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F. Cancer Genetics = 5 - 10% > RCE - High Yield Topics > Flashcards

RCE - High Yield Topics Flashcards

1
Q

VIP - Lynch syndrome in a 45 year old female.

  • Tumor / Cancer spectrum seen in Lynch syndrome (n=12)
  • Diagnostic criteria.
  • Gene - Protein - Mechanism - Inheritance
A 
Colorectal cancer (adenocarcinoma) < 50 years (proximal)
Rarely adenomatous polyps of the colon
Endometrial cancer
Ovarian cancer

Gastric cancer
Cancer of the small intestine, urinary tract, biliary tract
Brain cancer (usually glioblastoma),
Skin cancer (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas)
Pancreatic cancer
Prostate cancer

*NB: Insufficient data for breast, sarcomas, adrenocortical carcinoma

MNEMONIC:
It's a bad day for the Grinch:
Poo - Period - Pee - Pancreas - Prostate (5 p's)
Skin (green)
Brain (bad)

_____________________________

No consensus clinical diagnostic criteria for Lynch syndrome have been published.

_____________________________

Genes:
MLH1, PMS2, MSH2, MSH6
(germline heterozygous pathogenic variant)

EPCAM gene deletion
(causes methylation of the MSH2 region preventing MSH2 expression, an epigenetic mechanism)

Constitutional inactivation of MLH1 gene by methylation

Mechanism:

  • Loss of function mutations
  • DNA repair genes
  • Tumor suppressor genes
  • Mismatch repair pathway deficiency

Inheritance: Autosomal dominant

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2
Q

VIP - Lynch syndrome in a 45 year old female.

  • What is MSI instability?
  • What further investigations would you do?
A

GeneReviews:
Microsatellites are stretches of DNA with a repetitive sequence of nucleotides that are particularly susceptible to acquiring errors when the MMR gene function is impaired. Cancers arising in cells with defective MMR gene function exhibit an inconsistent number of microsatellite nucleotide repeats when compared to normal tissue, a finding referred to as “microsatellite instability” (MSI).

MSI testing is an effective method for determining which tumors arise from MMR deficiency. Studies have demonstrated that the sensitivity of MSI testing for identifying tumors that arise in individuals with a germline MMR gene pathogenic variant is 93%.

MSI testing may be positive (i.e., MSI-high, identifying a tumor as arising from MMR deficiency) when the IHC studies are negative due a protein that is present, but nonfunctional).

_____________________________

Immunohistochemistry of MLH1, PMS2, MSH2, MSH6 protein expression (expected to be negative in Lynch)

NB: If IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing.

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3
Q

VIP - Lynch syndrome in a 45 year old female.

  • What is the recommended surveillance?
A

ROUTINE SCREENING:

Colonoscopy with removal of precancerous polyps every one to two years beginning between ages 20 and 25 years or two to five years before the earliest CRC diagnosis in the family, whichever is earlier.

________________________

Consider transvaginal ultrasound examination and endometrial biopsy every one to two years in females.

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4
Q

VIP - Lynch syndrome in a 45 year old female.

  • Primary prevention?
A

Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed.

Aspirin therapy has been shown to decrease the risk for CRC in individuals with Lynch syndrome.

NB: Prophylactic colectomy prior to the development of colon cancer is generally not recommended for individuals known to have Lynch syndrome because screening colonoscopy with polypectomy is an effective preventive measure.

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5
Q

IMP - Predictive testing in Lynch syndrome

A

When a diagnosis of Lynch syndrome has been confirmed in a proband, molecular genetic testing for the Lynch syndrome-related pathogenic variant should be offered to first-degree relatives to identify those who would benefit from early surveillance and intervention.

NB: Although molecular genetic testing for Lynch syndrome is generally not recommended for at-risk individuals younger than age 18 years, a history of early cancers in the family may warrant predictive testing prior to age 18.

Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant in the family is known.

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6
Q

IMP - Tumor tissue testing suggestive of Lynch syndrome.

A

Microsatellite instability (MSI) testing showing that tumor tissue is MSI high.

Immunohistochemistry (IHC) demonstrating loss of expression of one or more of the mismatch repair (MMR) gene products: MLH1, MSH2, MSH6, and/or PMS2.

