Nanakarobi Yaoki (七転び八起き)
His eyes looked weary. The frown lines etched on his forehead were deep from single-minded despair. The shallowness of his temple had been gouged by the fear and worry of life. Life had not been kind to this unassuming kind and gentle soul. While he had traipsed through the early years with an uncommon benevolence that nature gifts to some – a total freedom to worry. The cruel trick behind those moments of frivolity was the test yet to come. He had been inured into this nature’s conspiratorial web. He looked upon it as a challenge, while his friends empathized with him of his bravery, courage and strength to fight. Ah yes, life was blooming every where but for him and yet there he was in his green striped pajamas and a plain white tee shirt, oblivious and reluctant to take a step back.
It must have been five years ago when he first located the lump on his chest. He ignored it as most often people do. But then the progressive thrust of this vile appearance could not be ignored. He sought attention of a competent physician and the rest was a history full of “shades of grey in the large canvas of black and white,” as he put it eloquently.
What really happened to this gentle soul from the Far East? That became the soul and cry of many a physician and nurse who encountered him. Why does one have to bear the burden of many?
To go back further into the deep recesses of medical thought, it appears that there was a switch in his genetic system that had been switched to an “on” position. So the question was, “Who or what.,’ had set this off. And there in lies the mystery of genetics, known to many through the insight of a monk named Gregory Mendel.
Now what happened in our good man was a change in a portion of his DNA that corresponds to the site that protects such issues from occurring. In other word, in the portion more richly if simply and aptly termed TP53.
Chromosome 17 (Red line at 013.1 site of TP53)
To most TP53 may mean little, but to the cancer community of physicians it is considered the “Guardian of the Genome.” It preserves the stability of the DNA by preventing mutation. This conservational ability grants it the title of “the master watchman.” Any stray, uncalled for or unnecessary genetic mutation that can harm an individual is reviewed by the TP53 gene and if found wanting the cell replication will be stopped and the cell will undergo a “suicide” program or apoptosis (Programmed cell death). Thus this small 20-kilobase length gene present on short arm of Chromosome 17 (17p13.1) location has great responsibility in preserving human kind health. This is also a “Tumor Suppressor Gene.”
TP53 can bring in a cadre of helper proteins that initiate DNA repair to try to fix a DNA mutational anomaly by arresting the cell cycle growth arrest at the G1/S phase. This allows time for the proteins to come in and do remediation. If however there is too much DNA mutational burden present, it simply chucks it to the “rubble heap” of the “suicide pile.”
What provokes the TP53 gene, are stresses that cause DNA damage. These include Ultraviolet, radiation damage, other chemicals, viruses, Oxidative stressors, even Transposons related Oncogene over-expressions and other mutagens. This provocation causes the TP53 to release p53 protein that goes to work in protection and preservation. The primary effect in the damaged or stressed cell is, the accumulation of the p53 followed by or simultaneously, conformational changes in the protein itself via phosphorylation to become active.
Cell Signaling Pathways and Apoptosis
Since two copies of the TP53 are required for normal cellular preservation, a loss of one copy (i.e. knocked off the one short arm (p) of the two-short-arms of chromosome 17 will cause dysregulatory influence on the cellular behavior of that individual with resultant cancers forming in early adulthood.
Almost 50% of human cancers have mutation and or deletions of the TP53 gene. This may constitute the “chicken or the egg” issue but other then in a hereditary mode it is the “chicken.” (Assuming you agree that the egg came first.)
p53 stained cells (in brown) in malignant Astrocytoma (brain tumor)
Two methods employed to restore p53 in the system have led to different results. Just by increasing the p53 amounts in the environment of the malignancy has resulted in “premature aging”. (this methodology is obviously not the right one). However the other mechanism is to restore the functionality of the existing or endogenous p53 and that holds promise.
Not until 1993 when the Journal Science published a paper touting p53 as the “molecule of the year” was this a known entity in the geneticist world. This article was on the heals of a published paper in the journal Nature Genetics in 1992 by Wafik El-Deiry, MD PhD
Wafik El-Deiry, MD, PhD.
and Bert Vogelstein, MD
Bert Vogelstein, MD
then at Johns Hopkins University. These brilliant scientists first determined the consensus sequence of the binding site of the p53 (produced by a baculovirus produced human p53) to the DNA TP53 via immunoprecipitation methodology.
Even though the mechanism of this disease became known not until 1992, it was through two other equally brilliant physician scientists Frederick Pei Li and Joseph F. Fraumeni, Jr.,
Joseph F. Fraumeni, Jr MD
who discovered this disease entity. Their criteria were simple. This composite syndrome of soft tissue sarcoma, bone sarcoma, acute myeloid leukemia, breast cancer, adreno-cortical carcinomas and brain tumors occurring in a patient probably had a common genetic link. Their screening methods were simple; any individual before the age of 45 with sarcoma with first degree relative (less than 45 years of age) with cancer and any family relative of similar age with cancer or at any age with sarcoma. This disorder was aptly termed as the “Li-Fraumeni Syndrome” in respect for the discoverers. It is an autosomal dominant hereditary genetic disorder. The damage to the TP53 gene cancer can occur through out the 20-kilobase location as evidenced below:
SNPs (Single Nucleotide Polymorphism(s)) leading to Li-Fraumeni syndrome include:
- rs11540652, TP53 R248Q
- rs121912651, TP53 R248T
- rs121912652, TP53 E258K
- rs121912653, TP53 L252P
- rs121912656, TP53 G245D
- rs121912657, TP53 V272L
- rs121912662, TP53 L344P
- rs121912663, TP53 K292I
- rs121912666, TP53 Y220S
- rs28934575, TP53 G245C
- rs28934576, TP53 R273H
- rs28934578, TP53 R175H
- rs28934873, TP53 M133T
- rs28934875, TP53 A138P
Now as the sun was rising from behind the curtains that were flailing helplessly to the gentle breeze from the air conditioner, he picked at his breakfast, a soft-boiled egg and a single slice of bread. The difficulty was all too apparent for anyone to see. This was his third battle. He had arrived at it with a measure of defiance and fortitude. Yet lying there weak and unable to hold together the very nuance of his existence, the idea of “chucking it all,: seemed very real. His eyes glanced at the photographs of his family members filling the long thin rectangular table against the far wall. “Should I subject them to this?” was the question on his mind.
