The Great Escape: Tumor-Suppressor Genes and Male-Female Cancer Disparity Reply

by Richard L. Lobb
American Association for Cancer Research

Stand Up To Cancer’s Innovative Research Grant (IRG) recipients,  early-career investigators who take fresh approaches to critical questions about cancer, continue to generate interesting and compelling research.

One of these IRGs is David M. Weinstock, MD, of Dana-Farber Cancer Institute and Harvard Medical School, who was awarded a grant to help develop a rapid system for the identification of molecular abnormalities that drive cancer causation.  Recently he was part of a team that studied a puzzling question:  Why is cancer more prevalent in men than women?

Glioblastoma, the most common type of brain cancer, occurs twice as often in men as in women, as does kidney and renal pelvis cancer and stomach cancer; liver cancer is even more likely to occur in men than women. Overall, men are 20 percent more likely than women to develop cancer, for reasons not fully understood.

The team came up with a possible explanation: Women have more copies of certain genes that fight cancer.

The sex of a human being is determined by the X and Y chromosomes. Men have one of each, so they are XY, while women have two X chromosomes, so they are XX. Since only one X chromosome is needed for proper development and growth, one of the female copies of the X chromosome is turned off. This process is called X-inactivation.

However, not all the genes on the chromosome are turned off. Some are said to “escape” from inactivation, and some of these play a role in suppressing tumors. The team named the gene set “escape from X-inactivation tumor suppressor” (EXITS) genes. The “escape” gives a woman an extra copy of some of these genes, an example of “biallelic expression,” whereas a man has only one copy.

To examine whether EXITS genes have anything to do with the greater predominance of cancer in men, the team studied alterations in genes that occurred during the patient’s life.

The team studied genetic sequencing data from more than 4,000 tumors across 21 different types of cancer, looking for genes that had mutations which caused the genes to lose their functions in human biology. They found six genes with loss-of-function mutations that are found more often in male tumors than female. Some of these genes are known to be tumor suppressor genes. Further, some of these mutations are known to be associated with glioblastoma and kidney cancer — which offers a potential mechanism for male bias in these tumor types.

“Male based mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon,” the team wrote in the journal Nature Genetics. “We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of tumor types.”

Gene mutations in EXITS are not the only reason for the differences in cancer incidence in men and women, but this study offers insight into how specific genes play a role in sex-specific differences in tumor genetics.

The disparity in the burden of cancer between men and women has never been fully explained. The hypothesis that it may be linked to tumor suppressor genes that escape X-inactivation is potentially an important step forward in understanding this disparity. (Other scientists are suggesting that escape from X-inactivation may also help explain disparities in other conditions, such as lupus and certain neurological disorders.) The research on EXITS by Weinstock and others is an example of SU2C’s support for basic as well as translational research.

Richard L. Lobb is Director, Communications, SU2C, at the AACR, scientific partner of SU2C.

Originally published on the blog of Stand Up To Cancer

 

“Rogue One:” In The Beginning Reply

“Rogue One” is the slam-bang prologue to the first “Star Wars” movie, ending moments before “A New Hope” begins. If you were binge-watching “Star Wars,” “Rogue One” would be the first episode.

The story, such as it is, revolves around the Rebel Alliance’s attempt to capture the plans for the Death Star that will show its fatal flaw. Key to this effort is Jyn Erso, played by Felicity Jones. Jyn’s father, Galrogue-oneen Erso, was conscripted by the Empire to design the Death Star; his revenge is putting in the back door that eventually allows the Alliance to blow it up.

Of course, Jyn and the rebel sharpshooter Cassian Andor (played by Diego Luna) have to battle their way across several planets or star systems (if you have hyperspace drive, what’s the difference?) before fetching up on the planet that holds the Empire’s database. The derring-do involved in finding the correct files and transmitting them to the rebels will remind computer users of a certain age of the old days of dial-up.

