HEREDITARY NON-POLYPOSIS COLORECTAL CANCER, LYNCH SYNDROME
This condition is commonly abbreviated as HNPCC and now preferably termed Lynch syndrome.
Background: History and Epidemiology
Lynch et al. (1985) delineated two disorders characterized by an autosomal dominantly inherited predisposition to colon cancer without florid polyposis. These disorders, “Lynch syndromes I and II” (the latter reserved for families with extracolonic cancers), are not distinct entities (Lynch et al. 1993).
Paradoxically, in some “HNPCC” pedigrees, colorectal cancer is absent and led to the reintroduction of the term “Lynch syndrome” to describe this condition (Umar et al. 2004a). The condition is due to inherited changes in the DNA mismatch repair (MMR) genes, most commonly MLH1, MSH2, and MSH6 and less frequently PMS2. Early studies suggested that in most affected individuals, there is a high risk of colon cancer, up to 80 % lifetime risk, somewhat lower in females (40 %) than in males (Dunlop et al. 1997), with an early age at diagnosis of colon cancer (40–50 years compared with 60–70 years in the general population), a preponderance of right-sided Tumours (60–70 % versus 15 %), and susceptibility to multiple primary cancers (25 % versus 5 %) and metachronous cancers (23 %) (Lynch and de la Chapelle 1999), and about 5 % of colorectal cancers occur before 30 years of age (Vasen et al. 2001).
In individuals with Lynch syndrome, there is a predisposition to a variety of extracolonic cancers, most commonly endometrial but also ovarian, gastric, pancreatic, hepatobiliary tract, urothelial, and small intestine (Watson and Lynch 2001). Estimates of the cumulative lifetime risks of the various cancer types in gene mutation carriers are 28–78 % for colorectal cancer in males (24–52 % in females), 27–72 % for endometrial cancer in women, 19 % for gastric cancer, 18 % for biliary tract cancer, 1–12 % for urinary tract cancer and 3–13 % for ovarian cancer in women, and with a 1–4 % risk of brain Tumours and 4–7 % risk of small bowel Tumours, representing a significantly increased relative risk for these Tumours types (reviewed in Vasen et al. 2007). The estimated cumulative risks of colorectal cancer by age 70 years in individuals with Lynch syndrome have been reported as 41 % (95 % confidence intervals [CI], 25–70 %) for MLH1 mutation carriers, 48 % (95 % CI, 30–77 %) for MSH2, and 12 % (95 % CI, 8–22 %) for MSH6. For endometrial cancer, corresponding risks were 54 % (95 % CI, 20–80 %), 21 % (95 % CI, 8–77 %), and 16 % (95 % CI, 8–32 %). For ovarian cancer, they were 20 % (95 % CI, 1–65 %), 24 % (95 % CI, 3–52 %), and 1 % (95 % CI, 0–3 %). The estimated cumulative risks by age 40 years did not exceed 2 % (95 % CI, 0–7 %) for endometrial cancer or 1 % (95 % CI, 0–3 %) for ovarian cancer. The estimated lifetime risks for other Tumours types did not exceed 3 % with any of the gene mutations (Bonadona et al. 2011; Aarnio et al. 1995, 1999; Barrow et al. 2013). These risks are lower than those published previously.
The estimated relative risks for extracolonic cancer vary with different germline mutations: those for small intestinal cancer are 291 for MLH1 mutation carriers and 102 for MSH2 mutation carriers; for gastric cancer 4 and 19, respectively; for ovarian cancer 6 and 8, respectively; and for urinary tract cancer 75 in MSH2 mutation carriers only (Vasen et al. 2001). Overall, MSH2 mutations appear to confer a higher risk of cancer than MLH1 mutations, mainly due to an increased risk of urinary tract and endometrial cancers in MSH2 mutation carriers. MSH6 mutations are associated with less of a risk of colorectal cancer but an increased risk of endometrial and, to a lesser extent, urothelial cancer (Wijnen et al. 1999; Vasen et al. 2001).