PB#147: Lynch Syndrome Flashcards by Gordon Skeoch

Percentage of cases of uterine cancer attributable to a hereditary causes; percentage of cases of ovarian cancer attributable to a hereditary cause

~3-5%; 8-13%

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Syndrome that accounts for most cases of hereditary uterine and CR cancer

Lynch syndrome

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Top two most common causes of inherited ovarian cancer (in order)

1) Hereditary breast and ovarian cancer syndrome
2) Lynch syndrome

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Inheritance pattern of Lynch syndrome

Highly penetrant AD condition

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General molecular defect caused by Lynch syndrome

Defects in DNA MMR

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Population prevalence of Lynch syndrome

~1 in 600-3,000 individuals

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Most common genes associated w/ Lynch syndrome (4)

MLH1, MSH2, MSH6, PMS2

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Gene that, when deletions present, may also lead to inactivation of MSH2 and result in Lynch syndrome

EpCAM

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Incidence of Lynch syndrome in pts presenting w/ endometrial cancer

~2.3%

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Incidence of Lynch syndrome in pts presenting w/ CR cancer

~2.2%

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Clinical feature of Lynch syndrome endometrial/CR cancers

Substantially greater portion of early-onset cancers

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Percentage of pts <50 y/o w/ endometrial cancer who will have a detectable deleterious MMR gene mutation associated w/ Lynch syndrome; percentage of pts <50 y/o w/ CR cancer who will have a detectable deleterious MMR gene mutation associated w/ Lynch syndrome

At least 5-9%; 5-7%

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Risk of CR cancer through 70 y/o for pts w/ Lynch syndrome; risk of CR cancer through 70 y/o in general population

18-61%; 1.7%

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Risk of endometrial cancer through 70 y/o for pts w/ Lynch syndrome

16-61% (equaling or exceeding risk of CR cancer)

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Risk of ovarian cancer through 70 y/o for pts w/ Lynch syndrome; risk of ovarian cancer through 70 y/o in general population; risk of ovarian cancer through 70 y/o for pts w/ BRCA1 mutation; risk of ovarian cancer through 70 y/o for pts w/ BRCA2 mutation

5-10%; ~1%; 38-46%; 12-20%

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Risk of endometrial cancer by 70 y/o among MLH1 mutation carriers; risk of endometrial cancer by 70 y/o among MSH2 mutation carriers; risk of endometrial cancer by 70 y/o among MSH6 mutation carriers;

20-54%; 21-49%; 16-61%

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Noteworthy clinical feature of endometrial cancer among MSH6 mutation carriers

Later average age of disease onset

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Is gyn cancer or GI cancer the more common presenting cancer among pts w/ documented Lynch syndrome and metachronous GI and gyn malignancies?

Gyn cancer (in >50% of cases)

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Median interval between dx of endometrial cancer and dx of CR cancer among Lynch syndrome pts w/ metachronous GI and gyn malignancies

11 years

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Mean age of onset of endometrial cancer among pts w/ Lynch syndrome

47-49 y/o

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Histological feature more common w/ Lynch-associated endometrial cancer

Nonendometrioid histology

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Percentage of pts w/ Lynch syndrome who have endometrial path characteristics w/ that warrant adjuvant therapy s/p hyst

~25% (despite earlier disease stage at dx)

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Mean age of dx of ovarian cancer in Lynch syndrome pts

42-49 y/o

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Disease stage seen w/ Lynch syndrome pts at dx compared to pts w/ sporadic ovarian cancer

Earlier disease stage

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Overrepresented histologies seen w/ Lynch-associated ovarian cancer compared to sporadic ovarian cancer (2)

Endometrioid, clear cell

Is 5-year survival rate higher in Lynch-associated ovarian cancer or sporadic ovarian cancer?

Not statistically different

Fundamental etiology of genomic instability that allows for development of types of cancer seen in Lynch syndrome

Defects in MMR

Is genomic instability limited to coding regions of genes?

No, it includes noncoding single nucleotide and dinucleotide repeats scattered throughout DNA (microsatellites)

What is microsatellite instability?

Insertion/deletion of additional nucleotides into/from microsatellites, leading to defects in MMR

One way that microsatellite instability can result from a noninherited mechanism

Methylation of MLH1 promoter

Percentage of cases of endometrial cancer associated w/ methylation of MLH1 promoter; percentage of cases of CR cancer associated w/ methylation of MLH1 promoter

20-30%; 15-20%

Guideline system developed to provide clinically useful recs for which pts w/ CR cancer should be considered for further evaluation of Lynch syndrome

Bethesda Guidelines

Criteria used by Bethesda Guidelines (5)