The film is an entertaining mash-up of Star Wars motifs plus samurai movies (the producers somehow restrain themselves from naming the blind warrior armed only with a staff something like “Zatoichi”) with quite a lot of Wild West and Power Rangers, about what you would expect from a Star Wars crew with an unlimited budget from Disney. Bits of the earlier movies are inserted seamlessly into this one, and even characters are revived via the miracle of CGI. The film won’t launch any acting careers, but if it makes money, it may well spawn a new generation of Star Wars spinoff movies.

“Arrival:” the future as prologue Reply

arrival-movie-amy-adams-jeremy-renner“Arrival,” with Amy Adams, Jeremy Renner, and Forest Whitaker, is a movie about aliens who attempt to communicate with humans, with profound effects on earthlings in general and with the linguistic expert played by Adams in particular.

The aliens are giant squidlike creatures who grunt and moan but also produce inky circular glyphs. Dr. Louise Banks, played by Adams, struggles to understand the messages, but she knows that when you learn another language, you reset your brain according to that language’s way of thinking. The aliens have a different sense of time, and as Dr. Banks deciphers their language, she begins to see the future. Which is what the aliens really need her to do.

The film belongs to Amy Adams, who delivers her most commanding performance yet. Renner is not much more than a sidekick, and Whitaker is the tough but fair military man. The most elusive character, however, is the script, so if you see the film, pay close attention.

Dr. Banks ends up with hard choices to make. If you know how your life will turn out, and how your decisions will affect others, would you do things differently? That dilemma is really at the heart of the movie. It carries a profoundly pro-life message, not so much in the way that term is usually understood, but in the sense that even a life cut short is well worth living. Unfortunately that is a radical message today.

Adele: At “25,”Still Sad After All These Years Reply

Adele is still sad about everything. It worked brilliantly on her last album, so why mess with success? Even if she is world-famous, filthy rich, and happily settled down with a boyfriend and baby, she can still be really sad about a love that ended long ago, the ravages of age (I mean, my God, she’s TWENTY-FIVE), and the restless longing for a better life that afflicts pretty much all of us.

adele-25
Consequently, there’s really nothing new on her latest album, named, like the previous two, for her age at the time of production. Most of the songs sound like “Rolling in the Deep” or “Take It All” or other cuts off “21,” her phenomenally successful album from 2011. “Hello,” from the new album, is almost as spine-tingling as “Set Fire to the Rain,” but not quite. “When we Were Young,” “Water under the Bridge,” “Love in the Dark,” and “Million Years Ago,” are fine songs that share the pervasive melancholy that is her trademark.  Listen to this album long enough and you will wonder what the hell is the point of going on, anyway.


What saves the album, of course, is her wonderful voice and her willingness and ability to throw herself emotionally into the music. Time and again, she draws you into the song with gentle, sorrowful lyrics and then bowls you over with a sudden emotional blast.


Maybe her fans will never get tired of Adele’s rehashing her former love life, but unless she wants to be remembered as the Carole King of R&B (one huge album followed by years of trying for another), she needs to find some new material.

“Spotlight:” Uncovering a Scandal Reply

In the new movie “Spotlight,” the Boston Globe takes the long-running, episodic story of sex abuse in the Catholic Church and discovers how it was covered up for years by the church hierarchy, the local establishment, and a pliant legal system. The Globe blew the lid off the scandal with consequences that reverberate today.

As with “Apollo 13” or “Captain Phillips” or other movies based on actual events, the interest is not in how the story turns out but in how skillfully it’s portrayed. “Spotlight” is carried by exceptionally good acting by every member of the cast, bar none. The lead actors are perfect. Liev Schreiber is the new top editor who wants to know why the story has been so little reported. Michael Keaton is the investigative editor who realizes that he has to atone for previous journalistic lapses. Mark Ruffalo is the ferocious young reporter, while Rachel McAdams is the sympathetic journo who gets the victims to open up.

