Paternal lineage may influence ovarian cancer risk

Genetics can play a huge role in the probability of developing cancer, for example, a woman’s risk of developing ovarian cancer is 20?30 times greater is she has a mutation in her BRCA1 gene. This has led to genetic screening of at-risk women, with preventative measures like oophorectomy and hysterectomy being offered to those with a BRCA1 mutation. Angelina Jolie underwent a double mastectomy and oophorectomy as her mother had breast cancer and later died of ovarian cancer, where testing revealed that she had a BRCA1 mutation. This led to what has been dubbed ‘The Angelina Effect’, as her high profile case resulted in a surge of women around the world undergoing screening.

Knowing how dramatically genetic mutations can influence cancer risk, researchers from Roswell Park Cancer Institute in Buffalo, New York, decided to investigate whether there is a gene on the X chromosome that influences the risk of developing ovarian cancer with the results published in the journal PLoS Genetics.

Your genetic material is organised into 23 pairs of chromosomes, 22 of which are called autosomes and one pair are allosomes, or sex chromosomes. Sex-determining genes, among others, are carried on sex chromosomes, with males having an X and a Y chromosome and females having two X’s. Genes carried on these chromosomes are called sex linked, with mutations here causing unusual inheritance patterns as males and females have a differing number of gene copies. For example, red-green colour-blindness is a recessive sex linked disorder caused by a mutation on the X chromosome. Because females have two X chromosomes, they need to inherit both copies of the mutant gene, one on each X chromosome inherited from each of her parents, to become red-green colour blind. Only inheriting one copy would lead to normal vision, however, they would be a carrier of the mutant gene and it can therefore be passed on to offspring. As males have only one X chromosome, only one copy of the mutant gene is needed for that trait to be expressed, leading to males being disproportionately affected by X linked disorders.

To investigate the link between a gene on the X chromosome and ovarian cancer risk, the researchers studied the incidence of ovarian cancer in paternal grandmother-granddaughter pairs, where the son/father could have amplified genetic risk factors. DNA data from 3,500 grandmother-granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute was analysed.

From the grandmother to her son, a gene carried on an autosome (non-sex chromosome) has a 50% chance that it will be passed on. This gene then has a 50% chance that it will be passed on from son to granddaughter, therefore the granddaughter has a 25% chance of inheriting that gene variant. A gene carried on an X chromosome has a 50% change of being passed from the grandmother to her son, however, as the son only has one X chromosome, there is a 100% chance that the gene will be passed on to his daughter, as one X chromosome comes from each parent, meaning that grandmother-to-granddaughter gene transmission will be 50%.

They found that the ovarian cancer rate was 28% in granddaughters whose paternal grandmother had ovarian cancer, compared with 14% in granddaughters whose maternal grandmother had ovarian cancer. This doubling of incidence suggests that genes on the X chromosome could be involved in ovarian cancer. They also found that granddaughters with a paternal link to ovarian cancer generally developed the disease earlier in life, and that the son/father tended to have a higher incidence of prostate cancer if his mother had cancer.  

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

As they were looking for a new gene, independent of BRCA1 & 2, the DNA from BRCA-negative families was examined with a possible mutation in the MAGEC3 gene found.

 

 

A family with three daughters who all have ovarian cancer is more likely to be driven by inherited X mutations than by BRCA mutations"

Kevin Eng, lead author

This potential X linked pattern of inheritance has wide-reaching implications for risk stratification, with extra genetic testing needed in the future. However, there is still a lot to be confirmed, with more research needed to ascertain if MAGEC3 influences how aggressive the cancer is and age of onset, if other cancers are affected and how much risk does this gene confer. The database used was also mostly comprised of people with white ethnicity, so risk could differ between ethnic groups.

Lead author Kevin Eng said: "What we have to do next is make sure we have the right gene by sequencing more families. This finding has sparked a lot of discussion within our group about how to find these X-linked families. It's an all-or-none kind of pattern: A family with three daughters who all have ovarian cancer is more likely to be driven by inherited X mutations than by BRCA mutations."

The complexity of inheritance and genetics makes it difficult to ascertain which cancer genes may be involved, and from where they came from. Just because a cancer patient’s paternal grandmother had ovarian cancer, it doesn’t unconditionally mean that an X linked cancer gene was passed on. Cancer genes can be inherited across many different chromosomes, from both the mother and father, so it could be another gene on another chromosome that’s responsible, or just random chance.

Although X linked inheritance is not a new discovery, the researchers believe that the potential identification of a novel cancer gene on the X chromosome is a significant breakthrough that could eventually pave the way for more in-depth and accurate genetic screening.