Rare mutations tied to breast, pancreatic cancers

Mutations in genes that fix mismatched DNA may put people at extra risk for breast cancer and pancreatic cancer, in addition to their well-known ties to colon and endometrial cancers, a new report suggests.

But close relatives of people with the inherited mutations, known collectively as Lynch syndrome, don't seem to have any extra cancer risk if they test negative for the defective genes, researchers reported Monday in the Journal of Clinical Oncology.

The mutations "are very rare," according to Mark Jenkins, from the University of Melbourne. Researchers don't know exactly how common Lynch syndrome is, in part because people aren't generally tested unless they have a family history of colon or endometrial cancer.

Jenkins, who worked on the study, said that at most one in 1,000 people probably has the condition.

Still, "the consequences for them are quite severe because the risks of cancer for them are quite high," Jenkins told Reuters Health.

People with Lynch syndrome have a mutation in one of four different genes that are responsible for fixing mistakes that occur when DNA is copied before cells divide—so some of those errors never get repaired.

The link between mutations in the DNA-fixing genes and colon and endometrial cancers is well established. Doctors recommend that people with Lynch syndrome get colonoscopies more often than guidelines suggest for normal-risk people, and women often have their uterus removed when they're done having kids.

But for breast and pancreatic cancers especially, evidence has been mixed. And in other cancers, no clear link to Lynch syndrome has been recorded.

"We don't really know why it increases the risk of some cancers but not others," Jenkins said.

His colleague Aung Win led a team of researchers from Australia, New Zealand, Canada and the United States who followed 446 people with the gene mutations and 1,029 of their mutation-free relatives that were tested because someone in their family had colon or another cancer.

At the start of the study, none of the participants had been diagnosed with cancer themselves.

Among people with a family history of colon cancer, four percent of those with mutations were diagnosed with the disease during the next five years, compared to less than half a percent of their mutation-free relatives.

Jenkins and his colleagues calculated that over five years, people with Lynch syndrome had 20 times the normal risk of colon cancer. Their risk was also 10 times higher than usual for pancreatic cancer, and four times higher for breast cancer.

People with the mutations also seemed to be at increased risk of endometrial, ovarian, stomach, bladder and kidney cancers.

In contrast, their relatives without the mutations didn't have an increased risk of any type of cancer, compared to expected rates of new diagnoses.

Link still controversial

The link between Lynch syndrome and breast cancer in particular is still a controversial one, according to Dr. Albert de la Chapelle, a cancer geneticist from The Ohio State University in Columbus.

"It could be that there really is a slightly increased risk to get breast cancer," said de la Chapelle, who has worked with some of the authors before but wasn't involved in the new report.

But the conclusions, he said "are based on very small numbers," for example just 12 cases of breast cancer in mutation carriers and non-carriers combined.

Dr. Jinru Shia, from Memorial Sloan-Kettering Cancer Center in New York, told Reuters Health that the breast cancer result "goes along with our anecdotal experience" at her hospital.

The findings don't mean that everyone who tests positive for Lynch syndrome should get frequent screening for all cancers that were tied to the gene mutations, researchers agreed.

"Currently, screening is recommended for bowel cancer for people with this mutation, and we know that that screening works. For other cancers, there's less evidence that screening is effective," Jenkins said.

For example, if screening tests aren't very specific or cancers are very rare, the tests may detect more false positives—leading to unnecessary tests and treatment—than real cancers.

"Before we would recommend increased screening for breast cancer, for example, we'd have to have stronger evidence that the increased risk we observed was real and that (mammography) or other types of screening are effective," he said.

"Good news for these people"

Meanwhile, Jenkins said the results are encouraging for the family members of people with Lynch syndrome who are themselves mutation-free and "don't need to worry" about any extra cancer risk.

That's been a concern because researchers have thought other genes, besides the four Lynch syndrome mutations, could be influencing cancer risks in those families.

"Now, one can say with confidence that those who turn out not to have the mutation, that their risk is the average risk," de la Chapelle told Reuters Health.

"That is very good news for these people."