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Research Highlight | September 06, 2017

TP53 polymorphisms and MDM2 SNP309 are not correlated with pre-menopausal cancer risk, study suggests


 While significant accolades are given to scientists who discover genetic mutations that are linked to cancer, it is equally important to determine factors that are not correlated – something that is the focus of a new Canadian study team investigating polymorphisms and risk of pre-menopausal breast cancer.

Only around five per cent of women diagnosed with breast cancer are under the age of 40, and of this population around five to eight per cent carry a germline (hereditary) mutation to the tumour suppressor gene. However, little research has been done on why early-onset breast cancer occurs in women without any apparent hereditary link. Hence, the study authors  (Human Mutation, January 2017) set out to examine the composite effects of TP53 variants (TP53 PIN3 and SNP309 of MDM2) on early-onset cancer risk in women without mutations to TP53 or the hereditary breast cancer-associated genes, BRCA1 and BRCA2.

Led by Dr. David Malkin (The Hospital for Sick Children, Toronto), they assessed the spectrum of polymorphisms in TP53 and its negative regulatory gene, MDM2 in 40 female patients with pre-menopausal breast cancer. No significant correlation was found, and while one polymorphism was frequently found in the cohort, it was not associated with the risk of developing cancer before the age of 35 years in an extended cohort of 1,420 breast cancer cases. The study (first author Dr. Nardin Samuel) also showed that functional studies of the rs1800372:A>G polymorphic allele reveal it does not affect p53 transactivation function.

While these findings suggest early-onset breast cancer is believed to be related to strong genetic predisposition, this cannot be attributed to TP53 polymorphisms alone, or MDM2 SNP309:T>G in the population surveyed. Many patients in the study’s cohort had an extensive familial – and often personal –  history of cancer despite testing negative for pathogenic mutations in TP53, and it is possible underlying genetic susceptibilities may exist. For example, polymorphic variants that contribute to risk may exist in the well-known cancer susceptibility genes CDH1, PTEN, STK11, and NF1.

Looking forward, researchers suggest genome-wide sequencing of germline mutations and variants in larger patient cohorts may be a good approach to identifying novel driver genes. Further, continuing the search for answers in the underlying heritability of early-onset breast cancer risk will be crucial to better understand why some women get cancer at such a young age.

Study: Assessment of TP53 polymorphisms and MDM2 SNP309 in pre-menopausal breast cancer risk

Authors: Nardin Samuel, Badr Id Said, Tanya Guha, Ana Novokmet, Weili Li, Laxmi Silwal-Pandit, Anne-Lise Børrsen-Dale, Anita Langerød, Thomas J. Hudson, and David Malkin.

Funding: Contract grant sponsors: Canadian Institutes for Health Research (CIHR); The Terry Fox Research Institute/Foundation; SickKids Foundation; Ontario Institute for Cancer Research, Ontario Ministry of Research and Innovation (Senior Investigator Award); Vanier Canada Graduate Scholarship through CIHR.

TFRI LINKS, Summer 2017