The Story of PALB2
A newly-discovered collaborator is implicated in breast and ovarian cancer.
Cancer genes shouldn’t have friends. They should be hermits, forced to eke out a meager living in solitude, not popular kids with collaborators who help accomplish their goals. Unfortunately, genes involved in cancer do have friends they interact with regularly. PALB2, which stands for, “partner and localizer of BRCA2” is a buddy and supporter of the gene BRCA2 that also works with BRCA1. Both BRCA1 and BRCA2 are genes closely associated with breast and ovarian cancer. Fortunately, researchers are now on to PALB2’s collaborator role in cancer risk, which will help empower patients to make decisions about their own health.
To understand what PALB2 does, you have to understand a little bit about how genetic mutations cause cancer. Cancer is a disease of unchecked cell growth. When cells work properly, they live, divide, and die according to the body’s normal schedule. Cancer occurs when cells divide too much and can’t stop dividing, and when cells don’t die according to plan, sticking around, and reproducing even more. Cellular DNA controls these processes – it creates proteins that turn switches on and off to regulate the life of the cell. PALB2 belongs to a class of genes called tumor suppressors – when PALB2 works properly, it is part of the body’s natural defense against tumors. If your body were a car, PALB2 would be part of the braking system.
In a cell that functions properly, PALB2 helps BRCA2 and BRCA1, which also work as tumor suppressor genes, to repair breaks in DNA. When PALB2 is broken, its buddies can’t do their job as well either – if BRCA2 were a carpenter, you could imagine a faulty PALB2 gene like an incompetent, or even destructive apprentice. When breaks in cellular DNA are not effectively repaired, the cell may quickly acquire other mutations that can lead to cancer.
Most cancer is caused by acquired mutations, errors in DNA that accrue over your own lifetime, individual cells that become damaged or mutated as the result of environmental damage or aging. Each person has two copies of each gene in each cell of their body – one from the mother, and one from the father. Usually, a single mutation in one gene in one cell is not enough to cause cancer – rather, several critical genes must become altered. The science is still coming in on PALB2, but early research has identified acquired PALB2 mutations in some cases of pancreatic cancer. The same research suggests that pancreatic cancer with PALB2 mutations may be more susceptible to treatments that damage DNA within the tumor.
It is also possible to inherit, as opposed to acquire, a genetic alteration, and some PALB2 mutations are inherited. Inherited mutations are passed down from generation to generation – they are part of cellular DNA and exist in every cell of the body. A parent with one PALB2 mutation has a 50 percent chance of passing that mutation down to their child. People with one inherited PALB2 mutation are at high risk for breast and pancreatic cancer.
You can think of PALB2 like a file on your computer that you’ve backed up on a disk drive. Let’s say it’s an important file that you need to keep track of – your most recent tax return. With two copies of your tax return, you’re in pretty good shape – it would take a lot of coincidences to corrupt or delete both the files. But if you start out with one good copy on your computer and a corrupted copy on your backup – then it will take comparatively fewer coincidences for you to lose the data.
Patients who have inherited one faulty PALB2 mutation have a higher risk of breast and pancreatic cancer than typical patients. Women with an inherited PABL2 mutation have a two to six-fold higher chance of developing breast cancer. Men and women with an inherited PALB2 mutation have a risk of developing pancreatic cancer that is 10 to 32 times that of the general population. Some families with a PALB2 mutation have also been found with cases of male breast cancer, stomach cancer, and ovarian cancer, suggesting that there might be a link between PALB2 and these cancers, but there hasn’t been enough research yet to confirm this.
It is also possible to have inherited two mutated or faulty PALB2 genes – one from each parent, which causes Fanconi’s anemia. Nearly 50 years ago, Swiss pediatrician Guido Fanconi gave his name to this syndrome, which leaves children with developmental abnormalities, ineffective bone marrow, and childhood cancers including Wilm’s tumor (a rare form of kidney cancer) and certain brain tumors. Patients with Fanconi’s also have bone marrow that doesn’t work as well as it should, causing anemia. Over the decades, researchers have ferreted out the genetic mutations that can cause Fanconi’s – PALB2 is one of about a dozen associated with the syndrome.
In studying Fanconi’s anemia, researchers ended up uncovering the secret of PALB2’s role in breast cancer. Here’s how: Fanconi’s is a recessive disorder — it requires a child to inherit mutations in a certain gene from both parents. It turned out that a small subset of Fanconi’s patients had mutations in both their BRCA2 genes. Researchers then focused their attention on what other genes BRCA2 hangs out with. Eventually, in 2006, their sights settled on PALB2, potentially guilty by association.
Scientists reasoned that if two mutated PALB2 mutations caused the same syndrome as two BRCA2 mutations – Fanconi’s – then maybe inheriting one altered copy of either gene would also cause similar syndromes. BRCA2 had already been identified as a gene that caused an inherited breast cancer syndrome, so perhaps a single inherited PALB2 mutation could cause a similar syndrome. Scientists identified PALB2’s association with breast cancer in 2007, and its association with pancreatic cancer in 2010. In 2014, a study in the New England Journal of Medicine finally pinpointed the extent to which PALB2 raises breast cancer risk. Dr. Mary-Claire King, a co-author on the paper who was intimately involved in the identification of BRCA1 in the early 1990s, said her lab had been screening patients for PALB2 since 2010, and said that essentially PALB2 was “BRCA3.”
Since PALB2’s connections with breast and pancreatic cancer risk have only been recently discovered, there are currently no national guidelines on who should test or how this cancer risk should be managed. Since the breast cancer risk numbers appear similar to those involved in BRCA2, it’s possible that the guideline for BRCA patients might be helpful. In general, medical surveillance – frequent mammograms and MRIs – are an option to try to catch cancer early, and preventive surgery – the removal of healthy breasts – has been shown to reduce breast cancer incidence in BRCA2 carriers. But unlike BRCA2, PALB2 mutations depend heavily on family history, so the guidelines may not map exactly. The editorial that ran alongside the 2014 New England Journal of Medicine article suggested that since PALB2 works with BRCA1/2, and BRCA1/2 cancer responds well to PARP inhibitors, that patients with PALB2-related cancer might also respond
well to PARP inhibitors. Clinical studies are ongoing.
Clearly, though, much more research is needed. Until firm guidelines are established through scientific study, working with a trained genetic counselor or other expert who keeps up on this emerging field of science is probably a good move. And of course, participating in a clinical trial might help research scientists draw the conclusions so desperately needed by PALB2 patients sooner rather than later.