Hereditary disorders in which CRC is an integral lesion
| Hereditary form of colorectal cancer (CRC) | Inheritance pattern | Gene | Polyps | Cancer |
|---|---|---|---|---|
| Familial adenomatous polyposis (FAP) | AD | APCgene at chromosome 5q, mutation distal to 5′ | Adenomatous, often start in distal colon/rectum; usually >100; adenomas may occur in small bowel; gastric polyps common, usually fundic gland polyps | CRC, average age onset 39; many cases teens and twenties; cancer of small bowel; stomach (particularly in Japan), papillary thyroid cancer, periampullary carcinoma, sarcoma, brain tumour |
| Attenuated familial adenomatous polyposis coli (AFAP) | AD | APC gene at chromosome 5q, proximal to 5′ | Ordinary adenomas but also flat adenomas with proximal colonic predominance; may be few (5–10), sometimes >100 | CRC with average age onset at 55; occasional periampullary carcinoma |
| Ashkenazi Jewish 11307K mutation | AD | 11307K mutation inAPC | Occasional adenomatous colonic polyps | CRC, “young” but average age of onset not known |
| Turcot’s syndrome (HNPCC) | AD | (Both FAP (APC) and HNPCC,hPMS2, hMLH1mutation variants) | Multiple colonic adenomas, but may not be florid | CRC and central nervous system, particularly brain tumours. In APC (FAP families) cerebellar medulloblastomas. In hMLH1 andhPMS2 (HNPCC families) glioblastoma multiforme |
| Juvenile polyposis coli | AD | Protein tyrosine phosphate gene (PTEN) SMAD4/DPC4 | Diffuse harmatomatous polyps (may have adenomatous component) of colon, but may occur in small bowel and stomach | CRC |
| Peutz-Jeghers syndrome | AD | Gene encoding serine threonine kinase (STK11) on chromosome 19p13.3LKB1/STK11 | Peutz-Jeghers polyps (may have adenomatous features) in stomach, small bowel, and colon | Stomach, small bowel, colon, sex cord tumours of ovary and testes |
| Hereditary mixed polyposis syndrome (IMPS) | AD | Unknown; possible site on chromosome 6q | Atypical colonic juvenile polyps, adenomatous and hyperplastic polyps; usually less than 15 colon polyps | CRC |
| Discrete colonic adenomatous polyps and CRC of Burt | AD; may be similar to some familial CRC | Occasional (never florid) adenomatous colonic polyps | CRC, average age in accord with population expectations | |
| Hereditary non-polyposis colorectal cancer (HNPCC) | AD | Germline mutations of any of the mismatch repair genes: hMSH2 at chromosome 2p; hMLH1 at chromosome 3p;hPMS1 at chromosome 2q;hPMS2 at chromosome 7q | Occasional colonic adenomas which are on average larger, more villous, and at younger age than general population. Colonic polyps no more frequent than general population | CRC most common with proximal predominance, an excess of synchronous and metachronous CRC. Others include cancer of the endometrium, ovary, small bowel, stomach, and transitional cell carcinoma of ureter and renal pelvis. Average age of cancer onset is 44; may show rapid progression from adenoma to CRC |
| Familial CRC | Empirical risk 3 fold increase for CRC in patients with one or more first degree relatives with CRC; likely multifactorial and/or low penetrant genes | Unknown | In accord with population expectations | CRC, comparabe to general population for age of onset and colonic location |
| Inflammatory bowel disease (ulcerative colitis (UC) and Crohn’s disease (CD)) | Unknown; possible AD in some families; polygenic also likely | Linkage to chromosome 16 (IBD1) and 12 (IBD2), findings which are tentative | Pseudopolyps (non-adenomatous) | CRC, lymphoma of GI tract |
| Non-cancer features | Screening | Surgical management/prophylaxis | Presymptomatic DNA testing | Genetic counselling |
|---|---|---|---|---|
| Gardner’s variant-epidermoid cysts of skin, osteomas of mandible, congenital hypertrophy of the retinal pigment epithelium. Desmoid tumours (intrabodiminal) do not metastasise but may kill by direct extension; desmoids may be initiated by surgery (dissected surfaces); adrenal adenomas | Baseline flexible sigmoidoscopy age 10–12, and annually thereafter, for APCgermline positive. If at risk but not tested forAPC, same strategy. If eventually found to be APC negative, then baseline flexible sigmoidoscopy at age 15–20; if negative, no further screening. Upper endoscopy every 1–3 years starting when colonic polyps first appear. Screen remaining rectal segment (annually) after surgical prophylaxis | Prophylactic subtotal colectomy with low ileorectal anastomosis when phenotype (florid polyposis) identified; may be considered rectal mucosectomy with ileal pouch anal anastomosis if too many rectal polyps to manage or if compliance for rectal segment follow up is poor. Consider sulindac chemoprevention (while reducing polyps, cancer may still occur) | Test for APCgermline mutation as early as age 10–12 | Initiate pre-teens, include parents |