Outstanding cast in "Spotlight"

Outstanding cast in “Spotlight”

The supporting cast is nothing short of extraordinary, since every single one of them is perfectly believable in the difficult task of portraying the victims of horrid crimes – or the perpetrators. My favorite might be the hapless Father Paquin, who answers a reporter’s knock on the door and immediately, right then and there, standing at the door, admits he molested children. But, he says, it wasn’t important because he derived no pleasure from it. Then his sister rushes to the door and pulls him back, and in her few seconds on the screen, perfectly portrays a harried old woman who is utterly sick of her demented brother but still completely protective of him.

The film is full of such performance gems. The only people who seem to be acting even a little are those who in real life really were acting, desperately trying to hide the truth and protect the church from a devastating scandal.

The film is sort of a police procedural about how the Globe’s “Spotlight” investigative team cracked the case. The church did its best to keep the facts out of public view, mostly by settling cases out of court. Stymied in their attempt to identify abusers, the reporters stumbled upon a Rosetta Stone published by the church itself: the annual directory showing where every priest in the archdiocese was assigned. Analysis showed which ones were being shuffled from parish to parish or sent to treatment centers and listed as on “sick leave” or “unassigned” or the like. Thus the church’s own phone book served up nearly 90 suspected perverts.

The Globe’s blockbuster story, published in January 2002 (appropriately enough on the Feast of the Epiphany, the “revelation” or “showing forth”) put the church’s sex abuse scandal squarely into the public eye and brought about overdue reforms nationwide. The film is a tribute to the type of investigative journalism that is fast disappearing with the collapse of big-city newspapers. It is also a memorial to the victims whose youthful innocence was stolen by truly evil men.

 

Metrics? Really? Reply

Let me say I think the United States should adopt the metric system. I mean, who wouldn’t love to drive 100 on the interstate? Most of the conversions are easy. A gallon is basically four liters. A meter is about a yard. If Starbucks made the venti slightly bigger, it would be half a liter, We could call it a “half,” and you could order a half-caf half with half and half.

But I digress. I realize I am in the minority on this one. That is why I was slightly amazed to see that some guy from Rhode Island (or is it Connecticut?) thinks he can seek the Democratic nomination for president on a platform that includes adoption of the metric system. Mr. Chafee, whose dad was such a Republican that he named him Lincoln, seems to be a little unrealistic about a lot of things. But coming out for metrics may be the goofiest move we have seen yet in what is shaping up as a highly entertaining campaign season. Wherever she is hiding from the press right now, Hillary Clinton must be smiling.

“Birdman:” Action hero seeks relevance Reply

A washed-up but dedicated actor struggling for relevance in a rapidly changing world he doesn’t really understand is a quick summary of the new release “Birdman,” but it also applies largely to the star, Michael Keaton, which may explain some of the intensity he brings to the role. Keaton and the rest of the cast turn in excellent performances, but the film ultimately can’t escape the weight of its own cleverness.

Riggan Thomson (Michael Keaton) and his alter ego, Birdman

Riggan Thomson (Michael Keaton) and his alter ego, Birdman


Keaton plays Riggan Thomson, an actor best known for playing a comic-book action hero, just as Keaton had his greatest success two decades ago in “Batman” movies. Riggan – may I call you Riggan, Mr. Thomson? — is trying to resurrect his career and give himself some legitimacy by taking a shot at theater. He is the writer, director, and star of a Broadway production of a play based on a collection of short stories by the late Raymond Carver.

Or he will be if he can get the production together and overcome his own demons, which include an impressive capacity for alcohol and the voice and eventually the image of the Birdman character belittling his attempt at a new life. His daughter, well played by Emma Stone, tells him, as even loving children sometimes do, just how irrelevant he is – why, he doesn’t even have Twitter or Facebook accounts!

A more serious problem is the open hostility of the New York Times critic, Tabitha Dickinson (Lindsay Duncan), who promises to sink the play with a bad review just because it is not Art. In the end, she saves it with a backhanded compliment, attributing to Riggan “The Unexpected Virtue of Ignorance.”

The film covers three nights as the cast and crew scramble to open the show, surviving mishaps such as a stage light falling on an actor’s head. He’s replaced by Mike Shiner (Edward Norton), who brings a well-established Broadway presence at the cost of supreme arrogance. Riggan stumbles into social media when he steps outside for a smoke only to have the locked stage door close behind him. He has to run through Times Square clad only in his socks and underpants to get back into the theater, a trip promptly captured and shared with the world by eager celebrity-watchers.

