12 Tumors Before the Age of 36

This case puzzled scientists and physicians for a long time. A woman developed 12 neoplasms, including five malignant tumors, before she was 36 years old. Finally, an analysis of her genes revealed something that had never seen before.

It seemed she was literally attracting tumors: She had her first chemotherapy and radiation treatment at age two, after a rhabdomyosarcoma was found in her left ear canal. When she was 15, she was diagnosed with cervical carcinoma – and the next radiation therapy followed. At the age of 20, a pleomorphic adenoma of the left parotid gland was removed. Between the ages of 20 and 25, several dysplastic nevi, a mammary lipoma, and a pilomatrixoma were removed. She later developed adenocarcinomas.

Whole-Exome-Sequencing and RNA-Seq provide answers

Spanish scientists became aware of the case and decided to dig deeper and find out why she was so prone to tumors. In the process, they discovered that she had a unique mutation that was responsible: whole-exome sequencing (WES) of peripheral blood samples revealed two different stop-gain mutations in the MAD1L1 gene.

The MAD1L1 gene helps align chromosomes before a cell divides, making it important for tumor suppression. But this woman thus had a mutation in both copies of the MAD1L1 gene, which does not actually occur like this in humans.

A mutation never seen before

Mutations in this gene are not unknown and several members of her family had them. However, this is the first time that both copies of the gene carry this particular mutation.

In this woman, the mutation was to blame for disrupting cell replication and causing her to form cells with a different number of chromosomes, a condition known as aneuploidy. As many as 30 to 40 percent of her blood cells are aneuploid. Yet it is known that a large proportion of tumors have cancer cells with an abnormal number of chromosomes – and aneuploidy is associated with worse cancer outcomes.

The estimation of aneuploidies from using single-cell RNA sequencing (scRNA-seq) data suggested a wide spectrum of chromosomal changes in different cell types. The lowest ratios of aneuploidy were found in progenitor cells, whereas 67.9% of intermediate (or transitional) B cells were aneuploid in the proband. 
Villarroya-Beltri et al., 2022

The authors conclude that these MAD1L1 mutations are likely the cause of a new variant of so-called mosaic aneuploidy with systemic inflammation and very high, unprecedented tumor susceptibility.

Read more

The study was published in the new issue of Science Advance (Volume 8 | Issue 46), November 18. Read all about the case here: https://www.science.org/doi/10.1126/sciadv.abq5914 .