Cancer

Question 1

Which of the following cancers is the most common malignancy after colorectal cancer seen in families with hereditary non-polyposis colon cancer (Lynch syndrome)

Answer 1

The cumulative incidence of endometrial cancer in women who carry HNPCC mutations is estimated to be approximately 70%. Ovarian, bile duct and pancreatic are all increased in HNPCC. Breast cancer is not.

Question 2

A four-year-old boy is diagnosed with pulmonary pleuroblastoma and the father has multicystic goiter? In taking a family history of cancer which of the malignancies listed below might beexpected to be found given this history?

Answer 2

• Pulmonary pleuroblastoma (PPB) is part of a cancer susceptibility syndrome due to DICER1 germline mutations which includes a variety of other benign (multinodular goiter) and malignant cancers.
• Rhabdomyosarcoma is found in families with PPB and DICER1 mutations.

Question 3

Age of bone marrow failure in Fanconi Anemia

Answer 3

Bone marrow failure rarely develops early in life and typically presents between age 6-8. For this
reason the patient may present with congenital anomalies or cancer prior to bone marrow failure
being clinically evident.

Question 4

Gorlin syndrome

Answer 4

There is an estimated 4-5% risk of developing medulloblastoma in patients with Gorlin syndrome. This can represent the first clinical manifestation of the disorder and when present precedes the development of basal cell carcinomas

Question 5

Dyskeratosis Congentia (DKC).

Answer 5

• leukoplakia, abnormal nails, and evidence of bone marrow
  failure

DKC results from a telomere defect and quantitative measure of
telomere length is the laboratory test that is now used to aid in making the diagnosis as patients with DKC have telomeres that are shorter than 1% for age.

Question 6

Cowden syndrome

Answer 6

• Hematoma of skin, GIT, breast, and thyroid
• gingival cobblestoning
• Fibromas at various sites in oral cavity
• Cowden Syndrome is due to mutations in the PTEN tumor suppressor gene and is associated with breast and thyroid cancer. Malignancies less frequently seen in Cowden Syndrome include endometrial cancer and renal cell carcinoma.

Question 7

Hepatoblastoma occurrence in which syndrome?

Answer 7

• Hepatoblastoma develops in very young children and recent publications recommend screening for hepatoblastoma in children identified to carry mutations in the APC gene.
• Approximately 5-10% of children with hepatoblastoma carry a mutation in the APC gene.
• Beckwith Weidemann Syndrome also carries an increased risk of hepatoblastoma.

Question 8

Bloom syndrome

Answer 8

• five-year-old child presents with rash on the cheeks, very short stature and she was recently diagnosed with leukemia
• The clinical features are typical of Bloom syndrome, including the butterfly rash on the face.
• Children with Bloom syndrome are very short from birth and remain short.
• The abnormal recombination that results from mutations in the BLM gene yields an increased number of sister chromatid exchanges which can be used as a laboratory test to aid in making diagnosis.

Question 9

Von Hippel-Lindau types of mutations

Answer 9

A significant percentage of patients (over 35%) with VHL carry missense mutations.

• In particular, missense mutations are associated with Type II VHL. The Type II families demonstrate an increased risk of developing pheochromocytomas.
• The other syndromes listed all have truncating mutations (nonsense, frameshift and splicing) as the predominant type.

The correct answer is E.

Question 10

What age do MEN 2 recommend prophylactic thyroidectomy

Answer 10

• The risk of medullary thyroid cancer in childhood is highest in MENIIA and MENIIB.
• However, in MENIIB the age of onset is considerably lower so that prophylactic thyroidectomy is recommended by age 1.
• In MENIIA it is recommended to be performed by age 5.
• FAP is associated with an increased risk of thyroid cancer compared to the general population but not to an extent to warrant prophylactic thyroidectomy.

Question 11

NF1 teenager age onset characteristic

Answer 11

Malignant peripheral nerve sheath tumors typically first appear during the teenage or young adult years.

• Acoustic lesions can be diagnosed in teenagers but occur in NF2 not NF1.