The film could work as a black comedy of the insular little world of theater, but this is a movie, so the Birdman trapped inside Riggan’s head plays an ever-bigger role, leading to obviously imaginary action-film sequences. Director Alejandro González Iñárritu ultimately can’t decide if the film is comical, fantasy, or some sort of magical realism. The ending undermines the rest of the picture.

“The Interview:” Them or Us? Reply

The germ of an idea for a good movie is present in “The Interview.” Airhead TV personality lands interview with Kim Jong-un, gets taken in by the dictator’s charm offensive, comes to his senses in the nick of time, and helps ignite a revolution with probing questions and the help of a disillusioned functionary of the regime.

Unfortunately, this promising outline is promptly buried in vulgar dialogue and jokes for which “crude” is too kind an adjective. Seeing the film through to the end is not so much a relief as an escape from an entertainment evidently aimed at 13-year old boys. Except that they are not supposed to be able to attend an R-rated movie by themselves. If 16-year-olds find it funny, I shudder at the future of our culture.

James Franco and Seth Rogen in lame comedy "The Interview"

James Franco and Seth Rogen in lame comedy “The Interview”

Seth Rogen and James Franco do their bit and display a few flashes of wit, but it takes more than that to pull off a successful comedy, even the Adam Sandler variety. Anus jokes can’t carry a film.

In real life, Rogen and Franco owe Kim and his army of hackers (assuming it was really they who pulled off the assault on Sony) a big wet Hollywood kiss for gifting them with a gazillion dollars’ worth of free publicity.

Of course, when the hackers threatened terrorism against theaters showing the film, the major exhibitors demonstrated that they are in fact made of cotton candy and canceled the bookings. If Kim wanted to demonstrate the moral cowardice of the West, he succeeded handily. Sony finally pulled itself together and offered the film to a handful of arthouses, which reveled in the chance to profit from the controversy.

Watching the film, one can see why Sony was then anxious to dump it into cheap, pay-for-view channels ($6 on YouTube) rather than wait for the momentum to build from the limited release. Fact is, the word of mouth would have killed it anyway. So better to go for a quick buck from a mass online release and then take credit for being brave, so brave, in the face of the dictator’s threats.

At bottom, the film is not about Kim Jong-un and his madhouse of a people’s republic. This film, sad to say, is about America and the business of its popular culture.

“Unbroken:” a story of endurance Reply

“Unbroken,” directed by Angelina Jolie, is the story of the courage and endurance of a young American held prisoner, and brutally mistreated, by the Japanese in World War II. With a slow pace and a running time of 2 hours 17 minutes, it is also something of a test of the endurance of the audience. By taking a straightforward biographical approach, broken up only by some flashbacks to fill in the backstory, Jolie achieves accuracy and honesty while giving up narrative intensity and a decisive climax.

The film is based on the nonfiction book by the same title, by Laura Hillenbrand (known previously for “Seabiscuit”). It’s the story of Louis Zamperini, a young athlete who placed eighth in the 5,000 meters in the 1936 Olympics. He is played very effectively by Jack O’Connell, an Anglo-Irish actor in his first big role. After attending USC, Louie enlisted in the Army Air Corps shortly before the U.S. entered the war, was commissioned as a lieutenant, and served as bombardier on a B-24 Liberator in the Pacific Theater.

Louis Zamperini about to be whacked by sadistic guard.

Louis Zamperini about to be whacked by sadistic guard.


Zamperini’s plane crashed in the ocean while on a search-and-rescue mission. He, the pilot, and one other crewman survived the crash and climbed into a life raft for what became the ghastly ordeal of floating adrift for six weeks in the hot sun, catching fish and birds to eat and hoping for rain to bring fresh water. A Japanese plane strafed the raft. The third man died after 33 days at sea; Louie and the pilot drifted 2,000 miles before touching land that was, unfortunately, occupied by the Japanese. Thus began Louie’s second hellish ordeal, imprisonment in several camps that ended only when the war did.