Next-generation sequencing in tumor tissue revealing MSI

Identification of a pathogenic variant in tumor tissue in an MMR gene

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7
Q

IMP - Table 2. Tumor Tissue Test Results, Interpretation, and Additional Testing Options

NB: For Lynch syndrome: Tumor testing strategies apply to colorectal and endometrial cancers

A

https://www.ncbi.nlm.nih.gov/books/NBK1211/

NB:
- Screen all CRC and endometrial cancers with MSI or IHC testing.

  • Lynch syndrome-related cancers do not have hypermethylation of the MLH1 promoter.
  • BRAF pathogenic variants are not common in sporadic endometrial cancers; thus, BRAF testing is not helpful in distinguishing endometrial cancers that are sporadic from those that are Lynch syndrome related.
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8
Q

VIP - Lynch syndrome

Notes to self: The approach to tumor testing in Lynch syndrome?

A

General rules:

  • If MSI-H = you need IHC for guidance or go straight to MMR sequencing if not available
  • If IHC is abnormal = you don’t need MSI, because you know it’s going to be abnormal
  • Never ignore MSI-H, even if IHC is normal
  • Loss of MLH1 = BRAF and MLH1 promoter methylation testing on the tumor = if normal or abnormal, still do MMR testing (germline/tumor)
  • If BRAF or MLH1 promoter methylation testing on the tumor is abnormal = consider Constitutional MLH1 epimutation + Germline (only test if young)
  • Loss of others = do MMR testing (germline/tumor)
  • Patients with MSI-H CRC with no germline mutation should have somatic testing of the tumor.
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9
Q

IMP - Lynch syndrome

Scenario 2:

Tumor Testing:
- Immunohistochemistry:
MLH1 (+)	
MSH2 (+)	
MSH6 (+)	
PMS2 (+)
  • MSI: MSI-high
A

Plausible Etiologies:

  • Sporadic cancer
  • Germline MMR gene pathogenic variant

Additional Testing Options for Lynch Syndrome:
- Germline MMR gene testing or paired germline/tumor tissue MMR gene testing.

NB: This still could be Lynch syndrome. Recall that it is possible that some missense germline pathogenic variants will not result in the absence of a detectable protein product on IHC.

  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
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10
Q

IMP - Lynch syndrome

Scenario 3:

Tumor Testing:
- Immunohistochemistry:
MLH1: not done	
MSH2: not done	
MSH6: not done	
PMS2: not done
  • MSI: MSI-high
A

Plausible Etiologies:

  • Sporadic cancer
  • Germline MMR gene pathogenic variant

Additional Testing Options for Lynch Syndrome:

  • IHC
  • If IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing.
  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
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11
Q

IMP - Lynch syndrome

Scenario 4:

Tumor Testing:
- Immunohistochemistry:
MLH1 (-)	
MSH2 (+)	
MSH6 (+)	
PMS2 (-)
  • MSI: not done
A

Plausible Etiologies:

  • Sporadic cancer
  • Germline MLH1 pathogenic variant
  • Germline PMS2 pathogenic variant (rare)

Additional Testing Options for Lynch Syndrome:

  • Targeted BRAF &/or MLH1 promoter methylation testing on tumor tissue
  • If BRAF/MLH1 methylation normal, germline MMR gene testing or paired germline/tumor tissue MMR gene testing
  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
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12
Q

IMP - Lynch syndrome

Scenario 5**:

Tumor Testing:
- Immunohistochemistry:
MLH1 (-)	
MSH2 (+)	
MSH6 (+)	
PMS2 (-)
  • MSI: not done
  • BRAF (V600E): positive
A

Plausible Etiologies:

  • Sporadic cancer
  • Germline MLH1 pathogenic variant (rare)
  • Constitutional MLH1 epimutation

Additional Testing Options for Lynch Syndrome:
- If early-onset cancer (< age 50 yrs) or significant family history of cancer: germline MMR gene testing and constitutional MLH1 epimutation testing

  • If not: no additional testing

NB: Constitutional MLH1 epimutation testing involves MLH1 promoter hypermethylation analysis on blood or other sources of normal tissue.

