High & moderate risk breast & ovarian cancer predisposition syndromes

Breast cancer risk factors

Age; prior breast cancer diagnosis; benign breast pathology; race/ethnicity; breast density; previous radiation; hormonal factors; reproductive history; lifestyle factors; family history; hereditary cancer predisposition syndromes

Ovarian cancer risk factors

Age; hormonal factors; reproductive history; lifestyle factors; family history; hereditary cancer predisposition syndromes

High risk breast cancer genes

BRCA1

BRCA2

CDH1

PALB2

PTEN

STK11

TP53

Moderate risk breast cancer genes

ATM

BARD1

CHEK2

NF1

RAD51C

RAD51D

New/possible risk breast cancer genes

BRIP1

Lynch syndrome (MLH1; MSH2; MSH6; PMS2; EPCAM)

High risk ovarian cancer genes

BRCA1

BRCA2

Lynch syndrome (MLH1; MSH2; MSH6; PMS2; EPCAM)

Moderate (or low) risk ovarian cancer genes

ATM

BRIP1

PALB2

RAD51C

RAD51D

Clinically actionable genes

Genes with medical management guidelines or recommendations for individuals with pathogenic/likely pathogenic variants

Mutation carriers have different management recommendations from the recommended average risk individuals

The identification of a mutation in the gene will change medical management

Hereditary Breast and Ovarian Cancer (HBOC) Syndrome

BRCA1

BRCA2

HBOC prevalence

BRCA1/2 combined carrier frequency: 1:400

AJ: 1:40

HBOC chromosome location

BRCA1 at 17q21

BRCA2 at 13q12

HBOC inheritance

Autosomal dominant

Autosomal dominant

Men and women are affected equally, and both parents can pass the mutation on to any son or daughter

Does not skip generations

BRCA1/2

Tumor suppressor genes

BRCA1/2 founder mutation populations

AJ

Icelandic

Dutch

Finnish

AJ BRCA1/2 founder mutations to be aware of

BRCA1 c.68_69delAG

BRCA1 c.5266dupC

BRCA2 c.5946delT

General population cancer risk

Breast (AFAB): 12%

Second breast (AFAB): 1.5% per year

Ovarian: 1-2%

Breast (AMAB): 0.1%

Prostate: 11%

Pancreatic: 1-2%

Melanoma: 1-2%

BRCA1 mutation cancer risk

Breast: 60-80%

Second breast (AFAB): 83% by age 70

Ovarian: 37-44%

Breast (AMAB): 1.2%

Prostate: Increased

Pancreatic: 2-3%

Melanoma: Unknown

BRCA1 mutation associated with _____

TNBC

Ovarian serous adenocarcinomas

Serous uterine cancer

BRCA2 mutation cancer risk

Breast: 50-70%

Second breast (AFAB): 62% by age 70

Ovarian: 16.5-20%

Breast (AMAB): 7-8%

Prostate: 20%

Pancreatic: 3-6%

Melanoma: 3-5%

BRCA2 mutation associated with _____

Ovarian serous adenocarcinomas

Ocular melanoma

BRCA1/2 medical management - AFAB

Breast

- breast awareness (18), clinical breast exam every 6-12 months (25), annual (25-29), annual mammogram and breast MRI (30-75)

- discuss option of breast risk-reducing mastectomy (90+% risk reduction)

- chemoprevention (i.e. Tamoxifen)

Ovarian

- no screening options

- risk-reducing salpingo-oophorectomy (96% risk reduction) and maybe hysterectomy

- ovulation suppression (i.e. oral contraception or hormonal IUD)

- referral to fertility specialists

BRCA1/2 medical management - AMAB

Breast cancer screening starting at 35

- self-exam and education

- clinical breast exam every 12 months

- consider annual mammogram in men at age 50 or 10 years before the earliest known AMAB breast cancer in the family

Prostate screening starting at 40 (BRCA2 for sure, maybe BRCA1)

BRCA1/2 medical management - all individuals

Pancreatic cancer screening at age 50 or 10 years younger than the earliest exocrine pancreatic cancer in the family

Melanoma screening via annual full body, skin, and eye exam

- minimize UV exposure

Fanconi Anemia (FA) is characterized by ____

- progressive bone marrow failure

- increased cancer risk

- physical differences

Biallelic gene mutations that cause FA

BRCA1

BRCA2

PALB2

BRIP1

RAD51C

PARP inhibitors

Anti-cancer drug that inhibits repair of single-strand DNA breaks (BRCA1/2 mutation means cannot repair DOUBLE-strand DNA breaks, so you knock out both...those cancer cells are dying...until they develop resistance)

