Clinical Cancer Genetics and Syndromes

Question 1

What are the three types of cancer in families?

Answer 1

1. Sporadic
2. Familial
3. Hereditary

Question 2

What represents moderately increased risk for cancer in the consultant? What is the normal age of onset?

Answer 2

Familial cancers, where two close relatives had a specific type of cancer, with a normal age of onset of a primary tumor

Question 3

What defines a hereditary cancer?

Answer 3

1. Two or more relatives in same lineage with same or related cancer
2. Early age of onset
3. Multifocal / bilateral tumors
4. Autosomal dominant inheritance of gene

Question 4

What is the primary difference between sporadic and hereditary retinoblastoma, particularly as it relates to etiology and outcome?

Answer 4

Hereditary - 40% of cases, will be bilateral since only one hit is needed in RB1 gene (one is germline)

Sporadic - 60%, will be unilateral since two hits (two somatic) mutations are needed.

Question 5

How does the two-hit theory of cancer explain reduced penetrance and age of onset in hereditary cancers?

Answer 5

1. Reduced penetrance - additional somatic mutation is required for development of cancer, which is random
2. Age of onset - younger in hereditary since only one mutation is needed

Question 6

What are three causes of familial cancer patterns?

Answer 6

1. Multifactorial
2. Low penetrance, single-gene
3. Shared environmental risk factors

Question 7

What are two causes of a misdiagnosis of a familial cancer pattern?

Answer 7

1. Masking of true hereditary -> Underreporting of cancer history or small family size
2. Masking of true sporadic -> random chance clustering of sporadic cases

Question 8

What is the clinical difference between treating patients with well characterized cancer syndromes vs less well characterized genes?

Answer 8

Well characterized: Gene specific management guidelines are published

Less well-characterized: Management is typically guided by family history, and there are no gene-specific guidelines published

Question 9

What are the functions of the BRCA1 and BRCA2 genes? What cancers will this mutation put you at risk for?

Answer 9

Tumor suppressor genes - autosomal dominant

Mutations = increased risk of breast, ovarian, and prostate cancer

Question 10

What is HBOC and why is it important to identify it early?

Answer 10

Hereditary Breast and Ovarian Cancer syndrome - Caused by BRCA1/2.

Important because breast cancer happens at earlier age, screening for breast cancer normally starts at age 40 in general population.

Question 11

What ethnic group has the highest prevalence of BRCA1/2? How are they screened?

Answer 11

Ashkenazi Jewish - 1/40 versus 1/400 for general population

Screened for one of three common founder mutations

Question 12

How is the general population screened for hereditary cancers, and specifically BRCA1/2?

Answer 12

Most commonly a point mutation, but sometimes indels. Use a gene panel to look for all hereditary cancer causes -> once mutation is found, single site analysis can be performed which is specific to the family and much cheaper

Question 13

What is the screening protocol for breast cancer in HBOC?

Answer 13

Mammograms starting at age 25 rather than 40
Breast MRI’s yearly
Option for bilateral masectomy for risk reduction

Question 14

What is the recommendation for ovarian cancer prevention in HBOC and why?

Answer 14

Bilateral salpingo-oophorectomy (tubes, ovaries) since screening modalities are ineffective at picking up the cancer at an early, treatable stage

Question 15

What is the gene implicated in Li Fraumeni Syndrome and what cancers are associated? How does this differ from HBOC?

Answer 15

TP53 gene
-Breast, osteo and soft tissue carcomas

Difference: Risk of childhood cancer in up to 42% of patients -> screen very early, annual MRI by age 20

Question 16

In all hereditary breast cancer syndromes other than HBOC, what is special about their ovarian cancer risk?

Answer 16

There is no increased risk above baseline, for all

Question 17

What is the gene implicated in Cowden Syndrome / Hamaratoma Tumor Syndrome and what cancers are associated? How does this differ from HBOC?

Answer 17

PTEN gene

Breast, thyroid, and endometrial cancers.

