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. Author manuscript; available in PMC: 2013 Jun 9.
Published in final edited form as: Cancer Discov. 2011 Dec 29;2(1):41–46. doi: 10.1158/2159-8290.CD-11-0194

ATM mutations in hereditary pancreatic cancer patients

Nicholas J Roberts 1, Yuchen Jiao 1, Jun Yu 2,3, Levy Kopelovich 4, Gloria M Petersen 5, Melissa Bondy 6, Steven Gallinger 7, Ann G Schwartz 8, Sapna Syngal 9, Michele L Cote 8, Jennifer Axilbund 3, Richard Schulick 10, Syed Z Ali 3, James R Eshleman 3, Victor Velculescu 1, Michael Goggins 2,3,11, Bert Vogelstein 1, Nikolas Papadopoulous 1, Ralph H Hruban 3,11,+, Kenneth W Kinzler 1,+, Alison P Klein 3,11,12,+
PMCID: PMC3676748  NIHMSID: NIHMS365908  PMID: 22585167

Abstract

Genome-wide sequencing identified heterozygous, constitutional, Ataxia telangiectaisa mutated (ATM) gene mutations in two kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wildtype allele. Sequence analysis of an additional 166 familial pancreatic cancer probands indentified four additional patients with deleterious mutations in the ATM gene, while no deleterious mutations were identified in 190 spouse controls (p=0.046). These results indicate that ATM mutations play an important role in familial pancreatic cancer predisposition.

Keywords: ATM, predisposition, familial, pancreas, cancer

Introduction

Pancreatic ductal adenocarcinomas (PDAs) carry a dismal prognosis, with fewer than 5% of patients surviving 5 years (1). This disease is particularly tragic when multiple individuals of a single family are affected, a situation that occurs in 5–10% of the 43,000 cases of PDAs that are diagnosed annually (1, 2). The genes responsible for 85–90% of familial pancreatic cancer kindreds, defined as those with at least two affected first-degree relatives, are unknown. In the remaining families, germline mutations of genes including BRCA2, PALB2, CDKN2A, STK11 and possibly BRCA1, have been identified (2).

Unbiased, genome-wide sequencing can be used to identify familial pancreatic genes, as demonstrated by the finding that PALB2 is a pancreatic cancer susceptibility gene (3). To identify additional familial pancreatic cancer genes, we evaluated the whole genome sequences of 16 individuals from six families and the whole exome sequences of an additional 22 individuals from ten families. All families included at least three members with PDAs and DNA was available from at least two such members. Families had enrolled into one of the familial pancreatic cancer registries participating in the Pancreatic Cancer Genetic Epidemiology Consortium (National Familial Pancreas Tumor Registry (NFPTR) at Johns Hopkins, Mayo Clinic, Dana Farber Cancer Institute, MD Andersen Cancer Center, Ontario Pancreas Cancer Study, Toronto and Karmanos Cancer Center). In this brief report, we present data from two families (FPC-A and FPC-B) that harbored inactivating mutations of a putative pancreatic cancer susceptibility gene.

Results

Whole genome sequencing was applied to three members of FPC-A and whole exome sequencing was applied to three members of FPC-B. These efforts produced an average of 113.0 and 7.1 gigabases per sample, resulting in 34-fold and 97-fold distinct coverage of the genome and exome, respectively (Table 1). On average, whole genome sequencing identified 6,132,376 variants per individual, of which 61.6% (3,778,674 variants) matched those deposited in SNP databases. Similarly, exome sequencing resulted in an average of 35,440 variants per individual, of which 55.3% (19,581 variants) matched those deposited in SNP databases (Table 1).

Table 1.

