https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827900/#:~:text=Somatic%20TP53%20mutations%20occur%20in,1
A neuroscientist prepares for death from cancer: https://www.theatlantic.com/ideas/archive/2021/12/terminal-cancer-neuroscientist-prepares-death/621114/
TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use
Abstract
Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome, which predisposes to a wide spectrum of early-onset cancers. Most mutations are single-base substitutions distributed throughout the coding sequence. Their diverse types and positions may inform on the nature of mutagenic mechanisms involved in cancer etiology. TP53 mutations are also potential prognostic and predictive markers, as well as targets for pharmacological intervention. All mutations found in human cancers are compiled in the IARC TP53 Database (http://www-p53.iarc.fr/). A human TP53 knockin mouse model (Hupki mouse) provides an experimental model to study mutagenesis in the context of a human TP53 sequence. Here, we summarize current knowledge on TP53 gene variations observed in human cancers and populations, and current clinical applications derived from this knowledge.
Genetic variations in the tumor suppressor gene TP53 (OMIM #191117) contribute to human cancers in different ways. First, somatic mutations are frequent in most cancers (Hollstein et al. 1991). The antiproliferative role of p53 protein in response to various stresses and during physiological processes such as senescence makes it a primary target for inactivation in cancer (Levine 1997). The main modes of TP53 inactivation are single-base substitution and loss of alleles, with inactivation by viral or cellular proteins playing a major role in specific cancers (Tommasino et al. 2003). Second, inheritance of a TP53 mutation causes predisposition to early-onset cancers including breast carcinomas, sarcomas, brain tumors, and adrenal cortical carcinomas, defining the Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes (Li et al. 1988; Olivier et al. 2003). Third, TP53 is highly polymorphic in coding and noncoding regions and some of these polymorphisms have been shown to increase cancer susceptibility and to modify cancer phenotypes in TP53 mutation carriers (Whibley et al. 2009).
Whereas tumor suppressors are commonly inactivated by frameshift or nonsense mutations, most TP53 mutations are missense and cause single amino-acid changes at many different positions. Mutations are thus diverse in their type, sequence context, position, and structural impact, making it possible to identify mutation patterns in relation with cancer type and etiology. The occurrence of special mutation patterns may inform on the nature of the mutagens that have caused them, making TP53 an interesting gene to analyze in the realm of molecular epidemiology.
Data on mutation prevalence in human cancer can be conveniently accessed through the IARC TP53 database (http://www-p53.iarc.fr/), a resource that compiles all TP53 gene variations reported in human cancers with annotations on tumor phenotype, patient characteristics, and structural and functional impact of mutations (Petitjean et al. 2007b). Recently, it has become possible to confront these observations with experimental data generated in a novel mouse model, the HupKi mouse, that contains a human TP53 sequence at the mouse TP53 locus and recapitulates the effects of environmental mutagens in a human sequence context (Luo et al. 2001). In this article, we review the current knowledge on the origin, causes, and consequences of TP53 variations and mutations in cancer and we discuss their significance as biomarkers in epidemiology and in the clinics.
TP53 VARIATION LANDSCAPES IN HUMAN CANCERS AND POPULATIONS
Somatic Mutations
Somatic TP53 mutations occur in almost every type of cancer at rates from 38%–50% in ovarian, esophageal, colorectal, head and neck, larynx, and lung cancers to about 5% in primary leukemia, sarcoma, testicular cancer, malignant melanoma, and cervical cancer (Fig. 1). Mutations are more frequent in advanced stage or in cancer subtypes with aggressive behavior (such as triple negative or HER2-amplified breast cancers) (Wang et al. 2004a; Wang et al. 2004b; Langerod et al. 2007). In cancers with low mutation rates, p53 is often inactivated by alternative mechanisms. This is the case for cervical cancer in which p53 is targeted for degradation by HPV E6 (Tommasino et al. 2003) or for sarcoma that overexpress amplified HDM2.
TP53 mutations prevalence in sporadic cancers. The proportion of tumors with somatic TP53 mutations is indicated. Data from IARC TP53 Database (R13, November 2008)(Petitjean et al. 2007b).
