Lars Joachim Lindberg

Outcome of 24 years national surveillance in different hereditary colorectal cancer subgroups leading to more individualised surveillance

Background Individuals with hereditary non-polyposis colorectal cancer (HNPCC) have a high risk of colorectal cancer (CRC). The benefits of colonic surveillance in Lynch syndrome and Amsterdam-positive (familial CRC type X familial colorectal cancer type X (FCCTX)) families are clear; only the interval between colonoscopies is debated. The potential benefits for families not fulfilling the Amsterdam criteria are uncertain. The aim of this study was to compare the outcome of colonic surveillance in different hereditary subgroups and to evaluate the surveillance programmes. Methods A prospective, observational study on the outcome of colonic surveillance in different hereditary subgroups based on 24 years of surveillance data from the national Danish HNPCC register. Results We analysed 13 444 surveillance sessions, including 8768 incidence sessions and 20 450 years of follow-up. CRC was more incident in the Lynch subgroup (2.0%) than in any other subgroup (0.0–0.4%, p<0.0001), but the incidence of advanced adenoma did not differ between the Lynch (3.6%) and non-Lynch (2.3–3.9%, p=0.28) subgroups. Non-Lynch Amsterdam-positive and Amsterdam-negative families were similar in their CRC (0.1–0.4%, p=0.072), advanced adenoma (2.3–3.3%, p=0.32) and simple adenoma (8.4–9.9%, p=0.43) incidence. In moderate-risk families, no CRC and only one advanced adenoma was found. Conclusions The risk of CRC in Lynch families is considerable, despite biannual surveillance. We suggest less frequent and more individualised surveillance in non-Lynch families. Individuals from families with a strong history of CRC could be offered 5-year surveillance colonoscopies (unless findings at the preceding surveillance session indicate shorter interval) and individuals from moderate-risk families could be handled with the population-based screening programme for CRC after an initial surveillance colonoscopy.

Towards gene- and gender-based risk estimates in Lynch syndrome; age-specific incidences for 13 extra-colorectal cancer types

Background:In Lynch syndrome, inherited mismatch repair (MMR) defects predispose to colorectal cancer and to a wide spectrum of extra-colorectal tumours. Utilising a cohort study design, we aimed to determine the risk of extra-colorectal cancer and to identify yet unrecognised tumour types.Methods:Data from 1624 Lynch syndrome mutation carriers in the Danish hereditary non-polyposis colorectal cancer register were used to estimate the sex- and age-specific incidence rate ratios (IRRs) for 30 extra-colorectal malignancies with comparison to the general population.Results:Significantly increased IRRs were identified for 13 cancer types with differences related to gender, age and disease-predisposing gene. The different cancer types showed variable peak age incidence rates (IRs) with the highest IRs for ovarian cancer at age 30–49 years, for endometrial cancer, breast cancer, renal cell cancer and brain tumours at age 50–69 years, and for urothelial cancer, small bowel cancer, gastric cancer, pancreatic cancer and skin tumours after age 70.Conclusions:The broad spectrum of tumour types that develop at an increased incidence defines Lynch syndrome as a multi-tumour syndrome. The variable incidences in relation to age, gender and gene suggest a need for individualised surveillance.

The utility of P16 in identifying Lynch Syndrome (LS)

P1-1 Reproducibility of Human Papillomavirus detection using the Roche cobas HPV Test, QIAGEN Hybrid Capture 2, Gen-Probe APTIMA, and Genomica CLART assays; Implications for molecular cervical screening Ejegod DM, Preisler S, Rebolj M, Untermann A, Lynge E, Rygaard C, Bonde J Department of Pathology, Copenhagen University Hospital, Hvidovre; Clinical Research Centre, Copenhagen University Hospital, Hvidovre; Department of Public Health, University of Copenhagen

Risk of Synchronous and Metachronous Colorectal Cancer: Population-Based Estimates in Denmark with Focus on Non-Hereditary Cases Diagnosed After Age 50

Background and Aims: The risk of synchronous and metachronous colorectal cancer is influenced by heritable and environmental factors. As a basis for comparative studies, we provide population-based estimates of synchronous and metachronous colorectal cancer with a focus on non-heritable cases. Material and Methods: Based on data from national Danish cancer registers, we estimated the proportion of synchronous colorectal cancer and the incidence rates and risks for metachronous colorectal cancer in 28,504 individuals, who developed 577 metachronous colorectal cancer above age 50. Results: Synchronous colorectal cancer was diagnosed in 1.3% of the cases. The risk of metachronous colorectal cancer was associated with sex, tumor location, and age with the strongest influence from the latter. The incidence rate ratios for metachronous colorectal cancer ranged from above 6 in patients below age 65 to <1–3.2 in patients above age 65. The absolute risk of metachronous colorectal cancer was ⩾10% in patients below age 65 and 1.0%–8.0% in patients above age 65. Conclusion: Individuals who develop sporadic, non-inherited colorectal cancer above age 50 are at a significantly increased risk of metachronous colorectal cancer with risk estimates that are strongly affected by age. This observation underscores the need for development of targeted surveillance in the most common clinical subset of colorectal cancer.

Unsolicited information letters to increase awareness of Lynch syndrome and familial colorectal cancer: reactions and attitudes

Dissemination of information on a genetically increased risk should according to guidelines primarily be family-mediated. Incomplete and incorrect information spread has, however, been documented and implies missed possibilities for prevention. In Denmark, the national HNPCC register has been granted an exception to send unsolicited letters with information on hereditary colorectal cancer and an invitation to genetic counseling to members of families with familial and hereditary colorectal cancer. To evaluate this approach, we investigated reactions and attitudes to unsolicited letters in 708 members of families with genetic predisposition and in 1600 individuals from the general population. Support for information letters was expressed by 78% of the family members and by 82% of the general population. Regarding route of information, 90% of family members preferred a letter to no information, 66% preferred information from the hospital rather than from family members and 40% preferred to obtain information from a close family member. Our results suggest that use of unsolicited information letters from the health care system may be a feasible and highly acceptable strategy to disseminate information to families at high risk of colorectal cancer.

Risk of multiple colorectal cancer development depends on age and subgroup in individuals with hereditary predisposition

Development of multiple colorectal cancers (CRCs), synchronously or metachronously, is associated with hereditary predisposition for cancer and accurate risk estimates of multiple tumour development are relevant to recommend rational surveillance programs. A cross-sectional study design was used to estimate the risks of synchronous CRC (SCRC) and metachronous CRC (MCRC) based on data from the National Danish Hereditary Nonpolyposis Register. In total, 7100 individuals from families within the subgroups Lynch syndrome, familial CRC (FCC) and moderate risk were used with estimates relative to a non-hereditary population control cohort. SCRC was diagnosed in 7.4% of the Lynch syndrome cases, in 4.2% of FCC cases and 2.5% of the moderate risk cases, which translated to relative risks of 1.9–5.6. The risk of MCRC was distinctively linked to Lynch syndrome with a life-time risk up to 70% and an incidence rate ratio of 5.0. The risk of SCRC was significantly increased in all subgroups of FCC and hereditary CRC, whereas the risk of MCRC was specifically linked to Lynch syndrome. These observations suggest that individuals with FCC or hereditary CRC should be carefully screened for second primary CRC at the time of diagnosis, whereas intensified surveillance for second primary CRC is motivated in Lynch syndrome with lower-intensity programs in families with yet unidentified genetic causes.