Li-Fraumeni Syndrome (LFS)

Gene: TP53

Prevalence: 1:20,000

Chromosome location: 17p13.1

Inheritance: autosomal dominant (7-20% de novo)

LFS-associated tumors

Premenopausal breast cancer

CNS tumors

Soft tissue sarcoma

Osteosarcoma

Adrenocortical carcinoma

Hematologic malignancies

(GI cancers, GU cancers, lung cancers, skin cancers, thyroid cancers, pediatric cancers)

LFS lifetime risk of cancer

AFAB: 100%

AMAB: 73%

Classic diagnostic criteria for LFS

1) Proband with a sarcoma before age 45 AND

2) A first degree relative with any cancer before age 45 AND

3) A first or second degree relative with cancer before age 45 or a sarcoma at any age

LFS management

- Annual breast MRIs, clinical breast exam every 6-12 months (20), annual mammograms (30), option of bilateral mastectomy

- Comprehensive physical exams every 6-12 months

- Annual dermatologic examination

- Annual brain MRA and whole body MRI

- Annual PSA (40)

- Pancreatic cancer screening (50)

- Organ-targeted surveillance based on family history

TP53 mosaic findings

~30% variant allele fraction

- constitutional

- acquired/somatic (ctDNA, CHIP)

PALB2 mutation cancer risk

32-53% risk of breast cancer by age 70 (AFAB)

0.9% risk of breast cancer by age 70 (AMAB)

2-5% lifetime risk of pancreatic cancer

3-5% lifetime risk of ovarian cancer

PALB2 medical management

- Annual mammogram with consideration of tomosynthesis & breast MRI (30); discuss risk-reducing mastectomy

- Pancreatic cancer screening (50 or 10 years earlier)

- Ovarian cancer screening via RRSO (45-50)

ATM mutation cancer risk

21-24% lifetime risk of breast cancer (AFAB)

- 69% risk if ATM c.7271T>G

5-10% lifetime risk of pancreatic cancer

2-3% lifetime risk of ovarian cancer

Emerging evidence for prostate and colorectal cancers...

ATM medical management

- Annual breast MRI (30-35) and annual mammogram/tomosynthesis (40)

- Pancreatic cancer screening (50 or 10 years earlier)

- PSA (40)

Ataxia Telangiectasia (AT) is characterized by ____

- Progressive cerebellar ataxia

- Telangiectasias

- Immunodeficiency

- Increased cancer risk

Biallelic gene mutations that cause AT

ATM

CHEK2 mutation cancer risk

23-27% lifetime risk of breast cancer (AFAB)

Emerging evidence for prostate cancer, male breast cancer, thyroid cancer, gastric cancer, kidney cancer...

CHEK2 medical management

- Annual breast MRI (30-35) and annual mammograph/tomosynthesis (40)

- PSA (40)

*Largely depends on the person and family history to guide screening recommendations and medical management

CHEK2 variants to be aware of

CHEK2 c.1100delC = 28.9% 10-year risk of developing contralateral breast cancer

CHEK2 c.470T>C = "low-penetrant" allele, no management recommended

CHEK2 c.1283C>T = "low-penetrant" allele, no management recommended

Neurofibromatosis Type I (NFI) mutation cancer risk

20-40% risk of breast cancer by age 50 (AFAB)

Malignant peripheral nerve sheath tumors

(GISTs leukemia, MDS, rhabdomyosarcomas, pheochromocytomas, glomus tumors, retinal vasoproliferative tumors...)

NF1 medical management (tumors)

- Annual mammogram with consideration of tomosynthesis (30) and MRI (30-50)

- Referral to NF1 specialist

*Consideration of false-positive MRI results with breast neurofibromas

BRIPI mutation cancer risk

5-15% lifetime risk of ovarian cancer

Possible increased risk for breast cancer (AFAB)

BRIP1 management

- Consider risk-reducing salpingo-oophorectomy (45-50)

*Or earlier based on family history

RAD51C mutation cancer risk

10-15% lifetime risk of ovarian cancer

20% lifetime risk of breast cancer (AFAB)

RAD51C medical management

- Risk-reducing salpingo-oophorectomy (45-50)

- Annual mammogram and consider breast MRI (40)

RAD51D mutation cancer risk

10-20% lifetime risk of ovarian cancer

20% lifetime risk of breast cancer (AFAB)

RAD51D medical management

- Risk-reducing salpingo-oophorectomy (45-50)

- Annual mammogram and consider breast MRI (40)