When Spanish scientists came across a strange case of a woman who had experienced 12 different types of tumors before the age of 36, they decided to dig a little deeper to find out why she was so susceptible to cancer.
The 36-year-old woman was first hospitalized for cancer at the age of two. At the age of 15 she was diagnosed with cervical cancer.
At 20, a salivary gland tumor was surgically removed. A year later, he underwent further surgery to remove a low-grade sarcoma.
And as she moved into her 20s and 30s, she was diagnosed with several different tumors.
In total, he has presented with 12 tumors, of which five were malignant.
With the permission of the woman and her family, an international team of researchers, led by the Spanish National Cancer Research Center, took blood samples and used single-cell DNA sequencing to examine genetic mutations within thousands of individual cells.
The researchers discovered something strange. this woman had a one-of-a-kind mutation that made her more prone to cancers.
He had a mutation in both copies of the MAD1L1 gene, which is unheard of in humans.
The MAD1L1 gene is responsible for a key piece of machinery that helps align chromosomes before a cell divides. MAD1L1 was previously suspected to play a role in tumor suppression.
Mutations in the gene are not unknown – in fact, members of the woman’s family carried one. But this is the first time that both copies of the gene have been found to carry this particular change.
A double (or homozygous) MAD1L1 gene mutation is lethal to mouse embryos, so it is a very surprising finding in humans.
In this woman, the mutation caused cell replication to malfunction and created cells with a different number of chromosomes. About 30-40 percent of her blood cells had an abnormal number of chromosomes.
Humans normally have 23 pairs of chromosomes inside the nucleus of every cell in our body.
Chromosomes are condensed packages of DNA that come in an “X” shape and are formed when a cell is about to undergo mitosis or cell replication.
In each pair of chromosomes, one comes from the individual’s mother and the other from the individual’s father.
People with a rare condition called ‘mosaic variegated aneuploidy’ (MVA) have different numbers of chromosomes in different cells, like a mosaic of different colored tiles. This condition can be caused by many different genetic mutations, including the one seen in the woman with 12 cancers.
People born with MVA often have developmental delay, microcephaly (where a child’s head is smaller than normal), intellectual disability, and other birth defects. They are often predisposed to cancer.
In this case, the woman did not have an intellectual disability and lived a relatively normal life (considering the number of rounds of cancer treatment she had undergone).
“We still don’t understand how this individual could have developed during the embryonic stage, nor could it have overcome all these pathologies,” says Marcos Malumbres, molecular biologist, co-author and head of the Cell and Cancer Group at the National Cancer Research Center of Spain, where this study was carried out.
Although the role of aneuploidy is not well understood in cancer, we know that about 90 percent of tumors have cancer cells with extra or missing chromosomes.
And we know that a high degree of aneuploidy is associated with worse outcomes in cancer.
The study revealed that people with aneuploidy, like this woman in the case study, have an “enhanced immune response” that “could provide new opportunities for the clinical management of these patients,” the researchers say.
This work was published in Advances in Science.