Pts w/ endometrial/CR cancer diagnosed at <50 y/o; pts w/ endometrial/ovarian cancer w/ synchronous/metachronous CR/other Lynch-associated tumor at any age; pts w/ CR cancer w/ tumor-infiltrating lymphocytes, peritumoral lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern diagnosed at <60 y/o; pts w/ endometrial/CR cancer and first-degree relative w/ Lynch-associated tumor diagnosed at <50 y/o; pts w/ CR/endometrial cancer diagnosed at any age w/ 2+ first-degree/second-degree relatives w/ Lynch-associated tumors, regardless of age

Lynch-associated tumors (10)

CR, endometrial, stomach, ovarian, pancreas, ureter/renal pelvis, biliary tract, and brain (usually glioblastoma as seen in Turcot syndrome), sebaceous gland adenomas/keratoacanthomas in Muir-Torre syndrome, carcinoma of small bowel

First-degree relatives (3)

Parents, siblings, children

Second-degree relatives (6)

Aunts, uncles, nieces, nephews, grandparents, grandchildren

General sensitivity and specificity of Bethesda Guidelines in identifying pts w/ Lynch syndrome

High sensitivity, low specificity

Do Bethesda Guidelines apply to pts w/ endometrial tumors?

Methods of testing for dysfunctional MMR system (2)

Direct germline DNA testing, tumor testing using IHC/microsatellite instability testing

What does direct germline DNA testing involve?

Sequencing and screening for large rearrangements of relevant MMR genes

Does absence of a deleterious mutation on direct gene screening exclude Lynch syndrome?

No, although identification of a deleterious mutation on direct gene screening conclusively proves the presence of Lynch syndrome

Method of Lynch syndrome testing w/ which most centers begin evaluation

Tumor testing using IHC/microsatellite instability testing

What does IHC testing involve (2)?

Evaluation for expression of four MMR genes via detection of presence of their protein products, as well as identification of which MMR proteins are absent in order to guide subsequent direct germline DNA testing

Meaning of presence of all four MMR proteins; exception to this rule

Rules out Lynch syndrome in almost all cases; exception is a deleterious mutation that allows production of full-length but nonfunctional MMR protein

Subsequent method of testing if all four MMR proteins are present, but there is very high clinical suspicion for Lynch syndrome

Microsatellite instability testing

Required components of tumor testing for microsatellite instability (2)

Normal tissue, tumor tissue from pt w/ potential Lynch-associated tumor

What does microsatellite instability testing involve?

By comparing normal and abnormal tissue, diagnostic molecular genetics lab can determine if there has been insertion or deletion of nucleotides to informative microsatellites

Meaning if there is no microsatellite instability detected

Essentially rules out Lynch syndrome

When is MLH1 promoter methylation testing needed (2)?

When results of IHC testing reveal absence of MLH1 protein (w/ or w/o absence of PMS2 protein), when microsatellite instability is present

Protein that is opposite MLH1 in heterodimer

PMS2

Meaning if MLH1 protein is absent and there is methylation of MLH1 promoter

Lynch syndrome is excluded

Meaning if MLH1 protein is absent and there is no methylation of MLH1 promoter

Pt requires germline DNA testing for Lynch syndrome

Percentage of cases (at any age) of endometrial and CR cancer that are attributable to Lynch syndrome

~2-3%

Percentage of cases of endometrial and CR cancer diagnosed at <50 y/o that are attributable to Lynch syndrome

5-13%

Approaches for assessing Lynch syndrome in pt affected w/ endometrial or CR cancer (3)

Perform tumor testing on any endometrial/CR tumor from pt identified to be at risk of Lynch syndrome through systematic clinical screen that includes focused personal/fam hx; perform tumor testing on all endometrial/CR tumors irrespective of age at dx; perform tumor testing on all endometrial/CR tumors diagnosed at <60 y/o (approach endorsed by SGO)

Which unaffected pts should be considered for genetic risk assessment (2)?

Pts who have a first-degree relative affected w/ endometrial/CR cancer diagnosed at <60 y/o, pts who have been identified to be at risk of Lynch syndrome by clinical screen

In which cases may it be reasonable to offer genetic risk assessment to an unaffected individual who is more distant from an affected relative (3)?

Few relatives have reached advanced age, there is a paucity of female relatives, multiple individuals in a lineage had hyst/oophorectomy

Which pts should be offered genetic risk assessment (and, if needed, germline DNA testing) for Lynch syndrome, irrespective of degree of relatedness to affected family member?

Pts from families w/ known mutation in DNA MMR gene who could have potentially inherited familial mutation

Components to address during genetic risk assessment for Lynch syndrome (3)

Personal hx, fam hx, poss tumor testing and/or germline DNA testing

Possible outcomes of germline DNA testing (3)

Positive, negative, uninformative/VUS results

What the federal Genetic Information Nondiscrimination Act of 2008 protects individuals against based on genetic info (2)

Health discrimination, employment discrimination (does not apply to other forms of insurance, such as life/disability insurance)

What sort of testing should be pursued if pt has personal hx of endometrial/CR cancer and tumor tissue is available?

