Paternal genes may influence ovarian cancer risk

"Fathers may pass ovarian cancer risk to daughters," reports BBC News after research found a possible new cancer gene on the X chromosome.

It's well known that mutations in the BRCA genes can increase the risk of breast cancer and ovarian cancer. But the researchers were interested in whether there might be a separate ovarian cancer risk gene on the X chromosome.

If a man carried the gene, inherited from his mother, then he would always pass it on to his daughter, as he only has one X chromosome.

The researchers analysed a large ovarian cancer registry in the US, looking at cancer rates among women whose paternal grandmothers had ovarian cancer.

Their findings supported the possibility of an ovarian cancer risk gene on the X chromosome, acting separately from BRCA. Further analysis identified a potential candidate: a mutation on a gene called MAGEC3.

If these findings are verified by further investigation, it could change our understanding of the hereditary risk of ovarian cancer, as women who have a paternal grandmother with ovarian cancer may be at higher risk.

Where did the study come from?

The study was conducted by researchers from Roswell Park Cancer Institute in Buffalo, New York, and was funded by the National Institutes of Health. It was published in the peer-reviewed journal PLOS Genetics and is free to read online.

What kind of research was this?

This was a cohort study that aimed to see whether the risk of ovarian cancer is partly inherited through the X chromosome.

As the researchers said, family history remains the most well-known risk factor for ovarian cancer. Following past studies observing that sisters can share a closer cancer risk than a mother and daughter, the researchers speculated that the risk could be coming from the father – possibly linked to the X chromosome that would pass from father to daughter.

The researchers theorised that this X-linked gene could be acting separately from BRCA1 and 2. The BRCA genes, which we all carry, are tumour-suppressing genes, and inherited mutations of them are known to increase the risk of breast and ovarian cancer.

The researchers analysed a large cancer database to investigate their theory.

What did the research involve?

The researchers used the Familial Ovarian Cancer Registry, located at Roswell Park Cancer Institute in New York state. This database comprises 35 years' worth of data for more than 50,000 participants and 5,600 cancers across 2,600 families.

The researchers were looking at how common it was to see ovarian cancer in paternal grandmother-granddaughter pairs where the risk could have been passed on by the son/father.

Normally when a gene is carried by the grandmother, she has a 1 in 2 chance of passing it to her son, who then has a 1 in 2 chance of passing it to his daughter. This gives a grandmother-to-granddaughter transmission risk of 1 in 4.

But if this was a gene on one of the grandmother's X chromosomes, there is a 1 in 2 chance she would pass it to her son and, as he only has one X chromosome, he would always pass that gene to his daughter. So in this case, the grandmother-to-granddaughter transmission risk would be 1 in 2.

The researchers therefore thought they might be able to tell whether risky genes were located on the X chromosome by looking at the transmission rate of ovarian cancer from paternal grandmother to granddaughter.

The researchers had data on about 3,500 grandmother-granddaughter pairs, and they analysed the DNA from both grandmother and granddaughter to see what the gene mutations might be.

What were the basic results?

The cancer rate among granddaughters who had only one grandmother with ovarian cancer was 28% if it was the paternal grandmother and 14% if it was the maternal grandmother. This means the cancer risk doubled when it came from the paternal grandmother, which was broadly consistent with the X-linked theory.

The researchers also observed that:

• ovarian cancers in granddaughters tended to develop at an earlier age when it was the paternal grandmother who had been affected
• the intermediate son/father tended to have a higher risk of prostate cancer if his mother had ovarian cancer

When looking at DNA from BRCA-negative families on the registry, they found a possible mutation on the MAGEC3 gene, which was also associated with earlier-onset cancer.

How did the researchers interpret the results?

The researchers said: "In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X chromosome contributes to ovarian cancer risk."

They added that this X-linked pattern of inheritance has implications for understanding hereditary risk, as women with an affected paternal grandmother are at increased risk of ovarian cancer.

Conclusion

This is valuable research that explores the possibility of there being an additional ovarian cancer risk gene positioned on the X chromosome. This could possibly explain the inheritance of any cases of cancer seen in a woman (and any sisters) and just her paternal grandmother.

The study benefited from using the largest database of families with ovarian cancer and, in MAGEC3, was able to identify a possible candidate gene.

As the researchers said, these findings could have important implications for understanding ovarian cancer risk – but they need to be confirmed by further research first. We need to know that there is a definite X-linked pattern of inheritance and that MAGEC3 is carrying the mutation.

There are still many questions that can't be answered at the moment, such as:

• the level of cancer risk attributable to this gene – in comparison with BRCA1 or 2, for example
• whether these cancers are more aggressive or develop earlier, or both
• whether the gene could increase the risk of other cancers, such as prostate or breast cancer

This database also mostly included only people of white ethnicity, and hereditary risk could differ in other ethnic groups.

On an individual basis for any woman who has a family history of ovarian cancer, it's difficult to guess which cancer genes could be involved. For example, if a woman's paternal grandmother had ovarian cancer, it doesn't definitely mean this was an X-linked cancer gene. Breast and ovarian cancer risk genes can be passed on in chromosomes from either the mother or father, so it could be a gene on another chromosome that's responsible, or the cancer may not be hereditary at all.

It's not a new finding that fathers can pass cancer genes on to their daughters, but the possibility that the researchers have found another ovarian cancer risk gene positioned on the X chromosome is novel and significant.