Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations

Abstract

Lynch syndrome or hereditary non-polyposis colorectal cancer is caused by mutations of DNA mismatch repair (MMR) genes. The extracolonic tumour spectrum includes endometrial, ovarian, gastric, small bowel, pancreatic, hepatobiliary, brain, and urothelial neoplasms. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with a Lynch syndrome spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. Kaplan-Meier analysis of risk to 70 years was calculated. One hundred and eighty-four Lynch syndrome spectrum extracolonic cancers in 839 proven, obligate, or assumed mutation carriers were analysed. Cumulative risk for females of an extracolonic tumour is 47.4% (95% CI 43.9-50.8). The risk to males is 26.5% (95% CI 22.6-30.4). There was no reduction in gynaecological malignancies due to gynaecological screening (examination, transvaginal ultrasound scan, hysteroscopy and endometrial biopsy). Males have a higher risk of gastric cancer than females (p = 0.0003). Gastric cancer risk in those born after 1935 does not justify surveillance. These penetrance estimates have been corrected for ascertainment bias and are appropriate for those referred to a high-risk clinic.

Family perspectives in lynch syndrome becoming a family at risk, patterns of communication and influence on relations

“…Lynch syndrome is one of the most common causes of hereditary cancer [1] with particularly high risks for colorectal cancer (50–80%) and endometrial cancer (40–60%) [2,3]. The syndrome is characterized by early age (mean 45 years) at onset, but age at onset varies, which implies that individuals in the same family may be affected at young age as well as at higher age.…”

Recent developments in brain tumor predisposing syndromes

“…In addition, patients are at risk of developing a wide range of tumors outside of the colon including but not limited to: endometrial, ovarian, gastric and pancreatic cancer. Patients with HNPCC also have a 3% lifetime risk of developing a brain tumor [115][116][117].…”

“…In addition to the classical HNPCC symptoms, patients sometimes display NF1-like symptoms, such as café au lait macules and even neurofibromas [119,120]. In a recent publication, all published cases of TST1 were reviewed [116]. Notably, virtually all patients with TST1 had some form of malignancy.…”

Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome

“…The hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is a major cause of hereditary colorectal cancer, predominantly within the proximal colon, with 50-80% cumulative life time risk in mutation carriers, and in addition female carriers are at a 40-60% risk of endometrial cancer and a 10-15% risk of ovarian cancer [5][6][7]. A number of other tumors types, i.e., gastric cancer, cancer of the small intestine and the upper urinary tract, skin tumors, brain tumors, and soft tissue sarcomas, have also been linked to HNPCC, albeit at lower frequencies.…”