Is early-onset cancer an emerging global epidemic? Current evidence and future implications

Over the past several decades, the incidence of early-onset cancers, often defined as cancers diagnosed in adults <50 years of age, in the breast, colorectum, endometrium, oesophagus, extrahepatic bile duct, gallbladder, head and neck, kidney, liver, bone marrow, pancreas, prostate, stomach and thyroid has increased in multiple countries. Increased use of screening programmes has contributed to this phenomenon to a certain extent, although a genuine increase in the incidence of early-onset forms of several cancer types also seems to have emerged. Evidence suggests an aetiological role of risk factor exposures in early life and young adulthood. Since the mid-20th century, substantial multigenerational changes in the exposome have occurred (including changes in diet, lifestyle, obesity, environment and the microbiome, all of which might interact with genomic and/or genetic susceptibilities). However, the effects of individual exposures remain largely unknown. To study early-life exposures and their implications for multiple cancer types will require prospective cohort studies with dedicated biobanking and data collection technologies. Raising awareness among both the public and health-care professionals will also be critical. In this Review, we describe changes in the incidence of early-onset cancers globally and suggest measures that are likely to reduce the burden of cancers and other chronic non-communicable diseases.

Journal Nature Reviews Clinical Oncology
Authors Tomotaka Ugai et al
DATE 06 September 2022
Healthy and unhealthy plant-based diets in relation to the incidence of colorectal cancer overall and by molecular subtypes


Plant-based foods have been recommended for health. However, not all plant foods are healthy, and little is known about the association between plant-based diets and specific molecular subtypes of colorectal cancer (CRC). We examined the associations of healthy and unhealthy plant-based diets with the incidence of CRC and its molecular subtypes.


While 123 773 participants of the Nurses’ Health Study and the Health Professionals Follow-up Study had been followed up (3 143 158 person-years), 3077 of them had developed CRC. Healthy and unhealthy plant-based diet indices (hPDI and uPDI, respectively) were calculated using repeated food frequency questionnaire data. We determined the tumoural status of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and BRAF and KRAS mutations.


Higher hPDI was associated with lower CRC incidence (multivariable hazard ratio [HR] comparing extreme quartiles, 0.86, 95% confidence interval [CI]: 0.77, 0.96; P-trend = .04), whereas higher uPDI was associated with higher CRC incidence (multivariable HR comparing extreme quartiles, 1.16, 95% CI: 1.04, 1.29; P-trend = .005). The association of hPDI significantly differed by KRAS status (P-heterogeneity = .003) but not by other tumour markers. The hPDI was associated with lower incidence of KRAS-wildtype CRC (multivariable HR comparing extreme quartiles, 0.74, 95% CI: 0.57, 0.96; P-trend = .004) but not KRAS-mutant CRC (P-trend = .22).


While unhealthy plant-based diet enriched with refined grains and sugar is associated with higher CRC incidence, healthy plant-based diet rich in whole grains, fruits and vegetables is associated with lower incidence of CRC, especially KRAS-wildtype CRC.

Journal Clinical and Translational Medicine
Authors Fenglei Wang et al
DATE 23 August 2022
Mechanisms of APOBEC3 mutagenesis in human cancer cells

The APOBEC3 family of cytosine deaminases has been implicated in some of the most prevalent mutational signatures in cancer1,2,3. However, a causal link between endogenous APOBEC3 enzymes and mutational signatures in human cancer genomes has not been established, leaving the mechanisms of APOBEC3 mutagenesis poorly understood. Here, to investigate the mechanisms of APOBEC3 mutagenesis, we deleted implicated genes from human cancer cell lines that naturally generate APOBEC3-associated mutational signatures over time4. Analysis of non-clustered and clustered signatures across whole-genome sequences from 251 breast, bladder and lymphoma cancer cell line clones revealed that APOBEC3A deletion diminished APOBEC3-associated mutational signatures. Deletion of both APOBEC3A and APOBEC3B further decreased APOBEC3 mutation burdens, without eliminating them. Deletion of APOBEC3B increased APOBEC3A protein levels, activity and APOBEC3A-mediated mutagenesis in some cell lines. The uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas the loss of the translesion polymerase REV1 decreased overall mutation burdens. Together, these data represent direct evidence that endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells. Our results identify APOBEC3A as the main driver of these mutations, indicate that APOBEC3B can restrain APOBEC3A-dependent mutagenesis while contributing its own smaller mutation burdens and dissect mechanisms that translate APOBEC3 activities into distinct mutational signatures.

Team Mutographs
Journal Nature
Authors Mia Petljak et al
DATE 20 July 2022
An international report on bacterial communities in esophageal squamous cell carcinoma

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One possible link between poor oral health and ESCC involves the alteration of the microbiome. We performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed similar ESCC-associated bacterial communities in these cancers. Because these genera are traditionally considered members of the oral microbiota, we next explored whether there was a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes were significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of some ESCC patients.

Team Mutographs
Journal International Journal of Cancer
Authors Matthew Meyerson, Elia J. Mmbaga, Katherine Van Loon
DATE 15 July 2022
Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science

Cancer is generally regarded as a localised disease, with the well-established role of the tumour microenvironment. However, the realm of cancer goes beyond the tumour microenvironment, and cancer should also be regarded as a systemic and environmental disease. The exposome (ie, the totality of exposures), which encompasses diets, supplements, smoking, alcohol, other lifestyle factors, medications, etc, likely alters the microbiome (inclusive of bacteria, viruses, archaea, fungi, parasites, etc) and immune system in various body sites and influences tumour phenotypes. The systemic metabolic/inflammatory status, which is likely influenced by exposures and intestinal physiological changes, may affect tissue microenvironment of colorectum and any other organs. Germline genomic factors can modify disease phenotypes via gene-by-environment interactions. Although challenges exist, it is crucial to advance not only basic experimental research that can analyse the effects of exposures, microorganisms and microenvironmental components on tumour evolution but also interdisciplinary human population research that can dissect the complex pathogenic roles of the exposome, microbiome and immunome. Metagenomic, metatranscriptomic and metabolomic analyses should be integrated into well-designed population research combined with advanced methodologies of artificial intelligence and molecular pathological epidemiology. Ideally, a prospective cohort study design that enables biospecimen (such as stool) collection before disease detection should be considered to address reverse causation and recall biases. Robust experimental and observational research together can provide insights into dynamic interactions between environmental exposures, microbiota, tumour and immunity during carcinogenesis processes, thereby helping us develop precision prevention and therapeutic strategies to ultimately reduce the cancer burden.

Journal Gut
Authors Kentaro Inamura et al
DATE 12 July 2022