Medullary thyroid cancer, leukemia, mesothelioma and meningioma associated with germline APC and RASAL1 variants: a new syndrome?

Our plain-English summary of Medullary thyroid cancer, leukemia, mesothelioma and meningioma associated with germline APC and RASAL1 variants: a new syndrome?, by A. Angelousi, N. Settas, F.R. Faucz, et al (Hormones, 2017).

The study

• Authors: A. Angelousi, N. Settas, F.R. Faucz, C. Lyssikatos, M. Quezado, N. Nasiri-Ansari, C.A. Stratakis, E. Kassi
• Journal: Hormones
• Published: 2017;16(4):423-428
• Type of article: Case report
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor hereditary in 35% of cases. The most common syndromic form is in the context of the multiple endocrine neoplasia type 2 (MEN 2) syndromes in association with other tumors and due to germline RET mutations. We describe a 57-year-old female patient diagnosed with sporadic MTC. The patient had a history of other neoplasias, such as acute myeloid leukemia, for which she had received chemotherapy, and two other solid tumors, peritoneal mesothelioma and meningioma. Genetic analyses were carried out including whole exome and Sanger sequencing (WES and SS) and loss-of-heterozygosity (LOH) testing for the respective loci. Immunohistochemistry (IHC) was used for the detection of proteins of interest. WES showed two germline variants in the APC and RASAL1 genes confirmed by SS. In MTC tissue only there was a RETvariant identified by SS; germline studies did not show any RETsequence changes. The pattern of tumors in this patient is unusual for either one of the APC- orRASAL1-associated neoplasms and her non-MEN 2-associated MTC contained a RET variant like other sporadic MTCs. As in other patients with more than one genetic variant predisposing to tumors, it is possible that this case represents a unique association.

In plain English

This case report describes a 57-year-old woman with medullary thyroid carcinoma, which the authors called sporadic. Her earlier history included acute myeloid leukemia at age 41, treated with chemotherapy. She also had a peritoneal mesothelioma removed at age 43 and a meningioma diagnosed at age 53. The article does not mention asbestos or any work exposure. Testing of her blood found two germline variants, one in the APC gene and one in the RASAL1 gene. The authors called them 'de novo', meaning not passed down from a parent. Computer predictions rated the APC change as probably damaging but were inconsistent for the RASAL1 change. A RET gene variant was found only in the thyroid tumor tissue, not in her blood. The authors concluded that both variants are probably involved in her thyroid cancer, and that the mesothelioma and meningioma are likely related to the APC variant. They also called both variants of uncertain significance. They added that her earlier chemotherapy could not be excluded as contributing to a later tumor, since it can cause mutations predisposing to new cancers.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case report of a single patient, with genetic testing (whole exome and Sanger sequencing) and tissue staining (immunohistochemistry)
• Who was studied: One 57-year-old woman with medullary thyroid carcinoma, followed at the authors' hospital. The authors were based in Athens, Greece and at the NIH in Bethesda, USA.
• Exposure: The article does not mention asbestos or any occupational exposure. The exposure the authors discuss is chemotherapy she received for acute myeloid leukemia diagnosed at age 41.
• Main results:
  • Besides the thyroid cancer, the patient had a peritoneal mesothelioma removed surgically at age 43 (the case description calls it a 'peritoneal mesothelium'). She was also diagnosed with a meningioma at age 53.
  • Whole exome sequencing of blood found two germline variants, one in the APC gene and one in the RASAL1 gene, confirmed by Sanger sequencing. The authors described them as 'de novo'.
  • A RET gene variant was found only in the thyroid tumor tissue. No RET changes were found in her blood.
  • Computer (in silico) analysis predicted that the APC variant is probably damaging to the protein. Predictions for the RASAL1 variant were inconsistent.
  • In the thyroid tumor tissue, staining for the APC protein was strongly positive, mainly in the cell cytoplasm, while staining for the RASAL1 protein was faint.
• The authors' conclusion: The authors concluded that the APC and RASAL1 variants are probably involved in the thyroid cancer, along with the RET variant in the tumor, and that the mesothelioma and meningioma are likely related to the APC variant. They called both germline variants of uncertain significance and said the case may represent a unique association.
• Limitations the authors state:
  • The authors stated that they could not exclude her earlier chemotherapy for AML as a possible contributor to a later tumor. Their reason was that chemotherapy can cause mutations, somatic or even germline, that predispose to a further cancer.
  • The authors described the RASAL1 variant as of uncertain significance, with unclear computer predictions. Both germline variants were characterized as of uncertain significance.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Carcinoma, Chemotherapy, Peritoneal Mesothelioma, Immunohistochemistry, Germline Mutation, Neoplasm.

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