Genetically Related Cancers

Key features and cancer risks associated with common hereditary cancer syndromes.

Hereditary cancer syndromes are caused by variants (mutations) in genes that control cell growth in multiple tissue types. These variants often cause differences in gene expression within specific tissues. Recognizing genetically related cancers is important not only for identifying families that are suspicious for hereditary syndromes, but also for thinking ahead about how results will be used. In addition, some hereditary cancer syndromes involve distinctive tumor histology or physical features. Recognizing these findings can alert you to the need to analyze a different or additional cancer risk gene. Genetic experts can help identify the best testing strategy.

As more people have genetic testing, and the number of genes being analyzed for each patient expands, our understanding of associated cancer risks has changed. The table below includes the cancers and features most commonly associated with the particular syndrome, but is not exhaustive. In addition, some individuals and families have an atypical history.

Name Most common genes Significantly increased risk  Moderately increased risk Occasional distinguishing features (1)

Hereditary breast and ovarian cancer syndrome

BRCA1
BRCA2

Breast
Ovarian

Male breast
Prostate
Pancreas
Melanoma

Breast tumor with triple negative histology (2)

Lynch syndrome

MLH1
MSH2
MSH6
PMS2
EPCAM

Colorectal
Endometrial
Gastric

Liver
Gall bladder
Urinary tract
Brain
Ovary
Small intestine
Pancreas

Tumor with absent MMR protein or high MSI (3)
Sebaceous gland tumor

Familial adenomatous polyposis syndrome

APC

Colorectal

Gastric
Duodenum
Soft tissue
Bone

10s-100s of adenomatous GI polyps
Dental abnormalities (4)
CHRPE (5)

MUTYH-associated adenomatous polyposis syndrome MUTYH  Colorectal

Duodenum
Ovary
Bladder
Skin

10s-100s of adenomatous GI polyps, may see polyps of other histologies.
Autosomal recessive inheritance; heterozygotes at moderate risk of CRC

Cowden syndrome

PTEN

Breast
Thyroid
Endometrial

Colorectal
Kidney
Melanoma

Head size ≥ 97th percentile
Mucocutaneous lesions
Hamartomatous GI polyps
Autism spectrum disorder
Arteriovenous malformation
Bannayan-Riley- Ruvalcaba syndrome
Proteus syndrome

Li-Fraumeni syndrome

TP53

Breast
Bone
Soft tissue

Leukemia
Lung
Adrenal
Brain

Very early age at cancer diagnosis (≤ 35 years)
Sarcomas

Familial multiple mole and melanoma syndrome

CDKN2A, CDK4

Melanoma

Pancreas

Multiple skin moles

Peutz Jeghers syndrome

STK11

Breast
Ovary
Colorectal
Gastric
Pancreatic
Small bowel
Cervical

Testicular
Endometrial
Lung

Hyperpigmented mucocutaneous lesions
PJS-type hamartomatous GI polyps
Sex cord tumors (SCTAT) of ovaries
Sertoli cell tumors (LCST) of testes

Hereditary diffuse gastric cancer

CDH1

Breast, lobular path.
Diffuse gastric

Colon

n/a

Juvenile polyposis syndrome

BMPR1A, SMAD4

Gastric
Colorectal

Small bowel
Pancreatic

GI tract polyps (Juvenile polyp histology)
Arteriovenous malformation

(1) These findings are neither pathognomonic nor present in every case
(2) ER-, PR-, HER2-
(3) Microsatellite instability
(4) May include supernumerary teeth, odontoma or other dental anomalies
(5) Congenital hypertrophy of the retinal pigment epithelium

Updated May 2019