Data from a large, long-term study of US families indicates women may inherit ovarian cancer through the X chromosome passed down from their dad, independently of genes on other chromosomes already associated with the aggressive condition.

“We have good, strong evidence to say there should be something on [the X chromosome],” said study lead author Kevin Eng of the Roswell Park Comprehensive Cancer Centre in Buffalo.

Dr Eng and his team have identified a potential gene on the X chromosome associated with the early onset of ovarian cancer, they reported today in the journal PLOS Genetics.

But much bigger genetic studies need to be done to identify whether any specific mutation exists, he stressed.

The ovarian cancer paradox

Ovarian cancer is the eighth most commonly diagnosed cancer in Australian women.

It is well known that women who’ve inherited the BRCA 1 and 2 gene mutations from their mother or father are at a high risk of developing ovarian or breast cancer.

“We know that BRCA are major risk genes, but we also know it doesn’t explain everything,” Dr Eng said.

One of the enduring puzzles in cancer research is why the sisters of a woman with ovarian cancer — even those without these mutations — are more likely to get ovarian cancer than their mother or their daughters.

“That paradox got us thinking … about going up a couple of generations to see if we could really explain this thing genetically,” Dr Eng said.

Women have two X chromosomes. One is inherited from their mum, the other is inherited from their dad.

BRCA mutations are on non-X chromosomes, meaning a daughter has a 50/50 chance of inheriting the mutation. But all daughters in a family would inherit an X-linked mutation if it existed.

Three generations in 30 years

The team trawled through data that had been collected over 30 years on the Familial Ovarian Cancer Registry and identified more than 890 grandmothers with ovarian cancer who had granddaughters with the condition.

About a quarter of this group (229 women) were the paternal grandmother of a woman with ovarian cancer.

Around 28.4 per cent of the paternal granddaughters had ovarian cancer, compared to 13.9 per cent of those with a maternal grandmother.

The researchers also observed that fathers were more likely to have prostate cancer if their mother and daughters had ovarian cancer.

To look at this pattern further, the researchers sequenced the X chromosome of 157 BRCA-negative women with ovarian cancer.

The sequencing identified a gene called MACEC3. Women who had inherited this gene were diagnosed on average more than six years earlier than those without it.

Focus on the X-chromosome — and grandmas

Dr Eng said the findings indicated more women may inherit ovarian cancer than we are currently aware of.

“There’s probably quite a few cases that seem like they are sporadic,” he said.

“As an only daughter you may not have siblings to communicate risk. You may not know much about your grandparents.”

He said he hoped the finding would open up new research into the role the X chromosome played in ovarian cancer.

“If we are right and the pattern does seem to be X-linked, eventually we’ll be able to nail down a variant … and begin to think about how to change the screening patterns [to identify people at risk].”

So what does this research mean for me?

The large number of the families involved was a “real strength” of the study, said Paul James, director of the Familial Cancer Centre at the Peter MacCallum Cancer Centre in Melbourne, who was not part of the study.

Dr James said the research could, “potentially help us with the process of personalising women’s risk in the future”.

But he said more work was needed to tease out the role of the gene they identified.

“[The gene is] something that happens in healthy people in the normal population, but they’re saying it happens more commonly in individuals with ovarian cancer,” Dr James said.

“It may help us understand the biology by pointing out this gene, but you can’t say, ‘Oh that’s like another BRCA gene we could use to detect women and work out their risk’.

“But what they have done is opened a new direction that further research might produce that kind of information.”

In the meantime, Dr James suggested talking to your doctor if you are concerned about your family history.

“If people have a strong history of ovarian cancer or anyone who has had a diagnosis of ovarian cancer, we would say it is worth talking to your doctor about whether or not there should be some sort of genetic investigation,” he said.

“We can show through genetics who still is at high risk and … can offer more of those high-risk-[prevention] strategies.