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13
Q

IMP - Lynch syndrome

Scenario 6**:

Tumor Testing:
- Immunohistochemistry:
MLH1 (-)	
MSH2 (+)	
MSH6 (+)	
PMS2 (-)
  • MSI: not done
  • BRAF (V600E): negative
  • MLH1 Promoter Methylation: positive
A

Plausible Etiologies:

  • Sporadic cancer
  • Germline MLH1 pathogenic variant (rare)
  • Constitutional MLH1 epimutation

Additional Testing Options for Lynch Syndrome:
- If early-onset cancer (< age 50 yrs) or significant family history of cancer: germline MMR gene testing and constitutional MLH1 epimutation testing

  • If not: no additional testing
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14
Q

IMP - Lynch syndrome

Scenario 7:

Tumor Testing:
- Immunohistochemistry:
MLH1 (-)	
MSH2 (+)	
MSH6 (+)	
PMS2 (-)
  • MSI: not done
  • BRAF (V600E): negative
  • MLH1 Promoter Methylation: negative
A

Plausible Etiologies:

  • Germline MLH1 pathogenic variant
  • Germline PMS2 pathogenic variant (rare)
  • Sporadic cancer

Additional Testing Options for Lynch Syndrome:
- Germline MMR testing or paired germline/tumor tissue MMR gene testing

  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
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15
Q

IMP - Lynch syndrome

Scenario 8:

Tumor Testing:
- Immunohistochemistry:
MLH1 (+)	
MSH2 (-)	
MSH6 (-)	
PMS2 (+)
  • MSI: not done
  • BRAF (V600E): not done
  • MLH1 Promoter Methylation: not done
A

Plausible Etiologies:

  • Germline MSH2/EPCAM pathogenic variant
  • Germline MSH6 pathogenic variant (rare)
  • Sporadic cancer

Additional Testing Options for Lynch Syndrome:
- Germline MMR testing or paired germline/tumor tissue MMR gene testing

  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
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16
Q

IMP - Lynch syndrome

Scenario 9:

Tumor Testing:
- Immunohistochemistry:
MLH1 (+)	
MSH2 (+)	
MSH6 (+)	
PMS2 (-)
  • MSI: not done
  • BRAF (V600E): not done
  • MLH1 Promoter Methylation: not done
A

Plausible Etiologies:

  • Germline PMS2 pathogenic variant
  • Germline MLH1 pathogenic variant
  • Sporadic cancer

Additional Testing Options for Lynch Syndrome:
- Germline MMR testing or paired germline/tumor tissue MMR gene testing

  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
17
Q

IMP - Lynch syndrome

Scenario 10:

Tumor Testing:
- Immunohistochemistry:
MLH1 (+)	
MSH2 (-)	
MSH6 (+)
PMS2 (+)
  • MSI: not done
  • BRAF (V600E): not done
  • MLH1 Promoter Methylation: not done
A

Plausible Etiologies:

  • Germline MSH2/EPCAM pathogenic variant
  • Sporadic cancer

Additional Testing Options for Lynch Syndrome:
- Germline MMR testing (which includes EPCAM) or paired germline/tumor tissue MMR gene testing

  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
18
Q

IMP - Lynch syndrome

Scenario 11**:

Tumor Testing:
- Immunohistochemistry:
MLH1 (+)
MSH2 (+)	
MSH6 (-)	
PMS2 (+)
  • MSI: not done
  • BRAF (V600E): not done
  • MLH1 Promoter Methylation: not done
A

Plausible Etiologies:

  • Germline MSH6 pathogenic variant
  • Germline MSH2/EPCAM pathogenic variant
  • Sporadic cancer w/treatment effect
  • *NB: Absent MSH6 IHC staining in rectal tumors may be due to treatment effect (neoadjuvant chemoradiotherapy)

Additional Testing Options for Lynch Syndrome:
- Germline MMR gene testing or germline/tumor tissue MMR gene testing

  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
  • If applicable, consider MSI analysis or repeat IHC on non-treated tumor.
19
Q

IMP - Lynch syndrome

Scenario 12:

