Hereditary non-polyposis colorectal cancer

Last revised by Aaron Li on 22 Oct 2023

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant condition which predisposes to a host of malignancies, including colorectal cancer. It is considered the most frequent form of hereditary colorectal cancer. Diagnosis requires evaluation using clinical criteria (see: Amsterdam criteria for HNPCC).

Historically a distinction was made between Lynch I and Lynch II syndromes, referring respectively to families affected only by colorectal cancer, and those affected by extracolonic malignancies in addition to colorectal cancer, but this distinction is no longer routinely made 7.

Lynch syndrome is the most common cancer syndrome, affecting 1 in 400 persons 3. Typically HNPCC patients present in their forties and fifties with colorectal cancer 2, or with one of the associated malignancies. It is 5 times more common than familial adenomatous polyposis syndromes (FAP) 6. It is the most common hereditary cause of endometrial cancer 9.

HNPCC is due to mutations in DNA mismatch repair (MMR) genes 2, resulting most frequently in colorectal cancer (10-82% lifetime risk 9) as well as extracolonic malignancies, including 1,2:

There is a described association with breast malignancy, although the relationship is inconsistent 9. The MMR genes most commonly affected are MLH1, MSH2 (these two 70-85% of cases, MSH6, and PMS2 or EPCAM, an upstream gene in MSH2 expression 3.

Radiographic features are related to the underlying conditions:

The high risk of colorectal cancer, and the relatively rapid progression from adenoma to carcinoma in these patients, warrants screening of the colon every 1 to 2 years starting from 25-40 years of age 2,3 and may require colectomy. With close surveillance and resection of any adenomas which develop, the risk of colorectal cancer can be reduced by 60% 3.

Due to a high number of extracolonic tumors, various screening programs have been instituted. Examples include transvaginal ultrasound screening of the uterus and ovaries (in post-menopausal women 9, at the clinician's discretion) and serum CA-125 2. One follow up regimen recommends annual transvaginal ultrasound and endometrial biopsy 3, although studies have found the sensitivity of ultrasound for screening in this high risk population low 12.

Lynch syndrome was first described by Aldred Scott Warthin (1866-1931) 8, an American pathologist, from University of Michigan in Ann Arbor, Michigan, in 1913, after research into a family with several members with cancers. In the mid 1960s, Henry T Lynch (1928-2019) 10, an American oncologist, published further detailed painstaking work on the same family studied by Warthin, shedding further light on these apparently hereditary cancers 7. The condition was later renamed after Lynch who doggedly pursued the then heterodoxy that cancer could be hereditary.

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