Summary data for familial pancreatic cancer families with inactivating ATM variants

Type Family Individual Length of read Bases mapped to genome Bases mapped to exome Exome bases with at least10 reads Average raw coverage Effective coverage Total number of variants Variants in SNP database
Whole genome sequencing FPC-A 1 100 115,388,854,300 1,294,030,427 34,681,602 35 95.1% 6,024,866 3,758,900
2 100 110,742,763,000 1,219,892,546 34,328,889 33 94.7% 6,181,369 3,793,150
3 100 112,771,643,500 1,271,909,140 34,656,841 34 95.1% 6,190,892 3,783,971
Exomic sequencing FPC-B 1 75 8,110,266,675 4,118,378,295 36,458,593 109 97.9% 35,674 19,573
2 75 7,597,985,850 4,076,171,309 36,560,365 108 98.0% 35,724 19,605
3 75 5,649,542,100 2,815,928,672 36,067,752 74 97.6% 34,923 19,564
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Sequence data were first evaluated for known predisposition genes (BRCA2, PALB2, CDKN2A, BRCA1, TP53, STK11, MLH1, MSH2, MSH6, PMS2, PRSS1 and PRSS2). No mutations in these genes were observed. We hypothesized that any causative variant would be rare in the general population and therefore heterozygous in an affected individual. Additionally, a causative variant would be inactivating and shared among all affected members of a family. We therefore filtered the variants according to the following criteria: (1) variants present in SNP databases were excluded from further analysis, (2) the fraction of distinct sequence reads containing a variant had to be between 25–75% of the total number of distinct sequence reads of the corresponding base (i.e. it had to be heterozygous), (3) the variant had to be present in all members of an affected kindred and, (4) the variant had to be inactivating, i.e. predicted to produce a nonsense mutation, frameshift insertion or deletion, or splice site alteration (IVS −1 or −2; IVS +1 or +2). Using these filters, the 18,503,448 variants initially identified in the sequenced members of families FPC-A and FPC-B were narrowed down to 156. Of these 156 variants, the most interesting were in ATM, as FPC-A and FPC-B family members harbored different heterozygous nonsense variants of this gene (c.8266A>AT; p.K2756X and c.170G>GA; p.W57X). The pedigrees of these families are shown in Figure 1. Both of these variants have been reported previously in patients with ataxia-telangiectasia, an autosomal recessive condition associated with an increased risk of multiple cancer types (4, 5).

Figure 1. Pedigrees of familial pancreatic cancer families FPC-A and FPC-B.

Figure 1

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I. Family FPC-A. Individuals interrogated with whole-genome sequencing. Individuals with an ATM mutation indicated with K2756X. II. Family FPC-B. Individuals interrogated with whole exome sequencing. Individuals an ATM mutation indicated with W57X.

To estimate the prevalence of deleterious ATM mutations in familial pancreatic cancer patients and controls, we conventionally sequenced the entire coding region of the ATM gene in an additional 166 familial pancreatic cancer patients and 190 spouse controls (Supplementary Table 1). Pancreatic cancer patients and controls were recruited as part of the NFPTR. Of the 166 familial pancreatic cancer patients, 71 were from kindreds with three or more pancreatic cancers. Chromatograms for all variants in ATM were visually inspected. Variants present in HGMD were then manually curated and pathogenic alterations previously seen in ataxia-telangiectasia patients were confirmed with Sanger sequencing in a second, independent PCR amplification. Four variants: c.3214G>GT; p.E1072X, c.6095G>GA; p.R2032K, IVS41-1G>GT and c.3801delG (Table 2) previously observed in patients with ataxia-telangiectasia (6–9) were identified in the 166 pancreatic cancer patients, while none were identified in the controls. The prevalence of ATM mutations was significantly higher in familial pancreatic cancer patients when compared with controls (4/166 vs. 0/190, Fisher’s Exact Test P=0.046). This association was even stronger in the most severe pancreatic cancer families, containing three affected members, where 4.6% (4/87 vs. 0/190, Fisher’s Exact Test P=0.009) of families carried deleterious ATM mutations. There was no significant difference in the youngest age at which a family member was diagnosed with pancreatic cancer among ATM carrier families vs. the 162 pancreatic cancer families without ATM mutations.

Table 2.