Type of somatic TP53 mutations in human cancers. (A) Pie charts showing the proportion of the different types of TP53 somatic mutations found in all human cancers. (B) Histogram displaying the position of somatic point mutations in the coding sequence of the TP53 gene. Data from the IARC TP53 Database (R13, November 2008)(Petitjean et al. 2007b).
Based on studies that examined the whole coding sequence, 86% of mutations cluster between codons 125 and 300, corresponding mainly to the DNA binding domain (Fig. 2). Most mutations in this region are missense (87.9%). In contrast, outside this region, missense mutations represent only about 40%, the majority of mutations being nonsense or frameshift. Among single-base substitutions, about 25% are C:G>T:A substitutions at CpG sites. CpG dinucleotides mutate at a rate 10 times higher than other nucleotides, generating transitions (Jones et al. 1992). About 3%–5% of cytosines in the human genome are methylated at position 5′ by a postreplicative mechanism that is restricted to CpG dinucleotides and is catalyzed by DNA methyltransferases. The 5′methylcytosine (5mC) is less stable than cytosine and undergoes spontaneous deamination into thymine at a rate five times higher than the unmethylated base. This process is enhanced by oxygen and nitrogen radicals, leading to a higher load of CpG transitions in cancers arising from inflammatory precursors such as Barrett’s mucosa or ulcerative colitis (Schmutte et al. 1996; Ambs et al. 1999; Vaninetti et al. 2008). Among the 22 CpG of the DNA-binding domain (DBD), three hotspot codons (175, 248, and 273) represent 60% of CpG mutations and another five residues (196, 213, 245, 282, and 306) account for 26% of these mutations. The lack of mutations at other CpG sites reflects the fact that substitution at these residues does not generate a dysfunctional protein. Although the same CpG hotspot mutations occur in many cancer types, other types of mutations tend to show differences from one cancer to the other. Some of these differences have been linked to the effect of specific mutagens. Geographic differences have also been reported in relation with environmental exposures. These aspects have been extensively discussed in other reviews (Hainaut et al. 2000; Olivier et al. 2004) and some examples are briefly discussed later in this article.
Germline Mutations: Li-Fraumeni Syndrome
T53 germline mutations are the underlying cause of LFS, a familial clustering of early onset tumors including sarcomas, breast cancers, brain tumors, and adrenal cortical carcinomas (Li et al. 1988; Malkin et al. 1990). Over the past 20 years, TP53 germline mutations have been detected in about 500 families or individuals with complete or partial LFS features (the latter defined as Li-Fraumeni-like, LFL) (Olivier et al. 2003). LFS/LFL has been generally considered as a rare syndrome (Eeles 1995). However, screening for TP53 germline mutation in patients with early onset breast cancer and unselected for familial history has shown TP53 mutations in 2%–3% of the cases (Lalloo et al. 2006), whereas screening of 525 patients with any kind of cancer family history has identified 91 (17.3%) TP53 mutations (Gonzalez et al. 2009). Based on these results, TP53 mutation may contribute to up to 17% of all familial cancer cases. Studies in southern Brazil have identified many families with a founder mutation (R337H) (Fig. 3). Thus, TP53 germline mutations may be more common than previously recognized, occurring in about 1 in 5,000 to 1 in 20,000 births (Lalloo et al. 2006) (Gonzalez et al. 2009).
Geographic distribution of germline TP53 mutations. Number of TP53 germline mutation carrier families in each world region. Data from the IARC TP53 Database (R13, November 2008) (Petitjean et al. 2007b).
Breast cancer and soft tissue and bone sarcoma account for over 50% of tumors in TP53 mutation carriers, followed by adrenocortical carcinomas and brain tumors (Fig. 4). Other cancers include hematological malignancies, gastric, colorectal, and ovarian cancers, occurring at earlier ages than in the general population (Olivier et al. 2003). Rarer cancers associated with TP53 germline mutation are choroid plexus carcinoma or papilloma before the age of 15, Wilms’ tumor, and malignant phyllodes tumors (Birch et al. 2001; Gonzalez et al. 2009).