Difference: Increased risk for GI polyps and skin lesions so colonoscopy is needed earlier (age 35), as well as thyroid + endometrial cancers

Question 18

What is the gene implicated in Hereditary Diffuse Gastric Cancer and what cancers are associated? How does this differ from HBOC?

Answer 18

CDH1 gene

-Lobular breast cancer, diffuse gastric cancer

Differences: Prophylactic gastrectomy needs to be done, lobular breast cancer (vs typically ductal)

Question 19

Why are multigene panels increasing in use?

Answer 19

You can cover many genes at once, takes less time than gene-by-gene strategy, less expensive, and identifies a mutation not suspected by family history

Question 20

What are some of the shortcoming of multigene panels?

Answer 20

There are high rates of variants of unknown significance, and some mutations when found will have much environmental interplay with little clear guidance in how to address them

Question 21

What percentage of colon cancer is hereditary, and what percent of this is caused by Lynch syndrome?

Answer 21

5%, 80% are caused by Lynch syndrome.

Question 22

What puts a person at increased risk of colon cancer relative to the general population?

Answer 22

History of polyp, colorectal cancer, or inflammatory bowel disease

Positive family history

Question 23

What is APC? How often are familial forms de novo?

Answer 23

Adenomatous polyposis coli gene, autosomal dominant tumor suppressor but de novo in 30% of cases. Causes FAP or attenuated FAP

Question 24

How do FAP and attenuated FAP differ with regards to polyp burden? Age of cancer diagnosis?

Answer 24

FAP: 100-1000, near 100% risk of cancer without colectomy, age of diagnosis of cancer is 39

Attenuated FAP: 10 to 100 adenomas, average of 30 polyps, cancers occur on right side of colon, average age >50

Question 25

How do FAP and attenuated FAP differ with regards to extracolonic manifestations?

Answer 25

FAP: dental anamolies, desmoids, benign cutaneous lesions, hypertrophy of RPE

Attenuated: Much rarer to have extracolonic

Question 26

What is FAP + extracolonic lesions called?

Answer 26

Gardner syndrome

Question 27

Why is sigmoidoscopy acceptable for screening in FAP but not attenuated FAP?

Answer 27

attenuated FAP is more likely to have cancer in ascending colon -> need colonoscopy.

FAP needs screen annually
Attenuated FAP needs screen every 2-3 years

Question 28

What is MAP and what causes it? Why is this special

Answer 28

MUTYH Associated Polyposis - symptoms very similar to attenuated FAP

-> autosomal RECESSIVE inheritance

Question 29

What causes Lynch syndrome? Where does it cause cancer?

Answer 29

DNA mismatch repair gene defect, autosomal dominant.

Causes cancer in early age of onset in proximal colon

Question 30

What other cancers are associated with Lynch syndrome?

Answer 30

1. Endometrial cancer
2. Ovarian cancer
3. Stomach cancer

Question 31

What are the screening guidelines for colorectal cancer in Lynch syndrome?

Answer 31

Colonoscopy at 20-25 years of age, repeating every 1-2 years.

Question 32

What genes are involved in Lynch syndrome? Why is EPCAM included?

Answer 32

MLH1, MSH2 (these two make up 90%), PMS2, MSH6

EPCAM is included in this because EPCAM can inactivate MSH2 if part of a germline deletion

Question 33

When is tumor tissue testing for colon cancer indicated, and what are the two types?

Answer 33

Always indicated, should check for Lynch syndrome everytime there’s cancer (only other time you diagnosis is when you’re screening a high risk individual)

1. Microsatellite instability
2. Immunohistochemical staining

Question 34

How does microsatellite instability work?

Answer 34

Marker of deficient DNA mismatch repair, cancers with poor DNA mismatch will have more fragments than just the two alleles at any given locus. Is not DIAGNOSTIC but rather suggestive of Lynch syndrome

Question 35

How does immunohistochemical staining (IHC) work? How does this relate to Lynch syndrome?

Answer 35

Test for expression of four mismatch repair proteins. Loss of one of these can occur in 10-15% of colon cancers, so this is not diagnostic. Need to verify mutation in germline cells for definitive Lynch syndrome diagnosis.