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Introduction: Lynch syndrome (LS) carriers have a 20-46% lifetime risk of colorectal cancer (CRC) due to mismatch repair gene variants. Mesalamine (5-ASA, 5-aminosalicylic acid), used safely in patients with ulcerative colitis, may reduce CRC risk in LS by decreasing microsatellite instability, a key driver of LS-related cancer. This study evaluates 5-ASA's efficacy as a tolerable chemopreventive drug, aiming to improve long-term CRC prevention in LS.

Methods and analysis: This multicentre, multinational, randomised, double-blind, two-arm, phase II clinical study will compare the effects of a 2-year daily intake of 5-ASA (2000 mg) to placebo in LS carriers. The primary objective is to assess whether mesalamine reduces colorectal neoplasia, both benign and malignant, compared with placebo in LS carriers, as detected by colonoscopy at the end of the treatment period (24 months±1 month) and on study completion. Secondary objectives include evaluating whether 5-ASA reduces neoplasia/tumour multiplicity and progression compared with placebo at specified time points, examining variations in the effects of 5-ASA versus placebo based on cancer history, sex and age (<45 years vs ≥45 years), and assessing the safety of 5-ASA in LS carriers.

Ethics and dissemination: The trial is currently open for enrolment, having received ethical approval from the Regional Ethical Review Board in Stockholm and funding from the Swedish Research Council. The study protocol is the finalised V.10.0 (11 April 2024), transitioned to the European Clinical Trials Information System. LS remains underdiagnosed, which may limit recruitment. The results are of global interest and will be published in peer-reviewed journals and presented at scientific conferences.

Trial registration number: ClinicalTrials.gov: NCT04920149. EudraCT: 2019-003011-55. EU CT: 2024-514765-19-01.

Background: To evaluate the psychosocial consequences of surveillance with whole-body MRI (WB-MRI) in individuals with the heritable TP53-related cancer (hTP53rc) syndrome, also known as the Li-Fraumeni syndrome, with regard to cancer worry, perceived benefits and risks to surveillance and overall health.

Patients and methods: Since 2016, the national Swedish TP53 Study (SWEP53) has offered surveillance with WB-MRI to all individuals with hTP53rc syndrome. Seventy-five individuals have been included in the study. Sixty consecutive participants fulfilled a base-line evaluation as well as an evaluation after 1 year with structured questionnaires including the Cancer Worry Scale (CWS), perceived benefits and risks of surveillance, and the 36-item Short Form Survey (SF-36). Individuals with or without previous personal cancer diagnosis were enrolled and results at baseline and after 1 year of surveillance were compared. For SF-36, a comparison with the normal population was also made.

Results: Participants with previous cancer tend to worry more about cancer, but both individuals with and without cancer had a positive attitude toward surveillance with no differences regarding perceived benefits and barriers to surveillance. Participants with a previous cancer scored significantly lower on some of the SF-36 subscales, but between-group differences were found only for social functioning after 1 year.

Conclusions: Surveillance with WB-MRI is feasible from a psychosocial point of view both among TP53 carriers with as well as without a previous history of cancer and does not increase cancer worry in any of the groups.

Plain language summary:

• Individuals with heritable TP53-related cancer syndrome (also known as the Li-Fraumeni syndrome) have a high lifetime risk of developing cancer.
• These TP53 carriers are offered surveillance with whole-body MRI to detect cancer early. There are few reports of the psychosocial impact of surveillance.
• In this study, we wanted to evaluate cancer worry, benefits and barriers to participation, and perceived overall health.
• Our study shows no increase in cancer worry after 1 year of surveillance, regardless of previous cancer.

Approximately 5% of patients with colorectal cancer (CRC) have a Mendelian predisposition for the disease. Identification of the disease-causing genetic variant enables carrier testing and tailored cancer prevention within affected families. To determine the panorama and genetic variation of Mendelian CRC syndromes among referrals at the cancer genetics clinics in Sweden, 850 patients clinically selected for CRC genetic investigation were included in a prospective study that tested for all major hereditary polyposis and nonpolyposis CRC conditions. Genetically defined syndromes were diagnosed in 11% of the patients. Lynch syndrome was predominant (n = 73) followed by familial adenomatous polyposis (n = 12) and MUTYH-associated polyposis (n = 8); the latter of which two patients presented with CRC before polyposis was evident. One patient with a history of adolescent-onset CRC and polyposis had biallelic disease-causing variants diagnostic for constitutional mismatch repair deficiency syndrome. Post-study review of detected variants of unknown clinical significance (n = 129) resulted in the reclassification of variants as likely benign (n = 59) or as diagnostic for Lynch syndrome (n = 2). Our results reveal the panorama of Mendelian CRC syndromes at the cancer genetics clinics in Sweden and show that unified testing for polyposis and nonpolyposis CRC conditions as well as regular reexamination of sequence data improve the diagnostic yield.

