Pål Møller’s research while affiliated with Oslo University Hospital and other places

This first prospective observational study evaluates the impact of extended versus segmental colorectal surgery on the risk of metachronous colorectal cancer (CRC) in patients with Lynch syndrome, analyzing data from the Prospective Lynch Syndrome Database version 5. Extended resection significantly reduced the risk of metachronous CRC in path_MLH1, path_MSH2, and path_MSH6 carriers compared to segmental resection.

Background & aims: In Latin America, genetic testing for Lynch Syndrome (LS) has been partially implemented. Traditionally, LS diagnosis relied on the Amsterdam criteria and Bethesda guidelines, collectively known as Traditional Screening (TS). However, TS may miss up to 68% of LS cases. To improve detection rates, Universal Tumor Screening (UTS) has been introduced. UTS involves screening all newly diagnosed colorectal cancer (CRC) patients for molecular markers to more effectively identify LS cases. Methods: Clinical and molecular data on 1,684 colorectal cancer (CRC) patients, collected between 1999 and 2020, were provided by 24 Latin American genetic cancer registries and centers. Germline genetic testing was not consistently performed across all cases. Results: LS screening strategies were available for 72% (1,209/1,684) of cases, with germline testing conducted in one-quarter (304/1,209) of these. Most cases (78%, n=943) underwent UTS, primarily in Argentina, Chile, and Uruguay, while 22% (266/1,209) were screened through TS. UTS identified deficient mismatch repair (dMMR) tumors in 29% (272/943) of cases. The rate of LS confirmed by sequencing was higher with UTS (53.3%, 65/122) compared to TS (47.8%, 87/182), though the difference was not statistically significant (P value = 0.175). Conclusions: UTS is widely implemented in Latin America; however, the low detection rate of LS demonstrated in this study raises concerns about the routine use of germline genetic testing in our region. Our study provides real-world outcomes that highlight disparities in screening uptake and counseling referrals, illustrating the challenges that Latin American countries face in hereditary cancer syndrome screening. These results contribute to the rationale for designing effective screening strategies for LS, which may also be applicable to other hereditary cancer syndromes, ultimately. Keywords: Latin America; Lynch syndrome; Traditional Screening; Universal Tumor Screening.

Carcinogenesis encompasses processes that lead to increased mutation rates, enhanced cellular division (tumour growth), and invasive growth. Colorectal cancer (CRC) carcinogenesis in carriers of pathogenic APC (path_APC) and pathogenic mismatch repair gene (path_MMR) variants is initiated by a second hit affecting the corresponding wild-type allele. In path_APC carriers, second hits result in the development of multiple adenomas, with CRC typically emerging after an additional 20 years. In path_MLH1 and path_MSH2 carriers, second hits lead to the formation of microscopically detectable, microsatellite unstable (MSI) crypts, from which CRC develops in about half of carriers over their lifetime, often without progressing through a diagnosable adenoma stage. These divergent outcomes reflect the distinct functions of. the APC and MMR genes. In path_MLH1 and path_MSH2 carriers, a direct consequence of stochastic mutations may be the occurrence of invasive growth before tumour expansion, challenging the paradigm that an invasive cancer must always have an non-invasive precursor. In contrast to other path_ MMR carriers, path_PMS2 carriers who receive colonoscopic surveillance exhibit minimal increase in CRC incidence. This is consistent with a hybrid model: the initial mutation may cause an adenoma, and the second hit in the wild-type PMS2 allele may drive the adenoma towards become cancerous with MSI. Since all mutational events are stochastic, interventions aimed at preventing or curing cancer should ideally target the initial mutational events. Interventions focused on downstream events are external factors that influence which tumour clones survive Darwinian selection. In Lynch Syndrome, surveillance colonoscopy to remove adenomas may select for carcinogenetic pathways that bypass the adenoma stage.

Background and aims Recent studies have shown that combining polygenic risk score (PRS) and carrier status for germline pathogenic variants in colorectal cancer (CRC) susceptibility genes (e.g. MLH1, MSH2, MSH6, PMS2) may increase the success of predicting CRC. This study aims to examine the prediction performance of CRC in Norwegian data using the status of pathogenic variants in the mismatch repair (MMR) genes with the available PRS models in the literature. Methods Our Norwegian cohort included 805 CRC cases, 86 of which carried a pathogenic variant in one of the MMR genes. As a control group, we included 8856 individuals without a cancer diagnosis, of which 179 were carriers for a pathogenic MMR variant. We first conducted a broad experiment to determine the best-performing PRS model for the Norwegian cohort. Afterwards, we established a combined analysis with the PRS model and the status of MMR genes. Results Among 10 PRS models tested, the best-performing PRS model for the Norwegian cohort included 204 single nucleotide polymorphisms (SNPs) (AUC=0.604). We also observed that the combined model of PRS and the status of MMR significantly improved the prediction performance. Conclusion The findings suggest that a combined model of a PRS and the status of MMR genes improves the prediction performance of CRC in Norwegian data.

Background The lifetime risk of pancreatic cancer in women with a germline mutation in BRCA1 and BRCA2 is not well established. In an international prospective cohort of female carriers of BRCA1 and BRCA2 mutations, the cumulative incidence of pancreatic cancer from age 40 until 80 years was estimated. Methods A total of 8295 women with a BRCA1 or BRCA2 mutation were followed for new cases of pancreatic cancer. Subjects were followed from the date of baseline questionnaire or age 40 years (whichever came last) until a new diagnosis of pancreatic cancer, death from another cause, or date of last follow‐up. Results Thirty‐four incident pancreatic cancer cases were identified in the cohort. The annual risk of pancreatic cancer between age 40 and 80 years was 0.04% for BRCA1 carriers and 0.09% for BRCA2 carriers. Via the Kaplan–Meier method, the cumulative incidence from age 40 to 80 years was 2.2% (95% CI, 1.1%–4.3%) for BRCA1 carriers and 2.7% (95% CI, 1.3%–5.4%) for BRCA2 carriers. Only two of the 34 cases reported a first‐degree relative with pancreatic cancer (hazard ratio, 4.75; 95% CI, 1.13–19.9; p = .03). Risk factors for pancreatic cancer included alcohol intake and a history of diabetes. The 5‐year survival rate for the 34 cases was 8.8%. Conclusions The lifetime risk of pancreatic cancer is approximately 2% in women with a BRCA1 mutation and 3% for women with a BRCA2 mutation. The poor survival in hereditary pancreatic cancer underscores the need for novel antitumoral strategies.

Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four genes associated with increased cancer risk; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer and CMTR2 for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; AURKB for any cancer, irrespective of site, and PPP1R15A for breast cancer, suggesting that inhibition of PPP1R15A may be a preventive strategy for breast cancer. Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis and cell stress response as a focus point for developing new therapeutics.