Hereditary Colorectal Cancer Syndromes
CRC is the third most common cancer in US men and women. In approximately 20–30% of cases, CRCs are associated with a family history of colorectal polyps or cancer, but only 3–5% of cases are associated with an identifiable inherited CRC syndrome. Timely identification of at-risk individuals offers an opportunity to intervene before cancer develops. Content below is from a textbook reference chapter (Sabiston Ch52 - Colorectal Neoplasia & Colon Cancer Surgery), not primary literature; the chapter itself refers readers to the ASCRS Clinical Practice Guidelines for the Management of Inherited Polyposis Syndromes and for the Surgical Treatment of Patients with Lynch Syndrome for fuller detail.
Syndromes at a glance
| Syndrome | Gene(s) | Polyp type | Inheritance | CRC risk |
|---|---|---|---|---|
| Classical FAP | APC | Adenoma | AD | 100% |
| Severe FAP (>1000 adenomas) | APC | Adenoma | AD | 100% |
| Attenuated FAP (<100 adenomas) | APC | Adenoma | AD | 80% |
| MUTYH-associated polyposis (MAP) | MUTYH (biallelic) | Adenoma | AR | 80% |
| Juvenile polyposis syndrome (JPS) | SMAD4, BMPR1A | Hamartoma | AD | 40% |
| Peutz-Jeghers syndrome (PJS) | STK11 | Hamartoma | AD | 40% (39% specifically per the chapter) |
| Lynch syndrome | MLH1, MSH2, MSH6, PMS2, EpCAM | Nonpolyposis adenoma | AD | 60–80% (chapter gives 70% men / 40% women) |
| Cowden syndrome (PHTS) | PTEN | Mixed (hamartoma + adenoma + others) | AD | 9–16% |
| Serrated polyposis syndrome | Not fully elucidated (BRAF, RNF43 implicated) | Serrated | Clinical criteria only | Up to ~50% (advanced neoplasia) |
| POLE/POLD1-related hereditary cancer (PPAP) | POLE or POLD1 | Adenoma | AD | Not well quantified — limited adenomatous polyposis, increased CRC risk |
See the dedicated pages for full detail:
- Familial Adenomatous Polyposis (FAP) — includes MUTYH-associated polyposis, which phenotypically mimics attenuated FAP.
- Lynch Syndrome — including its variants (Turcot syndrome, Muir-Torre syndrome, familial CRC type X).
- Hamartomatous Polyposis Syndromes — Peutz-Jeghers syndrome, juvenile polyposis syndrome, and Cowden syndrome.
- Colorectal Polyps — serrated polyposis syndrome (a genetically not-fully-elucidated syndrome diagnosed on clinical/endoscopic criteria alone, filed there alongside the general serrated-polyp content it extends rather than as a separate page).
POLE/POLD1-related hereditary cancer (PPAP)
A relatively newly described syndrome. Polymerase proofreading-associated polyposis (PPAP) is autosomal dominant with high penetrance, developing due to inactivating mutations in either POLE or POLD1 — both members of the highly conserved DNA polymerase family involved in synthesizing and proofreading DNA. POLD1 also participates in mismatch repair, and defective polymerase proofreading combined with deficient MMR can contribute to the phenotype. Patients with POLD1 or POLE mutations exhibit limited adenomatous polyposis and are at increased CRC risk; women with POLD1 mutations additionally have elevated risk for endometrial and breast cancers. No formal screening recommendations exist yet, though frequent colonoscopy and colectomy as indicated based on phenotype seem reasonable. (Content per ASCRS Ch22 - Sporadic and Inherited Colorectal Cancer.)
Open items / gaps
- No primary literature yet on any of these syndromes — all content is the textbook's summary (originally Sabiston Ch52 - Colorectal Neoplasia & Colon Cancer Surgery; Cowden syndrome, serrated polyposis syndrome, and PPAP added from ASCRS Ch22 - Sporadic and Inherited Colorectal Cancer).
- Genetic counseling workflow (who orders testing, how results are communicated, family cascade testing logistics) is not covered by this chapter — a practical gap for a colorectal surgery practice.
- PPAP's CRC lifetime risk isn't quantified precisely by the source chapter — reported here as-is rather than estimated.