Summary of heterozygous deleterious ATM variants found in pancreatic cancer patients

Variant Pancreatic cancer type Nucleotide (genomic)a Nucleotide (cDNA)b Amino acid (protein)c Type Number of cases
1 Familiald g.chr11:107711896A>T c.8266A>T p.K2756X Nonsense 3
2 Familiale g.chr11:107603810G>A c.170G>A p.W57X Nonsense 3
3 Familial g.chr11:107648719G>T c.3214G>T p.E1072X Nonsense 1
4 Familial g.chr11:107691848G>A c.6095G>A p.R2032K Missense 1
5 Familial g.chr11:107693309G>T IVS41-1G>T sp Splice site 1
6 Familial g.chr11:107660218delG c.3801delG fs INDEL 1
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a

Genomic positions are coordinates in the March 2006, hg18 36.1 UCSC release of the human genome. Genomic coordinates and sequences of mutations are on the coding strand. All changes are heterozygous. g., genomic sequence; c., cDNA sequence; p., protein sequence; del, deletion.

b

Mutations in non-coding sequences are annotated by intron number preceded by "IVS", with positive numbers starting from the G of the GT splice donor site and negative numbers starting from the G of the AG splice acceptor site.

c

fs, frameshift mutation; sp, splice site mutation.

d

Family FPC-A.

e

Family FPC-B.

Pancreatic tumor tissue was available from one of the ten pancreatic cancer patients with a germ line ATM mutation (IV-1 in family FPC-A; Figure 1). The entire coding region of ATM was sequenced using microdissected tumor DNA. This individual was heterozygous for a nonsense variant (c.8266A>AT, p.K2756X) in DNA from peripheral blood cells. Analysis of the pancreatic tumor from this individual demonstrated loss-of-heterozygosity (LOH) at the ATM locus with retention of the mutant, nonsense allele (Figure 2). Losses of the ATM locus is uncommon in sporadic PDAs (10), suggesting that the ATM loss in this patient was driven by a classic two-hit model for tumor suppressor genes (11).

Figure 2. Chromatograms from IV-1 of family FPC-A.

Figure 2

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I. Peripheral blood lymphocytes of IV-1 demonstrating heterozygosity for the ATM inactivating mutant c.8266A>AT; p.K1756X. II. Laser capture microdissected pancreatic tumor of IV-1 showing loss of heterozygosity with retention of the ATM inactivating mutant c.8266A>T; p.K1756X.

Discussion

The ATM protein is a serine/threonine kinase involved in DNA double strand break repair (12, 13). Ataxia-telangiectasia is caused by the inheritance of bi-allelic deleterious mutations in the ATM gene (12) and occurs in 1/40,000 to 1/300,000 live births. The reported carrier frequency of deleterious ATM variants in the population is 0.5–1% (13, 14). Ataxia-telangiectasia is characterized by progressive cerebellar ataxia, oculomotor apraxia, telangiectasias of the conjunctiva and skin, immunodeficiency, sensitivity to ionizing radiation and an increased rate of malignancies, in particular lymphoma and leukemia (13–15).

Women who carry pathogenic ATM mutations have an increased risk of breast cancer (14–16). However, the role played by ATM mutations in breast cancer susceptibility has proven controversial (17–20). There are no other prior reports of ATM mutations in the germline of patients with the PDAs. Similarly, no somatic mutations of ATM have been reported in PDAs. Pancreatic endocrine tumors, which arise from islet cells and have little in common with PDA, occasionally harbor a somatic mutation of ATM (21). However, these mutations may be passengers, as there is no genetic or biochemical evidence indicating that these mutations inactivate the gene product.

In our series of 166 familial pancreatic cancer probands 2.4% (4/166) carried deleterious ATM mutations. When considering only families with more than three affected members, 4.6% (4/87) carried deleterious ATM mutations. What is the evidence that these mutations are functional? The evidence is unambiguous, as we defined deleterious mutations in the most rigorous way possible: only those mutations which are known to cause ataxia-telangiectasia when inherited were considered deleterious. Thus, these mutations cause a recessive disease phenotype in humans under natural conditions. We identified other germline mutations of ATM in the families we studied, but could not conclude that they were functionally inactive because they had not been demonstrated to occur in the germline of patients with ataxiatelangiectasia. Future functional studies of these additional mutations may reveal an even greater role for ATM in pancreatic cancer susceptibility.

The identification of deleterious ATM mutations in probands has substantial implications for risk assessment and surveillance in other family members. Moreover, as ATM is a key participant in DNA repair, it is possible that new therapeutics based on synthetic lethal interactions can be developed to treat these patients, as has been accomplished for patients with BRCA gene mutations (22, 23).

