HBOC

Question 1

Identify the genes or syndromes contributing to a

hereditary susceptibility to ovarian cancer.

Answer 1

Hereditary Ovarian Cancer (5-10%)
   BRCA1  =  ~70%
   BRCA2  =  ~20%
   HNPCC  =  ~2%
   Other single genes  =  ~8%

Question 2

What features indicate an increased likelihood of

having a BRCA mutation?

Answer 2

Features suggestive of a BRCA mutation include:
Multiple cases of early onset breast cancer
Ovarian cancer
-in conjunction with a family history of breast or OC
Breast and ovarian cancer in the same woman
Bilateral breast cancer
Ashkenazi Jewish heritage
Male breast cancer
Basal phenotype (suggestive of BRCA1 only)
-ER negative, PR negative, her2neu negative
-if “triple negative” and diagnosed < 40y, 25% chance of BRCA mutation (irrespective of family history)

Question 3

Describe two disorders that are genetically related to germline mutations in BRCA2.

Answer 3

Familial pancreatic cancer
Two or more first- or second-degree relatives affected
BRCA2 mutations:
-seen in ~6% of moderate- and high-risk pancreatic cancer families
-reported in site-specific pancreatic cancer families
-may interact with modifier genes to produce overabundance of pancreatic cancer in some mutation positive families

Fanconi Anemia
BRCA2 = FANCD1 complementation group
Individuals with FA can be BRCA2 homozygotes or compound heterozygotes
-associated w/ early-onset leukemia and solid tumors

Question 4

Discuss the possible results of BRCA1/2 genetic testing

and the impact of each result on cancer risk.

Answer 4

BRCA1/2 Positive

• Deleterious mutation identified
• High-risk for BRCA1/2-associated cancers

BRCA1/2 Negative

1. If known familial mutation:
   
   • true negative result
   • general population risk for cancer
2. Proband/no known familial mutation:
   
   • uninformative– genetic risk for cancer is not R/O
     - cancer risk +clinical recommendations base on Fhx

BRCA1/2 Variant of Unknown Significance (VUS)

• Track variant until classified as either deleterious or normal variant
• Cancer risk and clinical recommendations based on family history

Question 5

Discuss the preventative surgeries available for individuals who are BRCA mutation positive. Identify the reduction in cancer risk provided by each procedure.

Answer 5

Prophylactic Mastectomy
Reduces risk for breast cancer by > 90%
Subcutaneous mastectomy is not recommended
-procedure removes less breast tissue (may not have reduce risk for cancer as significantly, due to remaining tissue)
Reconstruction options are available

Prophylactic Oophorectomy (w/ or w/o Hysterectomy)
Reduces risk for ovarian cancer by 80-90%
-small remaining risk for primary peritoneal carcinoma
Reduces risk for breast cancer by > 50% in pre-menopausal women
Recommended after childbearing is complete
Hormone replacement therapy (HRT) is available for young women who have not developed breast cancer (does not increase risk)

Question 6

Identify the cancers associated with BRCA1 and the approximate lifetime risk for each cancer in mutation positive individuals.

Answer 6

BRCA1-Associated Cancers + Lifetime risk

Breast cancer: 50-85%
Second primary breast cancer: 40-60%
Ovarian cancer:30-45%
 Some studies have found small increased risks of: colon, pancreatic, and male breast cancer.

Question 7

Identify the cancers associated with BRCA2 and the approximate lifetime risk for each cancer in mutation positive individuals.

Answer 7

BRCA2-Associated Cancers + Lifetime risk

Breast cancer: 50-85%
Ovarian cancer: 10-20%
Male breast cancer: 5-10%
Prostate cancer: 15-25%
Pancreatic cancer: 5-10%
Melanoma: 3-5%

Question 8

Identify the cancers associated with Cowden syndrome
and the approximate lifetime risk for each cancer in
mutation positive individuals.

Answer 8

Cowden Syndrome Associated Cancers +Lifetime Risk
Breast cancer
   - Onset in 30s and 40s
   - Male breast cancer reported 25-50%
Thyroid cancer
   - Usually follicular, rarely papillary
   - NEVER medullary 10%
Uterine cancer 5-10%

Question 9

Li-Fraumeni Syndrome

Answer 9

Inheritance: Autosomal dominant
Gene: TP53, ~20% de novo rate
Associated tumors:
   ●Adrenocortical carcinoma
   ●Brain tumors
       oChoroid plexus carcinoma
       oGlioblastoma
       oMedulloblastoma
       oAstrocytoma
  ●Sarcoma
  ●Breast
  ●Leukemia
  ●GI
  ●Genitourinary
  ●Skin
  ●Thyroid
  ●Neuroblastoma
  ●Pancreatic
  ●Lung
Multiple primary tumors, with the first primary often occurring before age 30. Lifetime risk for any primary is nearly 100%

Question 10

PTEN Hamartoma Tumor Syndrome (PHTS)

Answer 10

Encompasses a wide variety of syndromes that fall on a spectrum: Cowden, Bannayan-Riley-Ruvalcaba, Proteus and Proteus-like
Inheritance: Autosomal dominant
Gene: PTEN
Associated tumors:
●2 or more hamartomas in the colon
●Breast cancer
●Uterine cancer
●Follicular thyroid cancer
●Colon cancer
●Renal cell carcinoma
●Uterine leiomyomas (fibroids)
●Mucocutaneous lesions
    oTrichilemommas
    oAcral keratoses
    oPapillomatous lesions
    oLipomas
    oFibromas
Other features:
●Macrocephaly
●Autism and/or ID/learning disabilities
●Fibrocystic breasts
●Penile freckling
●Thyroid lesions

Question 11

Lhermitte-Duclos

Answer 11

PTEN with dysplastic gangliocytoma of the cerebellum

Question 12

HBOC: NCCN Guidelines

Answer 12

Management (NCCN GUIDELINES):
●	Breast awareness at age 18
●	Clinical breast exam every 6-12 months at age 25
o	Age 35 for men
●	Annual breast MRI at age 25
●	Annual mammogram and MRI beginning at age 30 (every six months 1, then the other)
●	Option of prophylactic mastectomy
●	Recommended BSO between 35-40