Other features are diagnosed in very young children:

A. Acoustic schwanoma
B. Axillary freckling
C. Learning disabilities
E. Optic pathway tumor

Question 12

Unilateral retinoblastoma recurrence risk

Answer 12

• Overall about 15% of unilateral retinoblastoma patients carry a germline mutation.
• There is the risk that this mutation may be the result of germline mosaicism in the parents (which for offspring with bilateral retinoblastoma results in a 5-7% recurrence risk for another child).
• In the unilateral setting described here this risk is diminished but is still approximately 0.5-1% for each pregnancy that another child may develop retinoblastoma.

Question 13

Risk of colorectal cancer ranked

Answer 13

FAP- 95%

HNPCC- 75%

JPC- 50%- (especially SMAD4 gene)

PJS- higher risk of other cancers

FAP and HNPCC have significantly higher risks, 95% and 70%, respectively, then JPC and PJS.

• Although initially controversial is it now clear that JPC families do have an increased risk of colorectal cancer (~50%) and that appears to be particularly true of families that carry mutations in the SMAD4 gene. Peutz-Jeghers syndrome is associated with higher risk of other cancers.

Question 14

Retinoblastoma germline mosaicism

Answer 14

• There is a significant risk of germline mosaicism in the fathers of children with constitutional RB1 mutations resulting in a 6-7% recurrence risk.
• Thus, even if parents test negative it is important to have all subsequent siblings tested at birth for the mutation identified in the affected child in order to determine if the newborn needs surveillance for retinoblastoma.

Question 15

Highest likelihood of Wilms tumor in BWS

Answer 15

• The IGF2 growth factor is thought to be important for growth control and tumor development. Children with abnormal methylation of the H19/IGF2 locus have a high Wilms tumor risk compared with the other options given. Clinically, children with hemihypertrophy and organomegaly also have a
• high Wilms tumor risk.

Question 16

Costello gene and mechanism

Answer 16

Costello syndrome is due to classic missense changes which constitutively activate the H-Ras oncogene.

• The second wild-type H-Ras gene is retained in the tumor and transfection assays of the mutant gene into NIH3T3 cells demonstrate transforming activity.

Question 17

Cockayne syndrome

Answer 17

cells are deficient for transcription-coupled repair and patients do not have a significant cancer risk

Question 18

Microsatellite instability

Answer 18

likelihood that analysis of a blood sample from this patient will
reveal a germline mutation in one of the mismatch repair genes= 5%

Question 19

pulmonary pleuroblastoma

Answer 19

The majority of patients (>80%) with pulmonary pleuroblastoma carry a germline mutation in DICER1, an enzyme involved in microRNA processing

Question 20

Risk for CDH1

Answer 20

• CDH1 encodes E-cadherin and mutations in this gene were first identified in familial diffuse gastric cancer.
• Analysis of these families demonstrated that there was an unexpected prevalence of lobular breast cancers in these families.
• Subsequently, analysis of familial lobular breast cancer kindreds also revealed CDH1 mutations.

Question 21

Renal and pulmonary cancers

Answer 21

• Chromophobe renal cancer is associated with the Birt-Hogg-Dube syndrome.
• Individuals with BHD often have a significant history of spontaneous pneumothorax as teenagers or young adults.
• Pulmonary fibrosis is seen in dyskeratosis congenita and pulmonary AVMs can be seen in hereditary hemorrhagic telangiectasia. Pulmonary hemangiomas are not a typical

Question 22

Breast Cancer models and guidelines

Answer 22

• BRCAPro was developed to predict the likelihood of BRCA1/2 mutationband can be used in women with or without a personal history of breast cancer.
• The Chompret criterion is helpful in determining the likelihood of TP53 mutations.
• The Claus tables are designed to determine the risk of breast cancer in healthy women based on their family history of breast cancer.
• The Gail model is also for healthy women (overage 35) to predict risk of breast cancer.
• The NCCN guidelines suggest TP53 testing for any woman diagnosed with breast cancer under age 35 if BRCA1/2 is negative.