Being a prisoner is always awful, but Louie was targeted for special abuse by a sadistic guard named Watanabe, who did everything he could to break the American’s spirit. The guard is played by Takamasa Ishihara, an actor better known in Japan as a somewhat androgynous singer-songwriter and rock band guitarist. He brings a creepily erotic note to his sadistic treatment of the Allied prisoners. Watanabe’s ultimately unsuccessful campaign of cruelty provides the only real rivalry in the film.

And therein lies the problem. We know that Louie will somehow survive and triumph, because otherwise there wouldn’t be a movie made about him. Watching him get beaten time and again is a lot to pay for a brief scene in which Watanabe sinks to his knees, defeated by Louie’s unbeatable spirit.

In other war movies – “Bridge on the River Kwai” comes to mind – at least we have the satisfaction of seeing the bad guys killed (along with some good guys, of course) and the bridge getting blown up. It isn’t widely known, but in the “Kwai” book, the ending is very different. David Lean knew that a successful movie has to have a spectacular ending, so he took the liberty of providing it. Jolie remains faithful to her source and provides a story that is satisfying in its own way, but not one you would gladly see again.

CGI armies battle in “The Hobbit” Reply

“The Hobbit: The Battle of the Five Armies,” is the final installment in Peter Jackson’s trilogy of films based loosely on J.R.R. Tolkien’s first fantasy novel set in Middle-Earth. Unfortunately, Tolkien gave the battle short shrift in the book, leaving Jackson’s scriptwriters to rely mainly on their own imaginations, which run to vast, computer-generated mob scenes of battle without much of the charm and wit that enliven the book.

Bard the Bowman holds off the bad guys in "Hobbit: Battle pf the 5 Armies"

Bard the Bowman holds off the bad guys in “Hobbit: Battle of the 5 Armies”

The story, briefly summarized, revolves around the fact that Smaug the Dragon is killed, and the dwarves retake Lonely Mountain and its enormous hoard of gold, only to be confronted by human refugees from Laketown trying to cash in on the dwarves’ promise to share the loot, plus the elves trying to recover some sacred jewelry. Gandalf the wizard comes along to warn of impending doom, and Bilbo Baggins goes about looking puzzled and asking why everyone can’t just get along. Then the orcs show up to try to kill everyone. The fifth army (I think) consists of eagles and bears on the allied side.

Naturally, there is a huge battle, complete with earth-eating creatures who punch holes in the ground to help the orcs infiltrate the combat zone. I hate it when they do that. Plus there are bats who are supposed to terrorize the good guys but also provide Legolas a ride up a mountain when he needs it.

The formulaic, almost Power Rangers-style fighting is interrupted by a couple of interesting single combats, but the warfare is well below the gripping level set by Jackson in the remarkable “Lord of the Rings” movies.

The “Rings” trilogy won 17 Oscars, an honor that has eluded the “Hobbit” series. Despite the abundance of gold in the recesses of Lonely Mountain, it seems unlikely that this film will bring home Hollywood treasure.

“Foxcatcher:” crime drama or portrait of madness? Reply

“Foxcatcher,” with Steve Carell, Channing Tatum, and Mark Ruffalo, is billed as a “crime drama,” but the term doesn’t quite fit. In a crime drama, the fascination is in seeing how the motivation for the crime unfolds, how the crime itself is conducted, and how its aftermath works out. In “Foxcatcher,” the crime is almost senseless; the criminal is clearly somewhat deranged, is something of an alcoholic and a drug abuser, and plays with guns to boot. You can see the horror coming; the question is who, exactly, will be the victim.

Steve Carell (front) as John E. du Pont, with Channing Tatum as Olympic wrestler Mark Schultz.

Steve Carell (front) as John E. du Pont, with Channing Tatum as Olympic wrestler Mark Schultz.


