Inherited pancreatic cancer risk is a very challenging problem. Pancreatic cancer strikes fear into many who have seen a relative diagnosed with the disease – which is unfortunately often relentlessly progressive and extremely challenging to treat.
Over the last couple of decades, extensive efforts to study families with aggregations of pancreatic cancer cases have led to the identification of several genes (for example, BRCA2, PALB2, and others) that when mutated confer elevated pancreatic cancer risk that can be passed from generation to generation within families.
A recent study provides evidence that the ATM gene can likely be added to this list.
A New Study Suggests that ATM Gene Mutation Carriers May Be at Elevated Pancreatic Cancer Risk
Drs. Alison Klein, Kenneth Kinzler, Ralph Hruban and colleagues utilized next-generation (i.e., high throughput) sequencing in the laboratory to initially study 38 individuals from 16 families with an impressive history of pancreatic cancer. Each family had 3 or more individuals with pancreatic cancer (specifically pancreatic adenocarcinoma).
In a recent report in the journal Cancer Discovery, they described the identification of ATM gene mutations in 2 of those families.
The researchers first looked for, and demonstrated the lack of, mutations in known genes that can impact pancreatic cancer risk. They excluded mutations in:
- BRCA2 and BRCA1
- PALB2
- CDKN2A
- STK11
- TP53
- MLH1
- MSH2
- MSH6
- PMS2
- PRSS1
- PRSS2
Then, they utilized a filtering strategy to narrow down the potentially important genetic changes in the affected members of the families studied from a massive amount of data to a more manageable number. Among other things, they focused on heterozygous (mutation present on only one of the individuals two copies of each gene studied) mutations that were: (1) carried by all of individuals with pancreatic cancer in a given family who had DNA available for testing; (2) not present in databases of common SNPs (single nucleotide polymorphisms); and (3) “inactivating” (either a frameshift, nonsense, or splice-site alteration).
The new research paper focuses on two of the studied families who were both found to have deleterious mutations in the ATM gene.
ATM is the Gene for the Autosomal Recessive Syndrome Ataxia-Telangiectasia
ATM is an important gene because when individuals inherit a mutated copy of the gene from both parents, they develop the autosomal recessive condition ataxia-telangiectasia (which is characterized by cerebellar ataxia in addition to a substantially increased risk of cancer – particularly leukemia and lymphoma).
Female carriers of a single ATM gene mutation (who, because they have one normal copy of the gene, do not have Ataxia-Telangiectasia) are known to have a modestly elevated (about 2-fold) risk of breast cancer – one of several potential explanations for a family history of breast cancer in BRCA Negative families (i.e., without BRCA1 or BRCA2 mutations). However, to the best of my knowledge, ATM mutations have not previously been implicated in hereditary pancreatic cancer risk.
Expanding the Study to More Pancreatic Cancer Families
Given the identification of the ATM mutations in the 2 families from the initial part of the study, they sequenced the ATM gene (coding region) in an additional 166 familial pancreatic cancer patients, in addition to 190 control individuals (who were spouses of familial pancreatic cancer patients). About 70 of the 166 familial pancreatic cancer patients were from families with 3 or more cases (like the initial families who were sequenced in this study).
In the additional 166 patients, they found 4 ATM mutations that have been previously seen in Ataxia-Telangiectasia patients.
Remember that these individuals have a single ATM mutation and that Ataxia-Telangiectasia patients have both copies of the gene mutated, so the individuals with mutations in this study are mutation carriers and do not have Ataxia-Telangiectasia.
Using the same approach and criteria, no ATM mutations were found in the spouses.
Therefore, this provides further evidence that ATM mutations are associated with pancreatic cancer risk.
The Association of ATM Mutations with Pancreatic Cancer was Strongest in Families with 3 or More Affected Individuals
In the follow up study, all four of the identified mutations were in pancreatic cancer patients from families in which there were at least 3 pancreatic cancer cases. In all, there were 4 mutations in 87 such families (4.6%).
Bottom Line for Individuals with Either a Significant Personal or Family History of Pancreatic Cancer or Known ATM Mutation Carrier Status
1. This new study suggests that heterozygous carriers (i.e., individuals with one mutated copy of the ATM gene and one normal copy of the ATM gene) appear to have an elevated pancreatic cancer risk. Given the small number of families in this study with clearly functional ATM mutations, further studies will be required to better quantify the extent of increased risk for pancreatic cancer.
2. Mutations of the ATM gene can be added to the list of genes for which there is some evidence that inherited mutations increase pancreatic cancer risk. As next-generation sequencing technologies are increasingly integrated into clinical labs, cancer type-specific risk tests with panels of cancer-specific risk genes (rather than tests of one gene at a time) will increasingly emerge. Although the frequency of ATM mutations in pancreatic cancer families is not tremendously high, with the increased efficiency (and hopefully cost reductions) that next-generation sequencing will bring to clinical laboratories, it seems that ATM should be on the list of genes included in such tests.
3. In this study, the authors used stringent criteria to assess what was a true ATM mutation. Specifically, they only considered mutations that had previously been shown to cause Ataxia-Telangiectasia in individuals inheriting two mutated copies of ATM. It is possible that one or more of the other sequence variants found in the families in this study might also impact pancreatic cancer risk. Thus, this study may indeed be underestimating the contribution of ATM mutations to inherited pancreatic cancer risk to some degree; however, sorting this out will require further functional studies of those ATM gene variants.
4. Given the unclear extent to which ATM mutations increase cancer risk and the unproven efficacy of aggressive screening measures for the disease (which themselves are associated with some health risks), we would primarily recommend the following to ATM carriers: IF YOU ARE A SMOKER, STOP SMOKING NOW. Smoking is an important risk factor for pancreatic cancer – and, of course, is associated with a number of other health risks.
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Selected References
Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discovery 2012; 2:41-6.