Intestinal and extraintestinal neoplasms in patients with NTHL1 tumor syndrome: a systematic review.

Germline biallelic pathogenic variants (PVs) in NTHL1 have since 2015 been associated with the autosomal recessive tumor predisposition syndrome: NTHL1 tumor syndrome or NTHL1-associated polyposis. In this systematic review, we aim to systematically investigate the phenotypic and genotypic spectrum of the condition including occurrence of both benign and malignant tumors. The databases PubMed, EMBASE, and Scopus were searched. The search was conducted the 25th of august 2021. We included patients with germline PVs, both heterozygous and homo-/compound heterozygous carriers. Twenty-one papers were selected including 47 patients with biallelic PVs in NTHL1 in 32 families. Twenty-three out of 47 patients (49%) were diagnosed with colorectal cancer (CRC) (mean age: 55, range: 31-73) and 12 out of 22 female patients (55%) were diagnosed with breast cancer (mean age: 49, range: 36-63). Apart from three, all patients who underwent a colonoscopy, had colonic adenomas (93%), and three patients (6%) had duodenal adenomatosis. We also identified 158 heterozygous carriers of germline PVs in NTHL1. Twenty-six out of 68 (38%) heterozygous carriers, who underwent colonoscopy, had colonic polyps or adenomas. Twenty-nine heterozygous carriers (18%) were diagnosed with CRC and 59 (49%) with breast cancer. We observed a high frequency of early onset CRC and breast cancer in patients with NTHL1 tumor syndrome. Subsequently, colorectal, breast, and endometrial cancer screening programs are recommended for NTHL1 biallelic carriers. Trial registry PROSPERO: CRD42021275159.

Benefit from extended surveillance interval on colorectal cancer risk in Lynch syndrome.

AIM: Although patients with Lynch syndrome have an increased risk of developing colorectal cancer, surveillance can reduce morbidity and mortality. Whether or not affected individuals benefit from lifetime surveillance depends on individual factors and patient adherence, and these may vary, complicating risk modelling. The aim of this study was to identify individual factors which influence patient adherence to surveillance programmes and whether extended surveillance interval influenced their risk of developing colorectal cancer. METHOD: Demographics and survival data were obtained from patients (n = 1223) with Lynch syndrome, identified by interrogating the Danish Hereditary Non-Polyposis Colorectal Cancer Register. These data were linked to patient surveillance interval data which had been divided into three subsets (< 27 months, adherent to the recommended biennial programme; > 27 months, extended surveillance interval; and no surveillance) to estimate the cumulative risks and hazard ratios (HRs) for colorectal cancer. RESULTS: In all, 147 colorectal cancers (99 first; 48 metachronous) were identified in 1223 patients. Factors associated with adherence to surveillance were female sex, a previous history of cancer and age < 75 years. The cumulative incidence for colorectal cancer was 38% (95% CI 27%-50%) for surveillance intervals < 27 months, 48% (95% CI 29%-67%) for intervals > 27 months and 72% (95% CI 61%-83%) with no surveillance. Adjusted HRs were 0.22 for surveillance intervals < 27 months and 0.32 for surveillance intervals > 27 months. Extended surveillance intervals > 27 months had a non-significant benefit with an HR of 1.51 (95% CI 0.83-2.75) compared to surveillance intervals < 27 months. CONCLUSION: This study demonstrates that adherence to colonoscopic surveillance in Lynch syndrome varies with age, sex and cancer history and demonstrates a consistent benefit from colorectal cancer surveillance, though it might be lower for individuals with extended intervals.

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.