08 November 2022


A strange clinical case interested Spanish researchers. A 36-year-old woman has suffered a total of 12 oncological diseases. The first tumor (rhabdomyosarcoma of the left middle ear) was detected at the age of two years, courses of radiation and chemotherapy were conducted. At the age of 15, she was diagnosed with cervical cancer, which required brachytherapy, and then removal of the uterus with appendages. At the age of 20, a tumor of the parotid salivary gland was discovered, it was surgically removed. A year later, she underwent another operation to remove low-grade salivary gland cancer. From the age of 20 to 25, a woman was found to have several dysplastic nevi, breast lipoma, pilomatrixoma. Then there were operations to remove nodular neoplasm of the thyroid gland, colon polyp, rectal adenocarcinoma. In total, the woman had 12 tumors, including five malignant ones.

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 DNA sequencing of single cells to study possible genetic mutations.

Researchers found a woman with a one-of-a-kind mutation in both copies of the MAD1L1 gene, which made her more prone to cancer. The MAD1L1 gene is responsible for the mechanism that helps to distribute chromosomes along the poles of the cell before its division. Scientists suspected that it plays a role in suppressing tumors.

Mutations in MAD1L1 were detected earlier – family members of the study participant were also carriers. But this is the first time that this change has been detected in both copies of the gene. A double (or homozygous) mutation of the MAD1L1 gene is fatal for mouse embryos, so the authors were surprised by this finding in humans.

A homozygous mutation of MAD1L1 in a woman caused a violation of cell replication and led to the appearance of cells with different numbers of chromosomes. About 30-40% of the cells in the blood sample had an abnormal number of chromosomes.

A condition in which cells have a different number of chromosomes is called mosaic aneuploidy. It can be caused by several genetic mutations, including in the MAD1L1 gene, as in the study participant.

Mosaic aneuploidy is often accompanied by developmental delay, microcephaly, mental retardation, other birth defects and a predisposition to cancer.

In this case, the woman had no intellectual disabilities, but there were developmental stigmas: deep-set eyes, hypoplasia of the face, micrognathia, abnormally formed auricles, high arch of the foot, hammer-like fingers and multiple pigmented spots on different parts of the body. It remains to be seen how a person with such a mutation was able to survive at the embryonic stage of development.

The role of aneuploidy in cancer has not been sufficiently studied, but it is known that about 90% of tumors contain cancer cells with an excess or lack of chromosomes. In addition, aneuploidy is associated with worse outcomes in cancer.

Article by C.Villatoria-Beltri et al. Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility is published in the journal Science Advances.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru .

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