Cancer protective घेणेस from Churchill to Elephants part2

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. 2024 Jan 18;15(1):118. doi: 10.3390/genes15010118

From Churchill to Elephants: The Role of Protective Genes against Cancer

Annalisa Gazzellone 1, Eugenio Sangiorgi 1,*

Editor: Peixin Dong1

PMCID: PMC10815068  PMID: 38255007

1. Introduction

In 1992, a famous best-selling book titled “Sharks Don’t Get Cancer” caused a sensation among the general public, by claiming that sharks are immune to cancer due to the properties of cartilage or its extract [1]. 

This pseudoscientific claim created significant controversy, particularly within the scientific community. The controversy reached its peak when a phase III clinical trial utilizing shark cartilage extract failed to demonstrate any significant benefits for patients in the treatment of cancer [2].

The notion of using miraculous nutraceuticals for cancer treatment goes back to the origins of medicine itself. In modern times, this pseudoscience often relies on specific biological mechanisms purported to mediate the claimed anti-cancer effects. The book “Sharks Don’t Get Cancer” was notable for initiating a false claim based on a different approach: the observation, albeit somewhat valid, that a particular species appeared somehow resistant to cancer development. This concept was not entirely new, as epidemiologist Richard Peto had observed in 1970 that larger animals, contrary to common belief, experienced fewer instances of cancer than smaller animals [3,4]. 

Until then, cancer had been largely viewed as a linear consequence of having many cells, with one of them eventually accumulating a critical number of mutations, leading to transformation into a cancerous cell. Peto’s paradox, as it came to be known, presented a puzzle that defied simple explanation. Various attempts were made to elucidate this phenomenon in biological terms, exploring factors such as the role of the immune system and different regulatory pathways. However, any explanation had to account for the fact that specific alleles or genes in larger animals could counteract the environmental factors influencing cancer cell proliferation. Evolution likely addressed this problem in diverse ways across different species.

The sequencing of the first human genome in 2000 ushered in a new era, allowing for the direct identification of genes or gene variants associated with specific phenotypes, first in humans, then in mice, and eventually in other living organisms. Initially, the genomic revolution primarily focused on identifying disease determinants, as most genes predisposing to cancer tended to manifest in more severe phenotypes, typically in younger individuals. These predisposing genes were relatively easy to discover, especially in cases where the phenotype ran in families, affecting younger individuals and resulting in multiple tumors within the same individual [5,6,7].

 This led to the identification of many genes predisposing to cancer, which paved the way for the development of numerous targeted treatments that are now available [8].

 Conversely, while one of the predisposing alleles was considered the disease allele, the other could be considered the healthy allele. However, studies concentrating on the genetic underpinnings of health lagged behind, partly due to the challenges in identifying “healthy” subjects and defining health in a quantifiable manner.

In a seminal paper, Topol described alleles in genes with a protective effect as those that, through a classical loss-of-function effect variant, could significantly influence the development of disease [9,10]. 

This rigorous definition proved instrumental in overcoming many of the challenges associated with discovering genetic determinants of health. Moreover, once the gene-allele combination was identified, it became possible to target the same molecule in an attempt to replicate the spontaneous phenotype observed in the healthy population. One of the most compelling examples was the discovery of loss-of-function mutations in PCSK9, which resulted in low levels of LDL cholesterol [11].

 This discovery promptly led to the production of monoclonal antibodies against PCSK9, heralding a completely new form of treatment for hypercholesterolemia [12].

The widespread availability of sequencing analysis in families with a history of severe genetic diseases unveiled a new cohort of individuals referred to as “genetic superheroes” or “human knock-outs” [13,14].

 These individuals carry heterozygous or homozygous alleles for severe genetic conditions, yet remain unaffected, likely due to the presence of alleles in different genes, possibly in the same or different pathways, which counterbalance the phenotypic effects of the disease-causing allele. Thus far, alleles with a major effect explaining the “genetic superhero” phenotype have yet to be discovered.

According to the most recent data from the World Health Organization, the estimated global lifetime risk of cancer from birth to death was approximately 20% in 2020 [15]. 