Tumor Testing:
- Immunohistochemistry:
MLH1 (-)	
MSH2 (+)	
MSH6 (+)	
PMS2 (+)
  • MSI: not done
  • BRAF (V600E): not done
  • MLH1 Promoter Methylation: not done
A

Plausible Etiologies:

  • Sporadic cancer: MLH1 promoter methylation or somatic MLH1 or PMS2 pathogenic variant
  • Germline MLH1 pathogenic variant
  • Germline PMS2 pathogenic variant

Additional Testing Options for Lynch Syndrome:
- Targeted BRAF &/or MLH1 promoter methylation testing on tumor tissue

  • If BRAF & MLH1 methylation normal: germline MMR gene testing or paired germline/tumor tissue MMR gene testing
  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
20
Q

IMP - Lynch syndrome

Scenario 13**:

Tumor Testing:
- Immunohistochemistry:
MLH1 (-)	
MSH2 (-)	
MSH6 (-)	
PMS2 (-)
  • MSI: not done
  • BRAF (V600E): not done
  • MLH1 Promoter Methylation: not done
A

Plausible Etiologies:

  • Germline MMR gene pathogenic variant
  • Sporadic cancer

Additional Testing Options for Lynch Syndrome:
- Targeted BRAF &/or MLH1 promoter methylation testing on the tumor AND germline MMR gene testing
(combining both branches)

OR

  • Paired germline/tumor tissue MMR gene testing (often incl MLH1 methylation testing)
  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
21
Q

IMP - Lynch syndrome

Scenario 1:

Tumor Testing:
- Immunohistochemistry:
MLH1 (+)	
MSH2 (+)	
MSH6 (+)	
PMS2 (+)
  • MSI: MSS
A

Plausible Etiologies:

  • Sporadic cancer
  • Cancer due to other hereditary cancer syndrome

Additional Testing Options for Lynch Syndrome:
- None (not Lynch) UNLESS there is a strong family history or other reason to believe that the diagnosis is Lynch syndrome, THEN additional testing may be warranted to rule out the possibility that the original tumor selected for testing was a sporadic colorectal cancer.

22
Q

IMP - Constitutional MMR deficiency (CMMRD).

  • Age of onset
  • Cause
  • Tumor/Cancer Spectrum + Skin finding
  • Clues on family history
A

AGE: childhood cancer predisposition syndrome.

CAUSE: biallelic pathogenic variants in MLH1, MSH2, MSH6, or PMS2

TUMOR/CANCER SPECTRUM:
- Colorectal adenomatous polyposis; small bowel cancer
(Annual C-scope, OGD, small bowel capsule)

  • Primary brain cancers (pNETs)
    (Brain MRI q6m)
  • Leukemia, lymphoma
    (CBC, LDH, ESR)
  • Urothelial cancer
    (abdominal ultrasound q6m)
  • Café-au-lait macules

MNEMONIC: 4 B’S - and blotchy skin

CLUES ON FAMILY HISTORY:

  • Family history of Lynch syndrome,
  • Consanguineous parents
23
Q

VIP - You are seeing a woman who has colorectal cancer that demonstrates MSI instability.

a. What is your differential?
b. What investigation would you do next?

A

DIFFERENTIAL DIAGNOSIS:

  • Sporadic cancer
  • Lynch syndrome: germline MMR gene pathogenic variant

INVESTIGATIONS:

  • IHC
  • If IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing.
  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)
24
Q

VIP - You are seeing a woman who has colorectal cancer that demonstrates MSI instability. You’ve requested IHC. IHC shows normal MSH2 and MSH6, but no MLH1 or PMS2 staining.

a. What is your differential?
b. What investigations could be ordered to clarify her risk for genetic counseling purposes?

A

DIFFERENTIAL DIAGNOSIS:

  • Sporadic cancer
  • Germline MLH1 pathogenic variant
  • Germline PMS2 pathogenic variant (rare)

INVESTIGATIONS:

  • Targeted BRAF V600E &/or MLH1 promoter methylation testing on tumor tissue
  • If BRAF/MLH1 methylation normal, germline MMR gene testing or paired germline/tumor tissue MMR gene testing
  • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing (Why?)

F. Cancer Genetics = 5 - 10% (9 decks)

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