Finlay A. Macrae

Description: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.

Description:Early-onset bowel cancer incidence (age <50 years) has increased worldwide and is highest in Australia, but how this varies across histology and anatomical site remains unclear. We aimed to investigate appendiceal, proximal colon, distal colon, rectal, and anal cancer incidence trends by age and histology in Australia. Cancer incidence rate data were obtained from all Australian cancer registries (1990-2020 period). Birth cohort-specific incidence rate ratios (IRRs) and annual percentage change in rates were estimated using age-period-cohort modelling and joinpoint regression. After excluding neuroendocrine neoplasms, early-onset cancer incidence rose 5-9% annually, yielding 5,341 excess cases (2 per 100,000 person-years; 12% appendix, 45% colon, 36% rectum, 7% anus; 20-214% relative increase). Trends varied by site, period, and age: appendiceal cancer rose from 1990-2020 in 30-49-year-olds; colorectal cancers rose from around 1990-2010 in 20-29-year-olds and from 2010-2020 in 30-39-year-olds; anal cancer rose from 1990-2009 in 40-49-year-olds. Across all sites, IRRs increased with successive birth cohorts since 1960. Notably, adenocarcinoma incidence in the 1990s versus 1950s birth cohort was 2-3-fold for colorectum and 7-fold for appendix. The greatest subtype-specific increases occurred for appendiceal mucinous adenocarcinoma, colorectal non-mucinous adenocarcinoma, and anal squamous cell carcinoma. Only later-onset (age ≥50) colorectal and anal adenocarcinoma rates declined. Appendiceal tumours, neuroendocrine neoplasms (all sites), anorectal squamous cell carcinomas, and colon signet ring cell carcinomas rose across early-onset and later-onset strata. Appendiceal, colorectal, and anal cancer incidence is rising in Australia with variation across age and histology, underscoring the need to identify factors driving these trends. ALM is supported by an Australian Government Research Training Program Scholarship, Rowden White Scholarship, and WP Greene Scholarship. DDB is supported by a National Health and Medical Research Council of Australia (NHMRC) Investigator grant (GNT1194896), a University of Melbourne Dame Kate Campbell Fellowship, and by funding awarded to The Colon Cancer Family Registry (CCFR, www.coloncfr.org) from the National Cancer Institute (NCI), National Institutes of Health (NIH) [award U01 CA167551]. MAJ is supported by an NHMRC Investigator grant (GNT1195099), a University of Melbourne Dame Kate Campbell Fellowship, and by funding awarded to the CCFR from NCI, NIH [award U01 CA167551].

Description:Background: Being able to estimate a colorectal cancer case's risk of metachronous colorectal cancer could enable risk-appropriate surveillance. The aim was to develop a risk prediction model to estimate individual 10-year risk of metachronous colorectal cancer following a colorectal cancer diagnosis. Methods: A cohort of population-based colorectal cancer cases were recruited soon after their diagnosis between 1997 and 2012 from America, Canada, and Australia. Cox regression with the least absolute shrinkage and selection operator penalization was used to identify factors that predicted the risk of a new primary colorectal cancer diagnosed at least one year after the initial colorectal cancer. Potential predictors included demography, anthropometry, lifestyle factors, comorbidities, personal and family cancer history, medication use, and diagnosis age and pathological features of the first colorectal cancer. Internal validation through bootstrapping was used to evaluate the discrimination and calibration. Results: 6,085 colorectal cancer cases were included. 138 (2.3%) were diagnosed with metachronous colorectal cancer over a median of 12 years (interquartile range 5 - 17 years). Metachronous colorectal cancer risk was predicted by body mass index, smoking, physical activity, family history of cancer and synchronous colorectal cancer, stage, grade, histological type and DNA mismatch repair status and diagnosis age of the first colorectal cancer. The model was valid with a c-statistic of 0.65 (95% CI: 0.63 - 0.68) and a calibration slope of 0.873 (standard deviation: 0.087). Conclusions: Metachronous colorectal cancer can be predicted with reasonable accuracy by this prediction model that consists of clinical variables collected as part of routine practice.

Description:Background: The relationship between aspirin, and/or other non-steroidal anti-inflammatories (NSAIDs), and colorectal cancer (CRC) risk in older adults is uncertain. This study investigated the association between non-aspirin NSAIDs (NA-NSAIDs) use, alone or combined with aspirin, on CRC incidence in older adults. Methods: This is a post-hoc analysis of ASPREE randomized controlled trial data and its observational continuation, ASPREE-XT (median follow-up, 8.4 years (IQR: 7.2-9.6)). NA-NSAID exposure was ascertained by self-report and medical record review at baseline, for all ASPREE participants, and for Australian participants, via linkage to the Pharmaceutical Benefits Scheme (PBS). CRC was an adjudicated secondary endpoint of ASPREE. We investigated the association between NA-NSAID use alone, and in combination with randomised aspirin use, on the incidence of CRC in time-to-event analyses. Results: Of 19,114 ASPREE participants, 2713 (14%) reported NA-NSAID use at baseline. NA-NSAID use was associated with a reduced incidence of CRC (HR NA-SAID use:Yes vs No = 0.74; 95%CI: 0.56-0.98). This association between NA-NSAIDs and CRC was not modified by aspirin (P-value for interaction term of 0.81). When assessing NA-NSAID use over 2 years post-randomization in Australian participants who consented to the use of PBS data (N = 13,725), a similar reduction in CRC risk was observed (HR High NA-NSAID use vs None = 0.52, 95%CI 0.32-0.83). Conclusions: NA-NSAID use in Australian and American adults over the age of 70 years was associated with a reduced CRC incidence, which increased with increasing exposure. Aspirin did not modify the effect of NA-NSAIDs on CRC incidence.