Risk of endometrial cancer for women diagnosed with HNPCC‐related colorectal carcinoma

Abstract

The risk of endometrial cancer (EC) subsequent to a diagnosis of colorectal cancer in women with a germline mutation in a mismatch repair gene [Lynch syndrome or hereditary non-polyposis colon cancer (HNPCC)] is unknown. We estimated the risk of EC following a diagnosis of colorectal carcinoma (CRC) for women with Lynch syndrome. A retrospective cohort study was performed on women diagnosed with CRC with a germline mutation in a mismatch repair (MMR) gene (Lynch syndrome cases), and women with microsatellite stable (MSS) CRC who were not known to carry a germline mutation (non-Lynch cases), identified from the Colon Cancer Family Registry. The incidence of EC following CRC was estimated and compared for women with and without Lynch syndrome, using adjusted hazards ratios calculated for time at risk among each group. A total of 112 women with Lynch syndrome and a previous diagnosis of CRC were compared with 908 women without Lynch and with a MSS CRC diagnosis. The estimated 10-year cumulative risk of EC subsequent to CRC was 23.4% [95% confidence interval (CI): 15-36%] for Lynch syndrome women compared with 1.6% (95% CI: 0.7-3.8%) for non-Lynch women. After adjusting for ascertainment, age at diagnosis and diagnosis of other cancers, risk of subsequent diagnosis with EC was elevated sixfold in women with Lynch syndrome compared with non-Lynch women (HR 6.2; 95% CI 2.2-17.3; p 5 0.001). Approximately one quarter of women diagnosed with Lynch syndrome-associated CRC developed EC within 10 years. This supports the sentinel cancer concept and suggests that active and early management is important for these women.Lynch syndrome [also known as hereditary non-polyposis colon cancer (HNPCC)] is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6 or PMS2. Carriers of MMR gene mutations are at increased risk of cancers of the colon, endometrium, ovary, upper urologic tract, stomach, small bowel, biliary/pancreas, skin and brain. 1 In individuals who carry such mutations, inactivation of the remaining normal allele in a cell results in dysfunctional or absent DNA MMR. These unrepaired mismatches typically occur in regions of repetitive nucleotide sequences, commonly referred to as microsatellites. The consequent phenotype, referred to as microsatellite instability (MSI), is the signature change in Lynch syndrome-associated cancers. 2,3 Detection of a deleterious germline mutation in a particular MMR gene in a case of cancer with MSI unequivocally establishes the diagnosis of Lynch syndrome, with MLH1 and MSH2 sequence variants accounting for 80% of all MMR gene mutations. 4 Early age of cancer diagnosis and multiplicity of cancers are considered hallmarks of Lynch syndrome. A meta-analysis 5 of data from three population-based studies, 6-8 and previous clinic-based work, 9 estimated that the risk of colorectal cancer for MLH1 and MSH2 carriers to age 70 years was 53% for males, 33% for females and for endometrial cancer (EC) was 44%. Although the increased risk of EC in women wi...

Continuing difficulties in interpreting CNV data: lessons from a genome-wide CNV association study of Australian HNPCC/lynch syndrome patients

“…The population frequency of LS has been estimated at approximately 1 in 3000 individuals [46,47]. By 70 years of age, 45% of men and 33% of women diagnosed with HNPCC/LS will develop CRC and 15% of women will develop endometrial cancer [48,49]. Given that mutations in DNA mismatch repair genes are generally not considered to display distinct genotype-phenotype correlations and are only identified in ~50% of individuals with a clinical diagnosis of HNPCC, it has become apparent that other genetic factors are likely to influence disease development.…”

Improving identification of lynch syndrome patients: A comparison of research data with clinical records

“…6 The risk of endometrial cancer subsequent to colorectal cancer is also increased. 7 A diagnosis of Lynch syndrome in a cancer patient thus has important implications for the clinical management of the patient and, given the autosomal dominant mode of inheritance, also for their family members. 8 Identification of a MMR mutation in an individual guides presymptomatic screening and surveillance for premalignant lesions and subsequent cancers in patients and their unaffected relatives, and consideration of prophylactic surgery (hysterectomy, oophorectomy) to ablate risk of cancer.…”

Gynecologic cancer mortality in Trinidad and Tobago and comparisons of mortality-to-incidence rate ratios across global regions

“…A family history of endometrial or ovarian cancer puts a woman at a twofold risk of developing the same cancer. Additionally, women who have a family history of HNPCC are at increased risk for carrying a HNPCC genetic insult which puts them at a tenfold increased risk of endometrial or ovarian cancer [28, 29]. Strikingly, more than 50% of women in Lynch syndrome families will present with a gynecologic cancer as their first malignancy [30].…”