| Fundic gland polyps in stomach; adenomas in duodenum | Colonoscopy and upper endoscopy, initiate at age 20 and annually forAPC germline positive patients or every 2 years if at genetic risk but not tested forAPC | Prophylactic subtotal colectomy if too many polyps to manage; consider chemo-preventative sulindac | Test forAPC germline mutation at age 20 | Initiate at age 20, include parents |
| None known | Full colonoscopy, start at age 30–35 in gene carriers | Standard CRC surgery | Ashkenazi APC mutation | Start at age 25 |
| Rare examples of multiple café au lait spots and pigmented naevi but not clear if truly integral to the syndrome | Baseline flexible sigmoidoscopy age 10–12 and annual flexible sigmoidoscopy thereafter; consider CT scan or MRI of brain | Prophylactic subtotal colectomy if colonic polyps present, as in FAP. In HNPCC variant, colonoscopy | Two DNA variants: (1) APC gene with predominance of cerebellar medulloblastoma, (2)hMLH1 or hPMS2 with predominance of glioblastoma multiforme | Initiate age 10–12, include parents |
| Children may manifest diarrhoea (may be severe) | Initiate colonoscopy age 10–12 | Prophylactic subtotal colectomy when phenotype present with too many polyps to manage | Tyrosine phosphate gene (PTEN) | Initiate preteens, include parents |
| Mucocutaneous melanin pigmentation | Baseline colonoscopy and upper endoscopy, initiate age 20; flexible sigmoidoscopy annually thereafter | Consider prophylactic subtotal colectomy if too many polyps to manage and if mixed adenomatous features | Serine threonine kinase (STK11) on chromosone 19p13.3 | Initiate teens, include parents |
| None known | Colonoscopy, initiate at age 20, 2–3 years | Polypectomy; consider prophylactic colectomy if polyps too many to manage | None known | Include initiation in teens |
| None known | Initiate baseline flexible sigmoidoscopy at age 40 and every 3 years thereafter | Standard CRC surgical approach | None known | Initiate at age 25–30 |
| Muir-Torre syndrome variant shows cancer features of HNPCC but includes sebaceous adenomas, sebacous epitheliomas, basal cell epitheliomas with sebaceous differentiation, meibomian gland carcinomas and sebaceous carcinomas; single or multiple keratoacanthomas | Colonoscopy, initiate age 20–25, annually for germline muttion carriers; every other year when mutation studies are lacking; endometrial aspiration biopsy at the same time as colonoscopy | Subtotal colectomy for initial CRC; consider option of prophylactic subtotal colectomy for germline carriers; consider prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy for patients with initial CRC who have completed their families | Test for germline mutations no earlier than age 18–20 | Initiate at age 18, before any consideration for gene testing |
| None | Baseline flexible sigmoidoscopy at age 35, repeat every 3 years; if two first degree relatives affected or one less than age 50 years, risk is 4–6 fold increased and full colonoscopy every 3–5 years is indicated | Standard surgical procedure for CRC | None known | Initiate at age 30–35 |
| UC: arthritis, pyoderma gangrenosum, annular erythemas, and vascular thromboses, sclerosing cholangitis CD: similar to UC but small bowel involvement prominent, and may involve colon | UC: colonoscopy, annual in patients with chronic pancolitis of 8 or more years duration; check for high grade dysplasia of colonic mucosa. CD: BE may help;x ray of small bowel may show rigidity, narrowing submucosal oedema or stenosis, inflammation, “cobblestoned appearance” may see clinical and genetic overlap in UC and CD | Subtotal colectomy for CRC; consider prophylactic subtotal colectomy for patients with persistent high grade dysplasia of colonic mucosa in UC. Proctocolectomy if IBD mandates | None known | Initiate at age 18–20 |
AD=autosomal dominant. CRC=colorectal cancer. IBD=inflammatory bowel disease. UC=familial ulcerative colitis. CD=Crohn’s disease.
Adapted with permission from Lynch et al.Eur J Cancer1995;31A:1039-46.