Colorectal Cancer Genetics: An Evolutionary Tale of Us

Mohammad Ali Abbass, MD, MPH

No matter how optimistic we are, it is not a secret that colorectal cancer is one of the leading causes of death in the United States and the world. It is also true that the incidence of young-onset colorectal cancer has been rising for all birth cohorts since 1960. By 2030, colorectal cancer will be the leading cause of cancer-related deaths.[1] [2]

However, things might differ, at least for the proclaimed 35 to 40% of patients with heritable susceptibility![3]

It has been three decades since the discovery of the APC gene and the MMR (mismatch repair) genes,[4] [5] [6] significantly changing how we view hereditary colorectal cancer syndromes. We evolved from offering diagnoses due to the presence of a phenotype to cascade testing and being able to diagnose family members early and offer early surveillance and even risk reduction measures. Our diagnosis of an inherited colorectal cancer syndrome was previously often correlated with an active cancer diagnosis and resulted in multiple interventions and significant psychological morbidity.[7] Now we can give patients hope with early diagnosis, risk reduction, prevention measures, and a new class of treatment like immunotherapy.

We continue using universal screening protocols to identify patients with Lynch syndrome and universal germline testing for all patients with solid tumors will soon be the standard of care.[8] [9] We initially valued somatic testing for targeted therapy and precision therapeutic protocols, but now we are learning how this could also influence and aid in our germline reflex testing and diagnosis.[10]

Although we have achieved many milestones in the diagnostic evaluation of this population, we still face many obstacles, such as cascade testing of family members and precise risk assessment. The feasibility and increased access to germline testing has informed us of our limitations due to gene expressivity. Thus, much work is ahead regarding better risk assessment of patients with hereditary colorectal cancer syndromes, including polygenic backgrounds, family history, and environmental factors.

In January 18, 2018, Bill Gates was the guest editor of Time magazine.[11] He celebrated Mohamad Nasir's 5th birthday on the magazine cover and titled his cover “The Optimist.” Mohamad received his vaccines against polio, measles, and more before he was 1 month old, making him a significant milestone in prevention for his community. We cannot help but reflect on that volume thinking about the era of vaccine clinical trials for patients with Lynch syndrome.

We are entering an era of cancer prevention rather than only surveillance and anticipation. The field of chemoprevention is also advancing for patients with polyposis and Lynch syndrome, which adds to the armamentarium of prevention efforts to change the disease phenotype. Immunotherapy is becoming a valuable treatment option for patients with microsatellite-unstable colorectal cancers and patients with Lynch syndrome. It also challenges our perspectives toward these cancers to make their management nonoperative due to the high incidence of complete clinical response, especially after the publication of NICHE2 results and the dostarlimab data for rectal cancer neoadjuvant immunotherapy.[12] [13]

Finally, our surgical approach to managing these patients and syndromes has evolved. Quality of life is one of the essential metrics when operating on these patients, parallel to the oncologic guidelines and risk reduction. Our knowledge of genotype-phenotype correlation in familial adenomatous polyposis has allowed us to discuss the risk of desmoid disease with patients after surgery,[14] thus allowing us to have shared decision-making about the operation we are planning.

We hope this volume brings knowledge to the reader and excitement to curious minds in genetics, colorectal surgery, gastroenterology, and public health. Our journey started from cancer diagnosis invoking surgical intervention to vaccine administration and chemoprevention as forms of prevention in this population.

We are indeed at an exciting time due to the perseverance and hard work of many scientists and clinicians in this field. We are only at the beginning of an exciting genomic revolution that will inform how we understand those syndromes, provide more precise personalized risk assessment, and, most of all, try to accomplish our universal vision of cancer prevention.

Publication History

Article published online:
31 August 2023

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