Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study

Abstract

Background: Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population. Methods: Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX. Results: The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX.

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

“…MSI/dMMR gastric carcinomas tend to occur as poorly differentiated adenocarcinomas in the antrum of elderly patients and to display abundant T-cell infiltration, intestinal histological type, a lack of lymph node metastases, and TNM (Tumor Node Metastasis) stage I-II [ 75 , 76 ]. In LS, the cumulative risk of developing gastric cancer is estimated to be 2.5–6% [ 2 , 4 ]. LS-associated gastric cancers are mostly of the intestinal type, but the diffuse type is also observed [ 77 ].…”

“…More than 60% of MSI/dMMR small bowel adenocarcinomas may be LS-related according to the family history and MMR protein expression pattern [ 81 ]. The lifetime risk for LS patients to develop small bowel cancer is estimated to be 4–12% [ 2 , 4 , 82 ]. LS-associated tumors are mainly located in the duodenum (43%) and the jejunum (33%), only 7% being located in the ileum [ 82 ].…”

“…As detailed above, there are different explanations for the absence of germline MMR gene variant detection, and some patients with LLS have cancers of hereditary origin, whereas others have cancers of sporadic origin. A few studies investigated the risk of colorectal and extracolonic LS-associated cancers in LLS patients and relatives and identified a lower risk compared to LS and a higher risk compared to sporadic cancer or to the general population [ 4 , 237 , 238 ]. However, in these studies, the proportion of cases explained by biallelic somatic variations in MMR genes was not determined, and LLS patients were considered as a single group, even if most likely heterogeneous.…”

“…LS is a hereditary cancer syndrome with an estimated population frequency of 1:300 individuals. It is characterized by an increased risk of colorectal cancer (CRC) and endometrial cancer but, also, of ovarian, hepatobiliary tract, upper urinary tract, small bowel, gastric, pancreatic, brain, and skin cancers, more often occurring at a young age [ 1 , 2 , 3 , 4 ].…”

Gynecological Surveillance and Surgery Outcomes in Dutch Lynch Syndrome Carriers

“…Pathogenic germline variants in MMR genes, causative for LS, were first discovered in the 1990s, with MSH2 being first (1993), followed by MLH1 (1994) and PMS2 (1994), MSH6 (1997) , and EpCAM (2009) [ 2 , 3 , 4 , 5 , 6 ]. Besides an increased risk of up to 57.1% to develop colorectal cancer (CRC), female carriers are also at high risk to develop gynecological malignancies, such as endometrial cancer (EC) and cancer in the ovaries (OC) [ 7 , 8 , 9 ]. A recent study showed that the risks for EC development by age 75 are 37%, 48%, 41%, and 12% for MLH1 , MSH2 , MSH6, and PMS2 carriers, respectively.…”