Epidemiology: Is early-onset cancer an epidemic or “another” Provocative Question?
Cancer has been on the spot of public health for several decades, considering the significant increase of its prevalence and the augmenting cancer-associated death rates. Nevertheless, it is relatively recently that the sub-division into early-onset and later-onset cancers has been introduced, defined by the age of diagnosis. In a collaborative extensive review from researchers in Harvard Medical School and Harvard T.H. Chan School of Public Health, the cut-off of 50 years old was used to serve as the definition criterion, with patients younger than 50 years old at the time of diagnosis belonging in the early-onset cancer cohorts, while patients of or older than 50 years old belonging in the later-onset cohorts, respectively.
Ugai and colleagues evaluated trends in incidence of cancers in distinct organs of early-onset patients. They used cohorts from 44 countries around the world that provided age-standardized data on cancer incidence for the period 2002-2012. Among these, ten countries were selected for they were indicative of trends in the respective specific geographical regions. In these, incidence of 14 cancer types was reported to be increasing among 20-49-year-old adults: breast, colorectal (CRC), endometrium, esophagus, extrahepatic bile duct, gallbladder, head and neck, kidney, liver, bone marrow, pancreas, prostate, stomach and thyroid.
Looking at the risk factors, the authors suggest a strong etiological role for early life- (birth to 19 years of age) and young adulthood-exposome, as that is consisted by diet, lifestyle, environmental exposures, physical activity, and the microbiome. Expectably, a thorough look at cancer risk factors easily reveals that most of them are also risk factors for other chronic diseases, i.e. diabetes and inflammatory bowel disease, which have been increasingly diagnosed over the past several decades. Therefore, the authors challenge whether this early-onset cancer epidemic is the tip of the iceberg or -even worse- just “an example of increasing trend towards greater incidences of many chronic diseases in young and/or future generations”.
They answer suggesting large, prospective cohorts, collection of metadata with the means of electronic health records, and biospecimens throughout early life that will allow for detailed, multi-omics information. They call for collaborations of researchers, healthcare providers, public health practitioners, policymakers and the public, shouting out for health literacy on early-onset cancers and beyond.
Etiology: Current evidence on the role of mycobiome in cancer
The role of bacteria in tumorigenesis, progression of cancer and responses to cancer therapy has been greatly evaluated the past decades. How much do we know about other microorganisms kingdoms in our body though? Recently, two in-depth, state-of-the-art, international studies, published in , reported comprehensive analyses of tumor-associated mycobiomes in a variety of human cancers.
Narunsky-Haziza L. and colleagues generated the first so-called “Pan-Cancer Mycobiome Atlas”. They characterized fungi in several sample types, including blood, plasma, and tumors, which they derived from four independent cohorts of patients with 35 distinct cancers. Using next generation sequencing techniques, the authors reported different compositions across the various cancer types, and therefore indicated cancer type-specific fungal signatures. Using intratumor fungal staining, they exhibited cancer-specific fungal localization patterns, as well as spatial association with immune and cancer cells. Lastly, using artificial intelligence and machine learning approaches, they prove that fungi hold potential diagnostic and prognostic value, and thus they highlighted once more the importance of the microbiome research (also) outside of the box of bacteria.
Dohlman A. and colleagues, followed a pan-cancer approach as well. They characterized fungi at multiple sites of the body of patients with cancer, and “confirmed” that human samples harbor tumor-associated mycobiota. Similar to Narunsky-Haziza et al., they could prove that the mycobiome is not only cancer specific, but cancer-type specific as well. “In lung cancer, Blastomyces was associated with tumor tissues. In stomach cancers, high rates of Candida were linked to the expression of pro-inflammatory immune pathways, while in colon cancers Candida was predictive of metastatic disease and attenuated cellular adhesions.” Of significant note, Candida species were increased in tumors of the gastrointestinal tract and predictive of decreased survival.
Diagnosis: Can we use microbiome-derived markers to succeed early diagnosis of colorectal cancer?
In both pan-cancer mycobiome studies mentioned above, the authors stressed the potential diagnostic and prognostic value of fungal signatures, but missed to mention the diagnosis timeline. Specifically for CRC, diagnosis at early stages allows for treatment with a high overall survival. Yet the current screening programs, which typically employ fecal biomarkers, followed by endoscopy, fail to provide diagnostic utility for early detection. Inclusion of microbiome-based biomarkers for screening and detection of CRC may proof beneficial.
Zwezerijnen-Jiwa and colleagues at Imperial College London and Amsterdam University Medical Centers recently reviewed all information available on microbiome-derived biomarkers for early detection of CRC. After screening 3,859 cancer-microbiome studies published until August 2022, the authors retrieved only 28 studies that reported the stage of colorectal cancer. They looked not only at the microbial composition, but the microbiome-derived metabolites, defined as co-metabolome, as well. All studies included in the systematic review evaluated solely the bacterial component of gut microbiome. Even studies that made use of the metagenomics approach, and could have evaluated non-bacterial signatures as well, tended to report only bacterial taxa as potential biomarkers. After looking at the confounding factors and large variations in study design and analytical precision, the authors suggested that “Gut microbial-derived biomarkers could be leveraged to enhance current screening programs for CRC. However, significant barriers must be overcome before this can be achieved.” Following up the very recent studies on cancer mycobiome above, inclusion of fungal biomarkers may help achieve this goal.
Ugai T., Sasamoto N., Lee H.Y., Ando M. et al. Is early-onset cancer an emerging global epidemic? Current evidence and future implications Nat. Rev. Clin. Oncol. 2022. doi: 10.1038 /s41571-022-00672-8
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