It is estimated that only 20% of tumors are associated with a mutation in a cancer predisposition gene, while about 75–80% of cancers are sporadic and result from a combination of multiple factors (environmental, lifestyle, or medical), with a significant role also attributed to genetic background [16].

Identifying alleles that confer protection against cancer is a much more complex endeavor. It is a common observation that many individuals, despite engaging in unhealthy lifestyles for a significant portion of their lives, somehow remain protected from the most severe consequences of cancer. 

Winston Churchill, known for his remarkable leadership during World War II, serves as a prominent example. Despite a documented lifestyle characterized by alcohol and cigar smoking, coupled with a lack of significant physical activity, Churchill lived to the age of 91, approximately 10 years longer than the average lifespan in the Western world nowadays [17].

While creating or retrospectively studying a cohort of individuals with characteristics similar to Churchill’s would be challenging and ethically problematic, the best approach to studying the “cancer resistance or cancer protection” phenomenon often arises from extreme examples, as previously mentioned. In this review, we will outline the various approaches taken by researchers in the cancer field to investigate the determinants of health against cancer in well-known genetic syndromes such as Down syndrome, Laron syndrome, and triplet diseases. Additionally, we will explore how evolution may have resolved Peto’s paradox in animals, devising strategies to counteract large cell populations.

 

चर्चिलपासून हत्तींपर्यंत: कर्करोगाविरुद्ध संरक्षण देणाऱ्या जनुकांची भूमिका

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Genes (Basel)

. 2024 Jan 18;15(1):118. doi: 10.3390/genes15010118

चर्चिलपासून हत्तींपर्यंत: कर्करोगाविरुद्ध संरक्षण देणाऱ्या जनुकांची भूमिका

ॲनालिसा गॅझेलोन १, युजेनियो सँजिओर्जी १,*

संपादक: पेइक्सिन डोंग १

सारांश

रिचर्ड पेटो यांचा विरोधाभास (Richard Peto’s paradox) - ज्याचे वर्णन सर्वप्रथम १९७५ मध्ये महामारीविज्ञानाच्या (epidemiological) दृष्टिकोनातून करण्यात आले होते - याने बहुपेशीय सजीवांमध्ये कर्करोग होण्याची शक्यता आणि त्यांच्या शरीरातील पेशींची संख्या यांच्यात व्यस्त संबंध असल्याचे स्पष्ट केले.

लहान प्राण्यांच्या तुलनेत मोठ्या प्राण्यांमध्ये ट्यूमर (गाठी) कमी प्रमाणात आढळतात, अर्थात यात काही अपवादही आहेत.

मानवांच्या तुलनेत उंदरांना कर्करोग होण्याची शक्यता अधिक असते,

 तर हत्ती आणि देवमासे यांच्यामध्ये कर्करोगाचे प्रमाण मानवांच्या तुलनेत लक्षणीयरीत्या कमी असते.

प्राणीसृष्टीमध्ये कर्करोगाच्या समस्येवर निसर्ग आणि उत्क्रांतीने कशा प्रकारे उपाययोजना केली आहे, याकडे अद्याप फारसे लक्ष दिले गेलेले नाही. वैद्यकीय क्षेत्रात, कर्करोगास प्रवृत्त करणाऱ्या (predisposing) जनुकांकडे अधिक लक्ष दिले गेले आहे; कारण ती जनुके कर्करोगाचा प्रतिबंध करणे, त्यांची क्रिया मंदावणे (downregulating), लवकर निदान करणे आणि लक्ष्यित उपचार (targeted treatment) करणे यांसारख्या उपाययोजनांसाठी संधी उपलब्ध करून देतात.

अशी प्रवृत्ती निर्माण करणारी जनुके बऱ्याचदा क्लिनिकली (वैद्यकीय लक्षणांच्या आधारे) लवकर आणि अधिक तीव्रतेने दिसून येतात, ज्यामुळे त्यांची ओळख पटवणे सोपे जाते.

तथापि, आधुनिक वैद्यकशास्त्रात लक्षणीय प्रगती होऊनही, संरक्षण देणाऱ्या जनुकांच्या (protective genes) भूमिकेचा अभ्यास अजूनही मागेच आहे.