The great strength of the movie is in the acting. Every character is utterly believable. Steve Carell is nothing like his usual hapless characters. As John E. du Pont, heir to a piece of one of the country’s great hereditary fortunes, he is full of icy determination but oddly detached even while he yearns for some human relationship. He wears a very convincing prosthetic nose and cocks his head back to look down on mere mortals, but connects with none of them.

Tatum and Ruffalo play Mark and David Schultz, who both won Olympic gold medals in wrestling in 1984. Tatum is a gifted athlete who is not so good as a coach at the training center du Pont establishes on the family estate. His brother Dave comes in to take over the coaching, alienating his brother and setting up a conflict with du Pont. The brothers attempt to help du Pont carry out his dreams of athletic glory, but are foiled by the multimillionaire’s long slide into madness.

Ruffalo actually wrestled in high school, and he and Tatum got enough training to make their performances look very realistic (although the finer points of wrestling are far beyond me). The episode in which Mark has to lose 12 pounds in 90 minutes before a weigh-in is actually true. (Solution: sweat.)

The story is based on real events at the du Pont estate in Pennsylvania in the 1980s and 1990s, but the filmmakers take certain liberties to make the movie work better. In the film, du Pont is driven by his hatred for his mother, who disdained wrestling as a “low” sport, far beneath her own love of horses. The story is meant to be a psychological thriller as du Pont rebels against the limitations of his privileged life. In reality, it appears that du Pont simply went nuts one winter’s day and shot someone close to him.

The film is well done and has generated Oscar buzz for the lead actors. But the characters played by Carell and Tatum are so unsympathetic that it is hard to imagine audiences identifying very strongly with the movie. It is a breakthrough of sorts for Carell, but who wants to be known for playing a deranged rich guy? In the old days, the filmmakers would have changed the story so the victim lives and rehabilitates the shooter, but in the new age of verisimilitude, we are left with a rather depressing movie.

“Exodus:” Biblical epic in a digital age Reply

The good news is that “Exodus: Gods and Kings” is pretty successful as a Biblical epic and reasonably faithful to the original source. The bad news is that people apparently don’t want to see Biblical epics anymore. After all, how many ways are there to part the Red Sea? Everyone knows the story – the sea comes back and the Egyptians are drowned. Been there, seen that. So what’s new?

In the Ridley Scott epic currently showing to sparse crowds, what’s new are giant crocodiles whose chomping on fishermen starts the process of turning the Nile blood-red. Okay, I can deal with crocodiles. But a few twists like that really can’t sustain interest in a two and a half hour movie.

Christian Bale as a fightin' Moses.

Christian Bale as a fightin’ Moses.

Also new is the idea of personifying God as an 11-year-old boy. Presumably Scott didn’t want Morgan Freeman or some other Voice of God actor speaking from the burning bush. So he hired an English schoolboy, Isaac Andrews, to play God in person. He is listed in the credits as a character named Malak, but no one else besides Moses can see him – Aaron sees Moses talking to thin air – so the character is an divine apparition, not a boy.

Christian Bale’s portrayal of Moses as a reluctant hero is the film’s biggest weak spot. Moses is content to launch a sort of intifada against the Egyptians. Malak/God has to take charge and show the Pharaoh he means business and that it does not pay to mess with the Lord. The God of the Old Testament was not the warm and fuzzy type.

The special effects, digital work, and stunts are all well done, but that is expected these days. Sorry, there’s nothing exciting about a digital ancient city or big wave.

I had the impression from some reviews that the film took great liberties with the Biblical text, like the “Noah” film starring Russell Crowe. In fact, the biggest departure from the book is that Moses is shown as a general of the Egyptian army and right-hand man to Pharaoh. The book of Exodus doesn’t go there; Moses could have been a busboy for all we know. But Scott’s version sets up the rivalry between two strong-willed men, so its works. Scott’s overall interpretation of the text seems reasonable and respectful to me.

Perhaps it is the very predictability of the story that that is keeping people away. Most people learned the Exodus story when they were children. If you have time for a long movie during the holidays, why not try something you don’t already know – something with hobbits and dwarves in it, perhaps?