FAP?

A

age 39

26
Q

List some of the extra colonic findings in FAP

A

-Desmoid tumors
-CHRPE (retinal freckling)
-Osteomas
-Epidermoid cyst
-duodenal adenomas
-Gastric polyps–upper gastrointestinal tumors too
-Hepatoblastomas
-Dental anomalies-super numerary teeth
-Periampullary cancer
-Brain tumors

27
Q

What does management look like for FAP?

A

-Starts in childhood with colonoscopy 10-15yr and screening for hepatoblastoma in infancy
-Recommendations for colectomy depends on polyp burden, still need endoscopic US of rectum
-Due to extra colonic findings: annual physical, thyroid US, upper endoscopy

28
Q

Brief overview of attenuated FAP

A

-Characterized by fewer colonic polyps (avg 30) than classic FAP
-Polyps tend to be proximally in colon
-Additional findings include upper gastrointestinal polyps and cancers like FAP, extraintenstinal manifestations of FAP but CHRPE and desmoid tumors are rare, thyroid cancer

29
Q

How does cumulative cancer risk for attenuated FAP compare to classic FAP?

A

FAP
-Avg age dx 39yr
-Essentially 100% risk for cancer

Attenuated FAP
-Avg age dx 50-55yr
-Cumulative risk for colon cancer is 70% by 80yr

30
Q

How is attenuated FAP managed?

A

-Like FAP colonoscopies started in late teens (10-15yr) and perform every
1-2yrs
-The decision for colectomy is based on polyp burden

31
Q

What is gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and what is its inheritance pattern?

A

-Newly described
-APC, AD inheritance
-Elevated risk for gastric cancer compared to FAP/AFAP
-Polyps are restricted to body and fundus of stomach
-Diagnostic criteria exists but management guidelines do not because it’s so new

32
Q

What is MUTYH associated polyposis (MAP) and its inheritance pattern?

A

-AR!!!!
-MAP diagnosis establish by biallelic pathogenic variants in MUTYH
-1-2% northern European carriers
-Characterized by 10-100 adenomatous colorectal polyps
-Additional cancer risks: duodenal, ovarian, bladder, possibly more

33
Q

What is the lifetime colorectal cancer risk without timely surveillance for MAP?

A

80-90%

34
Q

What does management look like for MAP?

A

-Colonoscopies beginning 25-30yr, every 1-2 yrs
-Surgical evaluation based on polyp number/size/histology
-Consider upper endoscopy

35
Q

Are MUTYH mutation carriers affected with symptoms?

A

Carriers have marginally increased risk for cancer, screening recommendations is based on family hx of colon cancer

36
Q

What is juvenile polyposis syndrome (JPS),type of polyps, and what percent of affected individuals will eventually develop cancer?

A

-Characterized by development of hamartomatous polyps in the GI tract
-Genes BMPR1A, SMAD4
-Age of onset: mid teens- late twenties
-68% of individuals with JPS will eventually develop cancer (CRC, upper GI tract cancer, pancreatic cancer)

37
Q

What syndrome can present alongside HHT due to shared variant in SMAD4?

A

Juvenile polyposis syndrome (JPS)

38
Q

What does management look like for JPS?

A

-Colonoscopy starting 12-15yr or earlier if symptoms, every 2-3yrs
-Upper endoscopy beginning 15yr
-Small bowel capsule endoscopy starting at 15yr or earlier

39
Q

T/F Juvenile in JPS refers to the age of onset for the disease manifestations

A

False!
Juvenile refers to the fact that the majority of polyps remain benign/juvenile and not cancerous

40
Q

Peutz-Jeghers syndrome (PJS) polyp type, gene, and recommendation to start colonoscopies?

A

-PJS-type harmartomatous polyps (big red flag for PJS!!)
-Gene: STK11
-Colonoscopy: 8yr

41
Q

Freckling of the oral buccal mucosa/lips/face should be red flag for what syndrome?

A

Peutz-Jeghers syndrome

42
Q

Cowden syndrome polyp type, gene, and management?

A

-Gastrointestinal harmartomas, ganglioneuromas, but excludes hypoplastic polyps
-Gene: PTEN
-Colonoscopy starting at 35 unless symptomatic

43
Q

Presence of gastrointestinal harmartomas and ganglioneuromas should be big red flag for what syndrome?

A

Cowden syndrome

44
Q

Li-Fraumeni syndrome polyp type, gene, and management

A

-Tubular adenomas most common
-Gene: TP53
-Colonoscopy starting 25yr

45
Q

What are the 4 autosomal recessively inherited colon cancer syndromes (some newly described)?

A

-CMMRD
-MAP
-NTHL1-associated polyposis
-MSH3-associated polyposis

46
Q

What percentage of colon cancer is inherited?

A

5-10% is hereditary

47
Q

What syndrome is the most common cause of hereditary colon cancer?

A

Lynch syndrome

48
Q

History of childhood hepatoblastoma might indicate what syndrome?

A

-FAP
-Liver cancer in childhood very rare but with FAP it is 700x more likely

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