Question 23

Trisomy 21 who develops transient myeloproliferative disorder. A somatic mutation in which gene is most likely to be found when examining the bone marrow

Answer 23

• Somatic GATA1 mutations are seem in almost all cases of TMP which is a frequent complication of children with Down syndrome.
• AKT undergoes somatic mutation in Proteus syndrome and is not a transcription factor,
• ETV6 is a translocation partner in AML,
• IKZF1 mutations and deletions are common in ALL and RUNX1 deletions and mutations cause familial platelet disorder with AML.

Question 24

IF the Retinoblastoma is sporadic then the risk of having another child with retinoblastoma is

Answer 24

Thus, with this information, there is much less than 1% risk to subsequent
siblings.

Question 25

bone marrow failure, dystrophy, and oral leukoplakia

Answer 25

• Although bonemarrow failure and head & neck cancer is also common in Fanconi anemia, it is very rarely X-linked and abnormal nails and leukoplakia are key features of dyskeratosis congenita.
• The most common form of DKC is X-linked and telomere flow FISH demonstrating very short telomere is the diagnostic test.

Question 26

Breast cancer models

Answer 26

• The NCCN guidelines suggest TP53 germline testing for any woman diagnosed with breast cancer under age 35 if BRCA1/2 is negative.
• A is wrong because the Amsterdam criteria are designed to determine the likelihood of Lynch syndrome.
• The Chompret criterion is helpful in determining the likelihood of TP53 mutations.
• The Claus tables are designed to determine the risk of breast cancer in healthy women (without breast cancer) based on their family history of breast cancer.
• The Gail model is also for healthy women (over age 35) to predict risk of breast cancer and can’t be used once a woman has a diagnosis of breast cancer.

Question 27

VHL

Answer 27

VHL is associated with pheochromocytomas of both the adrenal and extraadrenal locations.

Individuals with VHL have a significantly increased risk of endolymphatic sac tumors that are not seen in any of the other genes listed here.

All of the other genes are associated with pheochromcytoma or paraganglioma.

Question 28

hereditary leiomyomatosis with renal cell cancer (HLRCC) which is caused by heterozygous mutations in the fumarate hydratase (FH).

Answer 28

• The clinical description is typical of hereditary leiomyomatosis with renal
• cell cancer (HLRCC) which is caused by heterozygous mutations in the fumarate hydratase (FH).
• Birt Hogg Dube is associated with oncocytic RCC and not with uterine lesions;
• MET is associated with hereditary papillary renal cell cancer and not the other lesions;
• PTEN can be associated with RCC and endometrial cancer but the skin lesions are different;
• VHL is associated with RCC but no skin or uterine findings.

Question 29

Fanconi anemia, chromosome breakage syndromes

Answer 29

• The pedigree suggests an autosomal recessive pattern of inheritance.
• Most forms of Fanconi anemia are autosomal recessive except one X-linked form (FANCB).
• Bone marrow failure and head & neck cancer are common in both Fanconi anemia and Dyskeratosis congenita.
• However, radial ray anomalies are a classic feature of Fanconi anemia (as is short-stature).
• Thus, the diagnostic test is diepoxybutane testing of a peripheral blood sample to look for increased breakage and chromosome abnormalities.

Question 30

Rhabdoid predisposition syndrome.

Answer 30

Rhabdoid tumors of the solid organs and the CNS (referred to as atypical rhabdoid/teratoid tumors) are associated with both somatic and germline mutations in SMARCB1.

Question 31

Dominant mutations in cancer susceptibility genes in cancer screening

Answer 31

Multiple studies over the last five years of unselected pediatric cancer cohorts have all found between 6 to 10% of children cancer pathogenic/likely pathogenic variants in dominant cancer
susceptibility genes.

Less than 1% of patients have recessive cancer susceptibility disorders diagnosed with biallelic mutations.

Question 32

MEN2

Answer 32

• Multiple endocrine neoplasia is the classic example of where genetic testing can identify individuals at risk who have a high enough risk of cancer to merit prophylactic surgery.
• The variant described (missense variant of a cysteine residue in exon 10) is associated with classic MEN2 and prophylactic surgery is indicated by age 5.