Cancer Genetics - Hereditary Polyposis Colorectal Cancer Syndromes

APC Associated Polyposis Conditions

• Familial Adenomatous Polyposis (FAP)

• Attenuated FAP (AFAP)

• Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS)

Familial Adenomatous Polyposis

• FAP

• APC

  • Autosomal dominant

  • De novo rate: 20 - 25%

• Characterized by hundreds to thousands of adenomatous colonic polyps

• Colorectal adenomatous polyps begin to appear in 20s to 30s

  • Average age of polyp diagnosis is 16 years

    • By 35 years old, 95% of people with FAP have polyps

• Without colectomy, colorectal cancer is inevitable

  • The average age of colorectal cancer in untreated is 39 years old

    • 93% by 50

• Non-malignant features

  • Osteomas - bony growths most commonly found on skull and mandible

  • Dental abnormalities

  • CHRPE

  • Desmoid tumors - benign tumors that are invasive but do not metastasize

  • Adrenal masses

Attenuated FAP

• AFAP

• APC on chromosome 5q21

  • Autosomal dominant

• Characterized by fewer colonic polyps than classic FAP but still a significant risk for colorectal cancer

  • Average of 30 polyps, <100 polyps

• Average age of colorectal cancer diagnosis is 50 - 55 years

  • Cumulative risk for colorectal cancer risk by age 8- is estimated at 70%

• Thyroid and duodenal risk similar to classic FAP

• Typically no extraintestinal manifestations

Adenomatous Polyposis Testing Criteria

• Recommend testing if personal history of one or more of the following:

  • >= 20 cumulative adenomas

  • Multifocal / Bilateral Congenital Hypertrophy of Retinal Pigment Epithelium (CHRPE)

    • Flat, pigmented spot found in the back of the eye

  • Cribiform-morular variant of thyroid cancer

  • Family history of polyposis and family unwilling / unable to have testing

• Consider testing if personal history of one or more of the following:

  • Between 10 - 19 cumulative adenomas, desmoid tumors, hepatoblastoma, unilateral CHRPE, or individual meets criteria for serrated polyposis syndrome with at least some adenomas

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach

• GAPPS

• APC on chromosome 5q21

  • Autosomal dominant

• Characterized by Gastric polyps called Fundic Gland Polyps

  • Intestinal-type gastric adenocarcinoma: 13 - 25%

  • Typically no significant duodenal or colorectal polyposis

APC I1307K

• Common variant reported in Ashkenazi Jewish population

• NOT FAP

MUTYH - Associated Polyposis Syndrome

• MAP

• MUTYH

  • Autosomal recessive

• Characterized by ten to a few hundred colonic polyps

  • Sometimes have colorectal cancer with no polyposis

• Treatment of manifestations

  • CRC polyps should be removed

  • Duodenal polyps should be excised

  • Thyroid findings should be evaluated by thyroid specialist

• Surveillance

  • Colonscopy

  • Upper endoscopy and duodenoscopy

  • Thyroid ultrasound

• Individuals with heterozygous MUTYH inheritance

  • Offer average moderate-risk colorectal screening based on family history

Peutz-Jeghers Syndrome

• STK11

  • Autosomal dominant

• Clinical Diagnosis

  • Two or more Peutz-Jeghers-type hamartomatous polyps of GI tract

  • Mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia or fingers

  • Family history

  • Dark blue or brown moles around mouth, eyes, nostrils, and anus

    • Dark moles on the hands and feet

• Individuals with PJS develop hamartomatous polyps

  • GI - small intestine, stomach, large bowel

  • Extraintestinal sites - kidneys, lungs, gall-bladder, nose, bladder and ureters

  • Increased risk for colorectal, intestinal, gastric, pancreatic, breast, cervical, lung, testicular and ovarian cancer

    • Females are at risk for sex cord tumors and cervical cancer

    • Males can develop sertoli cell tumors of the testes

      • Secrete estrogen and can lead to gynecomastia

Juvenile Polyposis Syndrome

• BMPR1A and SMAD4

  • Autosomal dominant

  • 50% of individuals meeting clinical criteria have detectable mutations

• Clinical Diagnosis

  • 5+ juvenile polyps (type of hamartoma) of the colon

    • Juvenile refers to a type of polyp

  • Multiple juvenile polyps in GI tract

  • Any number of juvenile polyps with a family history of JPS

• Clinical Characteristics

  • Childhood-onset

  • Polyps cause iron deficiency anemia and bleeding

  • Significantly increased risks for cancer (colorectal, stomach, and small intestines

    • Risk for GI cancer range from 11% to 86%, mostly colon cancer

• Hereditary Hemorrhagic Telangiectasia (HHT)

  • SMAD4 variant

    • HHT features - arterial-venous malformations (AVMs), epistaxis (nosebleeds), telangiectasias, digital clubbing

Atrial-Venous Malformations

• Tangle of blood vessels that irregularly connects arteries and veins

• Result from the development of irregular connections between arteries and veins

Serrated Polyposis Syndrome

• Increased risks for colorectal polyposis and colorectal cancer

• Clinical diagnosis

  • >=5 serrated lesions / polyps all being >=5 mm in size, with >=2 being >=10 mm in size

  • >20 serrated lesions / polyps of any size with >=5 being proximal to the rectum

• NO clearly causative gene for most cases

  • Some associations with RNF43 gene have been identified

  • Biallelic pathogenic variants in MUTYH gene

Colonic Adenomatous Polyposis of Unknown Etiology (CPUE)

• Individuals with cumulative lifetime >=10 - 20 adenomas without a PV identified in a polyposis gene

• Management / Surveillance

  • Prior to managing CPUE, multigene testing including all polyposis and colorectal cancer genes should be considered

  • PVs associated with adenomatous polyposis include but not limited to monoallelic PVs in APC, GREM1, POLE, POLD1 and AXIN2 and biallelic PVs in NTHL1, MUTYH, MBD4, MLH3, and MSH3 genes