Tumor spectrum in individuals with a germline TP53 mutation. The proportion of specific tumor types among all tumors reported in confirmed TP53 germline mutation carriers is indicated. Data from IARC TP53 Germline Database (R13, November 2008, http://www-p53.iarc.fr/Germline.html).
The distribution of germline mutations is similar to somatic mutations, with mostly missense mutations (77%) located at the same hotspots. The proportion of CpG mutations (54% vs. 25% in somatic mutations) may reflect the spontaneous nature of germline mutations. Genotype–phenotype correlations suggest that the most significant defect is loss of function because large deletions encompassing the whole TP53 gene have been found in LFS families with aggressive features (Bougeard et al. 2003).
TP53 Polymorphisms
Over 80 TP53 polymorphisms have been identified and validated in human populations (IARC TP53 Database, R13). The majority (90%) are located in introns, outside splice sites, or in noncoding exons. Few of them have been tested in functional assays or studied for effects on cancer risk. Among 18 exonic SNPs (Table 1), five are silent and seven are located after the stop codon in exon 11. Four exonic polymorphisms alter the protein sequence and have only subtle effects on transactivation capacity as measured in yeast-based assays (Kato et al. 2003).
A Neuroscientist Prepares for Death
Lessons my terminal cancer has taught me about the mind
About the author: David J. Linden is a neuroscience professor at the Johns Hopkins University School of Medicine and the Kavli Neuroscience Discovery Institute. His most recent book is Unique: The New Science of Human Individuality.
When a routine echocardiogram revealed a large mass next to my heart, the radiologist thought it might be a hiatal hernia—a portion of my stomach poking up through my diaphragm to press against the sac containing my heart.
“Chug this can of Diet Dr. Pepper and then hop up on the table for another echocardiogram before the soda bubbles in your stomach all pop.”
So I did. However, the resulting images showed that the mass did not contain the telltale signature of bursting bubbles in my stomach that would support a hernia diagnosis. A few weeks later, an MRI scan, which has much better resolution, revealed that the mass was actually contained within the pericardial sac and was quite large—about the volume of that soda can. Even with this large invader pressing on my heart, I had no symptoms and could exercise at full capacity. I felt great.
The doctors told me that the mass was most likely to be a teratoma, a clump of cells that is not typically malignant. Their outlook was sunny. Riffing on the musical South Pacific, my cardiologist said, “We’re gonna pop that orange right out of your chest and send you on your way.”
While I was recovering from surgery, the pathology report came back and the news was bad—it wasn’t a benign teratoma after all, but rather a malignant cancer called synovial sarcoma. Because of its location, embedded in my heart wall, the surgeon could not remove all of the cancer cells. Doing so would have rendered my heart unable to pump blood. The oncologist told me to expect to live an additional six to 18 months.
I was absolutely white-hot angry at the universe. Heart cancer? Who the hell gets heart cancer?! Is this some kind of horrible metaphor? This is what’s going to take me away from my beloved family, my cherished friends and colleagues? I simply couldn’t accept it. I was so mad, I could barely see.
[And now comes the part where I’m weeping while I type.]
Five years ago, I met Dena and we fell for each other hard. This wasn’t mere “chemistry”; it was more akin to particle physics—a revelation of the subatomic properties of love. Dena has uplifted me with her pure and unconditional affection, her kindness, beauty, optimism, and keen intelligence. She is the best wife anyone could want, and she is way better than I deserve. Leaving her behind will be the very hardest part of this whole awful situation.
Until the moment of that diagnosis six months ago, I had been the luckiest man in town. My twins, Jacob and Natalie, have been nothing but a delight for 25 years. I’ve been fortunate to have a long career in academic science with the freedom to pursue my own ideas, which is a gift like no other. My good friends are a constant source of joy and amusement. By any reasonable measure, I’ve had a great life, full of love, creativity, and adventure.
