Table 4.

Hereditary Cancer Syndromes with Increased Risk of Colorectal Cancer in the Differential Diagnosis of Lynch Syndrome

Gene(s)DisorderMOIPolypsColorectal CancerOther Associated Cancers / Clinical Manifestations
RiskMean Age of Onset (Years)
RPS20 RPS20-assoc hereditary nonpolyposis CRC 1ADNoHigh (MMR proficient tumors)AdultNo other assoc cancers / clinical manifestations
APC Familial adenomatous polyposis (FAP) (See APC-Assoc Polyposis Conditions.)ADColonic, gastric & duodenal adenomas (>100 cumulative polyps)~100% if untreated
  • 39 (range: 34-43)
  • Polyp diagnosis: 16 (range: 7-36)
  • CHRPE
  • Osteomas, supernumerary teeth, odontomas
  • Desmoids, epidermoid cysts
  • ↑ risk of medulloblastoma, thyroid papillary carcinoma, hepatoblastoma, & pancreatic, gastric & duodenal cancers
Attenuated familial adenomatous polyposis (AFAP) (See APC-Assoc Polyposis Conditions.)ADColonic, gastric & duodenal adenomas (10-100 cumulative polyps)70% by age 80 yrs50
  • Upper GI findings & thyroid & duodenal cancer risks are similar to FAP.
  • Other extraintestinal manifestations are unusual.
  • Desmoid tumors assoc w/3' APC variants
POLE Polymerase proofreading-assoc polyposis (PPAP) (See OMIM 615083.)ADColonic adenomas (0-100 cumulative polyps)
  • 30%-40% by age 70 yrs 2
  • CRC may develop in absence of polyposis.
  • Note: Most CRCs are MSS; some are MSI high.
50 2
  • ↑ risk of cancers of endometrium, ovary, brain, breast, & other tumor types
  • Adenomas in upper GI tract
POLD1 Polymerase proofreading-assoc polyposis (PPAP) (See OMIM 612591.)ADColonic adenomas (0-100 cumulative polyps)
  • 50%-60% by age 70 yrs 2
  • CRC may develop in absence of polyposis.
  • Note: Most CRCs are MSS; some are MSI high.
35-40 2
  • ↑ risk of cancers of endometrium, ovary, brain, breast, & other tumor types
  • Adenomas in upper GI tract
MUTYH MUTYH polyposis AR
  • Colonic adenomas (10->100 cumulative polyps)
  • Hyperplastic &/or serrated polyps may occur.
  • Duodenal adenomas
  • 43%-63% by age 60 yrs
  • 80%-90% lifetime risk if untreated
  • CRC may develop in absence of polyposis
  • Note: Most CRCs are MSS; a minority are MSI high.
48
  • Duodenal adenomas are common w/↑ risk of duodenal cancer.
  • ↑ risk of ovarian & bladder malignancies
  • Additional features: thyroid nodules, benign adrenal lesions, jawbone cysts, & CHRPE
NTHL1 NTHL1 tumor syndrome AR
  • Colonic adenomas (1-100 cumulative polyps)
  • Hyperplastic &/or serrated polyps may occur.
  • Duodenal adenomas
High lifetime risk61 3
  • High risk of multiple primary tumors
  • ~35%-78% risk of extracolonic cancer by age 60 yrs
  • ↑ risk of breast & endometrial cancers & other tumors types: cervical, urothelial carcinoma of the bladder, meningiomas, unspecified brain tumors, basal cell carcinomas, head & neck squamous cell carcinomas, & hematologic malignancies
MSH3 MSH3-assoc polyposis (OMIM 617100)AR
  • Colonic adenomas (10-100 cumulative polyps)
  • Duodenal adenomas
UnknownAdult 4↑ risk of benign & malignant neoplasia; thyroid adenomas, mammary intraductal papillomas & cysts, gastric cancer, astrocytoma
MLH3 MLH3-assoc polyposis 5ARColonic adenomas (10->100 cumulative polyps)Unknown48-52↑ risk of breast cancer
BMPR1A
SMAD4 		Juvenile polyposis syndrome (JPS)ADHamartomatous polyps in GI tract (stomach, small intestine, colon & rectum)~68% by age 60 yrs42
STK11 Peutz-Jeghers syndrome ADPeutz-Jeghers-type hamartomatous polyps in GI tract (esp in small intestine, but also in stomach, colon, & rectum)39%42-46
  • Peutz-Jeghers-type hamartomatous polyps can occur in extraintestinal sites incl renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, & ureters.
  • Mucocutaneous pigmentation (melanocytic macules)
  • Gonadal tumors
  • ↑ risk of GI cancers, & cancers of the breast, ovary, cervix, endometrium, pancreas, & testis
Duplication upstream of GREM1Hereditary mixed polyposis syndrome (OMIM 601228)ADMultiple polyps of more than 1 histologic type (adenomas, hyperplastic/serrated, & juvenile), &/or individual polyps w/overlapping histologic features (atypical juvenile w/admixed histologic features)↑ CRC risk (unknown estimate)
  • 40s 6
  • Polyp diagnosis: late 20s or later (also reported in adolescence)
Unknown
RNF43 RNF43-assoc serrated polyposis (OMIM 617108)ADColonic serrated polyposis (0->100 cumulative polyps)↑ CRC risk (unknown estimate)AdultNo extracolonic clinical manifestations reported

AD = autosomal dominant; AR = autosomal recessive; CHRPE = congenital hypertrophy of the retinal pigment epithelium; CRC = colorectal cancer; FAP = familial adenomatous polyposis; GI = gastrointestinal; MOI = mode of inheritance; MSI = microsatellite instability; MSS = microstatellite stable

1.
2.

Buchanan et al [2018]. Data should be taken with caution due to the limited number of heterozygotes considered for the estimation of risks.

3.

Grolleman et al [2019]; data obtained from 33 individuals with biallelic NTHL1 pathogenic variants

4.

Adam et al [2016]. Data obtained from four individuals with biallelic MSH3 pathogenic variants. One individual developed CRC at age 55.

5.

Olkinuora et al [2019] identified MLH3 c.3563C>G (p.Ser1188Ter) in three Finnish individuals and one Swedish individual. Experimental data supports founder origin.

6.

From: Lynch Syndrome

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