“How’re you doin?” The young resident walked into the room and asked without much preamble.
“Ok.” He replied weakly as he eyed the entrant.
“Well, I have some good news for you.” He looked expectantly at his patient and not getting a response, he continued, “ Yesterday’s PET scan fails to show any residual evidence of the breast cancer.”
His patient just nods.
“I would hope you would be more elated that that.”
“Yeah, I am,” his patient replies with a shrug of his shoulders.
“You should be able to go home tomorrow.” The resident states with his hand in his pockets, then remembering additional information he stops and turns back, “Also tonight we will have a conference by your bedside, it would help if your wife was here. Around 5’O’clock?” The resident recedes out into the hallway.
“What? Why?” He mutters to himself. “Conference?” He shrugs his shoulders and goes back into the land of dejected thought. Crypted communication are the norm in the fast paced medical world. But he does not want to delve into any of this. His mind is burdened by more weighty issues.
It is around 4:45PM and he can see the buildup of a lot of youngish intern/resident crowd outside his room. Most seem excited and energized, some are looking at their smart phone screens while others are allowing their gaze to wander around. He sees all this and his mind starts to wander at the prospects of this “conference.”
“Mr. T,” as he is called by most of the staff, begins the resident in charge, “has successfully conquered his third malignancy. As some of you know, he had a soft tissue sarcoma on his left chest, which was removed and radiated twelve years ago. He then had a bout with AML and following a bone marrow transplant, he remains disease free from that and this time he had the left sided mammary carcinoma.” The resident pauses to make sure he has everyone’s attention, “we originally surmised that the breast cancer was in some way radiation induced since the site was on the same side as the soft tissue sarcoma, but one of the intern has through diligent research and testing discovered the real problem behind Mr. T’s dilemma.” Now all eyes are on him except one female intern who coyly keeps her eyes rooted to the floor. She is possibly the referred-to intern, shy in her humility.
“Anybody?” The Resident asks. The crowd remains mute while Mr. T looks expectantly to understand the significance of this gathering and this discovery.
“We believe Mr. T has LF-1!” There is a minor emphasis on the letters LF.
“Ah!” a gasp escapes a few in the crowd.
“Right, so Mr. T, what we are saying is that you have a flaw in your genetic system that allows bad cells to escape and become cancerous.” The resident takes both his hands out of his pockets and explains creating shapes only his mind can fathom. Mr. T’s wife looks dejected after the explanation and so does her husband. The resident finally looks at his patient and understanding to some extent the husband and wife’s dilemma, chimes, “You see, Mr. T you will be a frequent visitor at this facility for observation. The risk of another cancer is real but with close observation we can mitigate that and arrest the disease. This may not sound as good news to you just yet but you will hopefully not have to fight malignancies when they have spread and early detection will result in better eradication through close follow up.”
The silence fills in behind the words and but for a few coughs and a sneeze the echo of the couple’s fears ring loud and true. Just then the slightly bent figure of an older man walks in. The hush is deafening.
“So did you explain to Mr. T and the lovely Mrs. T the issues we discussed this morning?” The man asks the resident.
“Yes sir!” the resident answers. This professor has generated more literature and earned more accolades then anyone in the university is in the minds of many, a walking encyclopedia. Yes he is entitled to that respect.
“So Mr. T,” The professor begins slowly, “What we are faced with is a warning from your genetic system that tells us that there is a mechanism that is misaligned and that we have to keep a close watch on you to prevent it from hurting you. Your surveillance, as we call it, will become a routine for you. It will encumber you, may be, one visit per every six months and as we do with some executives of large corporations you will undergo some screening tests that will all be accomplished on the same day. The dates will be in accordance with your convenience. All what I have said is considered prevention!” The professor stresses on the word and leaves a moment of quiet before he continues, “It is fortunate that we were able to discover this anomaly. It is of great help for you.”
Mr. T has a brief smile on his face. This explanation is so much more confidence inspiring. He face relaxes and his burden seems to ease somewhat. His brows are relaxed and his eyes still in questioning slits are more open in receiving the light of this information. He grabs his wife’s hand and startles her momentarily. His spine is now straight and there is conviction in his eye. The cataract of despair has been washed away. He says; “ Nanakarobi Yaoki.”
The assembled physicians and would be physicians all have quizzical looks.
“It means, Fall down seven, Stand up eight.” Mr. T interprets for the group.
And there in those words lies courage!
1. el-Deiry WS, Kern SE, Pietenpol JA,Kinsler KW, Vogelstein B. Definition of a consensus binding site for p53. Nat Genet. 1992 Apr;1(1):45-9.
2. Li FP, Fraumeni JF (October 1969). "Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?". Ann. Intern. Med. 71 (4): 747–52
3. Koshland DE (December 1993). "Molecule of the year". Science 262 (5142): 1953.
4. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991). "p53 mutations in human cancers". Science 253 (5015): 49–53.
5. Clemens A. Schmitt; Fridman, JS; Yang, M; Baranov, E; Hoffman, RM; Lowe, SW (April 2002). "Dissecting p53 tumor suppressor functions in vivo". Cancer Cell 1 (3): 289–298.