A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families

Abstract

BackgroundLynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families.MethodsData were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population.ResultsA total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations.ConclusionLynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2-carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types.

Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome

“…Median age at GC diagnosis and male predominance were in concordance to previously published reports. 11,12,15,27,28 Consistent to previous studies, we confirm the predominance of GC diagnoses in MLH1 and MSH2 mutation carriers, whereas it seems to be a rather rare cancer type in MSH6, PMS2 and EpCAM carriers. [10][11][12]29 In contrast to other authors, but in alignment with Geary et al as well as fered from GC.…”

“…10 In a Swedish study, the amount of GCs that occurred as single cases within LS families was even higher with 87%. 15 Here, upper GI endoscopy was performed in 132 patients, revealing 4 cases of intestinal metaplasia (3%) and 8 cases of GC (4.5%). 44 The third study is a small Canadian study analyzing retrospective data of the performance of 32 gastroscopies in 21 LS patients without finding any GC.…”

“…[10][11][12]29 In contrast to other authors, but in alignment with Geary et al as well as fered from GC. 10,15 We are the first to report an EpCAM mutation carrier with GC out of a total of 29 EpCAM mutation carriers in our registry (3.4%). In alignment to some previous reports, none of the 88 PMS2 mutation carriers in the German registry were diagnosed with GC.…”

“…Although the lifetime risk of being diagnosed with GC is estimated to be less than 1% for the general population of Western countries, the lifetime risk for LS patients is substantially higher at 6% to 13%. [8][9][10][11][12][13][14][15] Due to the absence of evidence-based data, the value of esophagogastroduodenoscopy (EGD) for GC surveillance in LS patients remains a controversial issue leading to a variety of different national surveillance strategies. According to the German S3 guideline for CRC, regular EGDs beginning at the age of 35 are recommended for LS patients.…”

Family history of colorectal cancer and survival: a Swedish population‐based study

“…We included endometrial (ICD7: 172), ovarian (175.0 and 175.9), small bowel (152.0 and 152.9), stomach (151.0 and 151.9) and urinary (i.e. ureter: 181.1 or renal pelvis: 180.1) cancers in the definition of Lynch‐related cancers based on the literature that shows these cancers are more common in Lynch patients .…”