सौम्य स्वरूपात कर्करोगाची प्रवृत्ती निर्माण करणाऱ्या जनुकांची ओळख पटवणे हे एक मोठे आव्हान आहे.

परिणामी, जनुकांद्वारे मिळणाऱ्या संरक्षणात्मक कार्याचे आकलन करणे अधिक कठीण होते आणि त्यांच्या अस्तित्वावरच प्रश्नचिन्ह निर्माण होऊ शकते. अनेक अनुवांशिक कर्करोग सिंड्रोम्समध्ये, एकाच जनुकीय प्रकाराची (variant) भिन्न अभिव्यक्ती (variable expressivity) आणि 'पेनिट्रन्स'मधील दोष (penetrance defects) यांची भूमिका चांगल्या प्रकारे नोंदवली गेली आहे; परंतु संरक्षण देणाऱ्या किंवा सुधारणा करणाऱ्या (modifier) ​​ॲलील्सचे (alleles) कार्य स्पष्ट करण्याचे प्रयत्न मात्र काही मोजक्या उदाहरणांपुरतेच मर्यादित राहिले आहेत.

या आढावा लेखामध्ये (review article), आम्ही प्राणीसृष्टीमध्ये आणि विशिष्ट अनुवांशिक सिंड्रोम्समध्ये आढळणाऱ्या अशा संरक्षण देणाऱ्या जनुकांच्या भूमिकेवर प्रकाश टाकण्याचा प्रयत्न करत आहोत, जी जनुके कर्करोगास प्रतिबंध करणारी किंवा दडपून टाकणारी (repressor) ॲलील्स म्हणून कार्य करतात.

याव्यतिरिक्त, कर्करोगास प्रवृत्त करणाऱ्या परिस्थितींमध्ये संरक्षण देणाऱ्या ॲलील्सची भूमिका काय असते, याचाही आम्ही शोध घेत आहोत. विन्स्टन चर्चिल यांच्यासारख्या व्यक्तींनी अत्यंत कमी शारीरिक हालचाल, दररोज मोठ्या प्रमाणात मद्यपान आणि धूम्रपानाचा त्याग न करणे या गोष्टी असूनही वयाच्या ९१ व्या वर्षापर्यंत आयुष्य कसे जगले, हे शोधून काढणे हेच मुख्य उद्दिष्ट आहे.

Cancer protective genes from Churchill to Elephants

. 2024 Jan 18;15(1):118. doi: 10.3390/genes15010118

From Churchill to Elephants: The Role of Protective Genes against Cancer

Annalisa Gazzellone 1, Eugenio Sangiorgi 1,*

Editor: Peixin Dong1

Abstract

Richard Peto’s paradox, first described in 1975 from an epidemiological perspective, established an inverse correlation between the probability of developing cancer in multicellular organisms and the number of cells. 

Larger animals exhibit fewer tumors compared to smaller ones, though exceptions exist.

 Mice are more susceptible to cancer than humans, while elephants and whales demonstrate significantly lower cancer prevalence rates than humans. 

How nature and evolution have addressed the issue of cancer in the animal kingdom remains largely unexplored. In the field of medicine, much attention has been

 devoted to cancer-predisposing genes, as they offer avenues for intervention, including blocking, downregulating, early diagnosis, and targeted treatment.

 Predisposing genes also tend to manifest clinically earlier and more aggressively, making them easier to identify. 

 However, despite significant strides in modern medicine, the role of protective genes lags behind. 

Identifying genes with a mild predisposing effect poses a significant challenge.

 Consequently, comprehending the protective function conferred by genes becomes even more elusive, and their very existence is subject to questioning. While the role of variable expressivity and penetrance defects of the same variant in a family is well-documented for many hereditary cancer syndromes, attempts to delineate the function of protective/modifier alleles have been restricted to a few instances.

 In this review, we endeavor to elucidate the role of protective genes observed in the animal kingdom, within certain genetic syndromes that appear to act as cancer-resistant/repressor alleles. 

Additionally, we explore the role of protective alleles in conditions predisposing to cancer. 

The ultimate goal is to discern why individuals, like Winston Churchill, managed to live up to 91 years of age, despite engaging in minimal physical activity, consuming large quantities of alcohol daily, and not abstaining from smoking.