I may be dying, but I’m still a science nerd, and so I think about what preparing for death has taught me about the human mind. The first thing, which is obvious to most people but had to be brought home forcefully for me, is that it is possible, even easy, to occupy two seemingly contradictory mental states at the same time. I’m simultaneously furious at my terminal cancer and deeply grateful for all that life has given me. This runs counter to an old idea in neuroscience that we occupy one mental state at a time: We are either curious or fearful—we either “fight or flee” or “rest and digest” based on some overall modulation of the nervous system. But our human brains are more nuanced than that, and so we can easily inhabit multiple complex, even contradictory, cognitive and emotional states.
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This leads me to a second insight: The deep truth of being human is that there is no objective experience. Our brains are not built to measure the absolute value of anything. All that we perceive and feel is colored by expectation, comparison, and circumstance. There is no pure sensation, only inference based on sensation. Thirty minutes fly by in a conversation with a good friend, but seem interminable when waiting in line at the DMV. That fat raise you got at work seems nice until you learn that your co-worker got one twice as large as yours. A caress from your sweetheart during a loving, connected time feels warm and delightful, but the very same touch delivered during the middle of a heated argument feels annoying and presumptuous, bordering on violation.
If someone had told me one year ago, when I was 59, that I had five years left to live, I would have been devastated and felt cheated by fate. Now the prospect of five more years strikes me as an impossible gift. With five more years, I could spend good times with all of my people, get some important work done, and still be able to travel and savor life’s sweetness. The point is that, in our minds, there is no such thing as objective value, even for something as fundamental as five years of life.
The final insight of my situation is more subtle, but it’s also the most important. Although I can prepare for death in all sorts of practical ways—getting my financial affairs in order, updating my will, writing reference letters to support the trainees in my lab after I’m gone—I cannot imagine the totality of my death, or the world without me in it, in any deep or meaningful way. My mind skitters across the surface of my impending death without truly engaging. I don’t think this is a personal failing. Rather, it’s a simple result of having a human brain.
The field of neuroscience has changed significantly in the 43 years since I joined it. I was taught that the brain is essentially reactive: Stimuli impinge on the sense organs (eyes, ears, skin, etc.), these signals are conveyed to the brain, a bit of computation happens, some neural decisions are made, and then impulses are sent along nerves to muscles, which contract or relax to produce behavior in the form of movement or speech. Now we know that rather than merely reacting to the external world, the brain spends much of its time and energy actively making predictions about the future—mostly the next few moments. Will that baseball flying through the air hit my head? Am I likely to become hungry soon? Is that approaching stranger a friend or a foe? These predictions are deeply rooted, automatic, and subconscious. They can’t be turned off through mere force of will.
And because our brains are organized to predict the near future, it presupposes that there will, in fact, be a near future. In this way, our brains are hardwired to prevent us from imagining the totality of death.
If I am allowed to speculate—and I hold that a dying person should be given such dispensation—I would contend that this basic cognitive limitation is not reserved for those of us who are preparing for imminent death, but rather is a widespread glitch that has profound implications for the cross-cultural practice of religious thought. Nearly every religion has the concept of an afterlife (or its cognitive cousin, reincarnation). Why are afterlife/reincarnation stories found all over the world? For the same reason we can’t truly imagine our own deaths: because our brains are built on the faulty premise that there will always be that next moment to predict. We cannot help but imagine that our own consciousness endures.
While not every faith has explicit afterlife/reincarnation stories (Judaism is a notable exception), most of the world’s major religions do, including Islam, Sikhism, Christianity, Daoism, Hinduism, and arguably, even Buddhism. Indeed, much religious thought takes the form of a bargain: Follow these rules in life, and you will be rewarded in the afterlife or with a favorable form of reincarnation or by melding with the divine. What would the world’s religions be like if our brains were not organized to imagine that consciousness endures? And how would this have changed our human cultures, which have been so strongly molded by religions and the conflicts between them?
While I ponder these questions, I am also mulling my own situation. I am not a person of faith, but as I prepare for death, I have a renewed respect for the persistent and broad appeal of afterlife/reincarnation stories and their ultimately neurobiological roots. I’m not sure whether, in the end, faith in afterlife/reincarnation stories is a feature or a bug of human cognition, but if it’s a bug, it’s one for which I have sympathy. After all, how wonderfully strange would it be to return as a manatee or a tapeworm? And what a special delight it would be to see Dena and my children again after I’m gone.