A surveillance strategy of the heritable TP53-related cancer syndrome (hTP53rc), commonly referred to as the Li–Fraumeni syndrome (LFS), is studied in a prospective observational nationwide multi-centre study in Sweden (SWEP53). The aim of this sub-study is to evaluate whole-body MRI (WB-MRI) regarding the rate of malignant, indeterminate, and benign imaging findings and the associated further workup generated by the baseline examination. Individuals with hTP53rc were enrolled in a surveillance program including annual whole-body MRI (WB-MRI), brain-MRI, and in female carriers, dedicated breast MRI. A total of 68 adults ≥18 years old have been enrolled to date. Of these, 61 fulfilled the inclusion criteria for the baseline MRI scan. In total, 42 showed a normal scan, while 19 (31%) needed further workup, of whom three individuals (3/19 = 16%) were diagnosed with asymptomatic malignant tumours (thyroid cancer, disseminated upper GI cancer, and liver metastasis from a previous breast cancer). Forty-three participants were women, of whom 21 had performed risk-reducing mastectomy prior to inclusion. The remaining were monitored with breast MRI, and no breast tumours were detected on baseline MRI. WB-MRI has the potential to identify asymptomatic tumours in individuals with hTP53rc syndrome. The challenge is to adequately and efficiently investigate all indeterminate findings. Thus, a multidisciplinary team should be considered in surveillance programs for individuals with hTP53rc syndrome.

Background: Inherited pathogenic variants (PVs) in the CDKN2A gene are among the strongest known risk factors for cutaneous melanoma. Carriers are at high risks to develop multiple primary melanomas and other cancers, in particular pancreatic cancer. In this study, the CDKN2A testing, carried out in Sweden in the years 2015–2020, was evaluated.

Materials and methods: Included families had (1) three or more cases of melanoma and/or pancreatic cancer, (2) two melanomas in first-degree relatives, the youngest case <55 years or (3) individuals with three or more multiple primary melanomas, the first before the age of 55 years, and no other affected family members. The included families had at least one affected member that had been tested for CDKN2A PVs.

Results: In total, 403 families were included, whereof 913 family members had been diagnosed with cutaneous melanoma and 129 with pancreatic cancer, 33 (8.2%) were found to have PVs in CDKN2A. Frequencies ranged from 0.9% in families with only two melanomas to 43.2% in families with three or more melanoma cases and pancreatic cancer (p < 0.001). The frequency of PVs ranged from 2.1% to 16.5% in families where the youngest case was ≥55 years or <35 years (p = 0.040). In families with or without CDKN2A PVs, 37.6% and 10.0% had melanoma cases that had died from melanoma, respectively (p < 0.001).

Discussion: Significant differences were seen in the frequencies of CDKN2A PVs, dependent on numbers or age at diagnosis of melanomas and diagnoses of pancreatic cancers in the family. Further, melanoma cases belonging to families that tested positive for CDKN2A PVs had a significantly higher mortality. To summarize, the current evaluation shows that, with adequately selected criteria to guide genetic testing, CDKN2A PVs are identified at significant frequencies. Identification of carrier families is of importance to ensure that members are enrolled in a preventive surveillance program.

Introduction: Numerous prior studies, even from countries with free access to care, have associated long travel time to care with poor survival in patients with colorectal cancer.

Methods: This is a data-linkage study of all 3718 patients with colorectal cancer, diagnosed between 2007 and 2013 in Northern Sweden, one of the most sparsely populated areas in Europe. Travel time to nearest hospital was calculated based on GPS coordinates and multivariable Cox regression was used to analyse possible associations between travel time and cause-specific survival.

Results: No association between travel time and survival was observed, either in univariable analysis (colon HR 1.00 [95% CI 0.998-1.003]; rectal HR 0.998; [95% CI 0.995-1.002]) or in multivariable Cox regression analysis (colon HR 0.999 [95% CI 0.997-1.002]; rectal HR 0.997 [95% CI 0.992-1.002]).

Conclusions: In contrast to most other studies, no association between travel time and colorectal cancer survival was found; despite that longer travel time was associated with known risk factors for poorer outcome. In the Swedish health care setting, travel time does not appear to represent a barrier to care or to negatively influence outcomes.

Background: Geographic cancer health disparities have been reported in Sweden. The disparities are not fully understood, but may be attributed to differences in exposure to risk factors as well as differences in health care, socioeconomics and demography. The aim of this study was to describe the new nationwide population based RISK North database and its potential by analysing health disparities in colorectal cancer between Northern and Southern Sweden.

Methods: Cancer-specific data from the National Cancer Quality Registers for colorectal, gastric and oesophageal cancer and brain tumours were linked to several nationwide registers hereby creating a new database – RISK North. To exemplify the potential of RISK North, we analyzed differences in colorectal cancer incidence, mortality and survival in relation to gender, age, cohabitation and education between Northern and Southern Sweden 2007–2013.

Results: In colon cancer, the age-adjusted incidence per 100.000 was lower in Northern than Southern Sweden, 35.9 in the North vs. 41.1 in the South (p < .01); mortality rates were 11.0 vs. 12.2 (p < .01). For rectal cancer, incidence rates were 17.6 vs. 19.7 (p < .01) and mortality rates 5.33 vs. 5.89 (p = .07), respectively. The largest difference in incidence was demonstrated for colon cancer among individuals >79 years old (190. vs. 237, i.e., ∼20%). Survival in colon cancer was higher in Southern Sweden, HR 0.92 (0.87–0.98) adjusted for age, gender, co-habiting, education and m-stage at diagnosis. No difference in survival was seen for rectal cancer.

Conclusions: The new RISK North database enabled analysis of cancer disparities between Northern and Southern Sweden. The incidence of colorectal cancer were lower in the North of Sweden whereas colon cancer survival was higher in the South. These differences can be further analysed utilising the RISK North database.

Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a large cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linkoping, Uppsala and Umea between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.