IHC testing off tumor tissue

What sort of testing should be pursued if pt has fam hx of endometrial/CR cancer but is not personally affected?

Effort should be made to obtain tissue block from Lynch-associated cancer in affected relative (w/ which genetic counselors can often assist)

What next step should be pursued if either MLH1 or PMS2 protein is not present and no methylation of MLH1 promoter is detected?

Germline DNA testing of MLH1 gene and/or PMS2 gene

Lynch protein heterodimers (2)

MLH1 and PMS2, MSH2 and MSH6

Poss indications of absence of PMS2 protein (2)

Abnormal MLH1 gene function, abnormal PMS2 gene function

What next step should be pursued if either MLH1 or PMS2 protein is not present?

Germline DNA testing of MSH2 gene and/or MSH6 gene

Poss indications of absence of MSH6 protein (2)

Loss of function of either MSH2 gene or MSH6 gene

What testing should be pursued if there is a personal/fam hx of Lynch-associated cancer and tumor tissue is unavailable?

Germline DNA testing of MMR genes

Does finding a deleterious germline DNA mutation confirm the presence of Lynch syndrome?

Yes

Does the absence of a germline DNA mutation exclude Lynch syndrome?

What testing should be pursued if tumor testing is suspicious for Lynch syndrome but germline DNA testing is normal?

Consider consultation w/ genetics

Percentage of cases of endometrial cancer w/ loss of either MLH1 or PMS2 gene expression that will not be identified by germline DNA tests; percentage of cases of endometrial cancer w/ loss of either MSH2 or MSH6 gene expression that will not be identified by germline DNA tests

10-15%; 35-40%

How many years earlier does Lynch-associated endometrial cancer occur compared to the mean age of dx in pts w/ sporadic endometrial cancer?

10-15 years

Why is irregular bleeding less likely to be evaluated in pts at risk of Lynch-associated endometrial cancer?

Because Lynch-associated endometrial cancer frequently occurs in premenopausal years

When is colonoscopy recommended for pts w/ Lynch syndrome; how frequently is colonoscopy recommended for pts w/ Lynch syndrome?

20-25 y/o, or 2-5 years before earliest cancer dx in family (whichever is earlier); q1-2 years

When is EMB recommended for pts w/ Lynch syndrome; how frequently is EMB recommended for pts w/ Lynch syndrome?

30-35 y/o; q1-2 years

What technique should pts w/ Lynch syndrome use to monitor for endometrial cancer?

Menstrual calendar

What technique can be used to combine endometrial and colon cancer screening for pts w/ Lynch syndrome?

Combined screening under conscious sedation

How should pts w/ Lynch syndrome be screened for ovarian cancer?

No consensus

How much do OCPs reduce endometrial cancer risk in general population?

Up to 50%

What therapies have been shown to be effective for chemoprevention of endometrial cancer (3)?

OCPs, Depo Provera, progestin therapy

Amount of ethinyl estradiol and norgestrel recommended in OCPs in order to decrease endometrial proliferation

30mcg ethinyl estradiol/0.3mg norgestrel

Risk of endometrial cancer before and after rrHyst (w/ mean f/u time of 7 years)

33% > 0%

Risk of ovarian cancer before and after rrBSO (w/ mean f/u time of 11 years)

5.5% > 0%

Poss Lynch-associated cancer seen in pts s/p oophorectomy

Primary peritoneal carcinoma (though magnitude of risk is unclear)

Can HRT be considered for symptomatic surgical menopause?

Yes, though HRT has not specifically been studied in pts w/ Lynch syndrome

Estimated endometrial cancer risk by 40 y/o in pts w/ Lynch syndrome; estimated ovarian cancer risk by 40 y/o in pts w/ Lynch syndrome

~2-4%; 1-2%

Estimated endometrial cancer risk by 50 y/o in pts w/ Lynch syndrome; estimated ovarian cancer risk by 50 y/o in pts w/ Lynch syndrome

8-17%; 3-7%

When should rrHyst/BSO be performed in pts w/ Lynch syndrome?

Discussed by early to mid-40s, and performed on completion of childbearing

What approach should be used for rrHyst/BSO?

Vaginal or minimally invasive

What screening modalities should be UTD prior to hyst (2)?

Colonoscopy, endometrial sampling

Is salpingectomy recommended if oophorectomy is not being pursued?

Yes, 2/2 occult tubal malignancies

Has CR cancer surveillance demonstrated mortality reduction in pts w/ Lynch syndrome?

Yes

Pharmacotherapy that may reduce CR cancer incidence in pts w/ Lynch syndrome?

Aspiring 600mg daily for >2 years