Materials and Methods

Study Participants

This study was reviewed and approved by the Institutional Review Board of the Johns Hopkins Medical Institutions, and informed consent was obtained from all study participants. Study participants were enrolled into one of the familial pancreatic cancer registries participating in the Pancreatic Cancer Genetic Epidemiology Consortium (National Familial Pancreas Tumor Registry (NFPTR) at Johns Hopkins, Mayo Clinic, Dana Farber Cancer Institute, MD Andersen Cancer Center, Ontario Pancreas Cancer Study, Toronto and Karmanos Cancer Center). The Pancreatic Cancer Genetic Epidemiology Consortium and NFPTR have been previously described (24, 25).

Preparation of genomic DNA

Genomic DNA from familial pancreatic cancer cases was extracted from peripheral blood lymphocytes (PBLs) or Epstein-Barr virus transformed PBLs using QIAamp DNA mini kit (cat# 51304, Qiagen, Valencia, CA) according to the manufacturer’s protocol. Similarly, genomic DNA from control individuals was extracted from PBLs using QIAamp DNA mini kit (cat# 51304, Qiagen).

Preparation of genomic DNA libraries and whole genome sequencing

5–10 micrograms (µg) of genomic DNA per sample were sequenced with the Illumina GAIIx Genome Analyzer using the Illumina Whole (Illumina, San Diego, CA) Genome Fast-Track Sequencing Service to yield, yielding 200 (2 × 100) base pairs from the final library fragments. Sequencing reads were analyzed and aligned to human genome hg18 with the Eland algorithm in CASAVA 1.7 software (Illumina). SNP databases used in the analysis of data included: http://www.ncbi.nlm.nih.gov/projects/SNP/.

Preparation of genomic DNA libraries and whole exome sequencing

Genomic DNA libraries were prepared using 1.5–3 µg of genomic DNA and human exome capture was performed following a modified protocol from Agilent’s SureSelect Paired-End Version 2.0 Human Exome Kit (Agilent, Santa Clara, CA) as previously described (26).

Captured DNA libraries were sequenced with the Illumina GAIIx Genome Analyzer, yielding 150 (2 × 75) base pairs from the final library fragments. Sequencing reads were analyzed and aligned to human genome hg18 with the Eland algorithm in CASAVA 1.7 software (Illumina). SNP databases used in the analysis of data included: http://www.ncbi.nlm.nih.gov/projects/SNP/.

Evaluation of ATM in additional pancreatic cancers, normal controls and tumor samples

The coding region of the ATM gene was sequenced in 166 familial pancreatic cancer patients and 190 spouse controls. PCR amplification and Sanger sequencing were performed following protocols described previously (27) using the primers listed in Supplementary Table 3.

Laser capture microdissection and DNA extraction of pancreatic tumor samples

To identify somatic mutations and copy number changes in patients with germ line ATM mutations, primary pancreatic cancer cells (~1 × 105) were meticulously microdissected from frozen sections with the PALM micro-laser system (Carl Zeiss microimaging Inc., North America, Thornwood, NY) as previously described (27). Genomic DNA was then extracted with the QIAamp DNA Micro Kit (Qiagen).

Statistics

Two-tailed P-values were calculated using Fisher’s exact test. A P-value < 0.05 was considered significant.

Supplementary Material

supplemental tables

Significance.

Up to 10% of pancreatic ductal adenocarcinomas occur in families with multiple cases and the overwhelming majority of these familial cases (85–90%), are of unknown genetic etiology. We describe the identification of ATM as a pancreatic cancer predisposition gene through whole genome and exome sequencing. This discovery illustrates the power of next generation sequencing to identify the hereditary basis of cancer predisposition syndromes.

Acknowledgements

We thank N. Silliman, J. Ptak, L. Dobbyn, M. Whalen, M. Borges and D. Echavarria for expert technical assistance.

Grant Support

Supported by the Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D. K. Ludwig Fund for Cancer Research; Sol Goldman Pancreatic Cancer Research Center NIH grants CA62924, CA057345, CA123483, CA121113 and RO1CA97075, the Michael Rolfe Pancreatic Cancer Foundation, The Stringer Foundation, The Joseph L. Rabinowitz Fund for Pancreatic Cancer Research, the family and friends of Dick Knox and Cliff Minor, The Karp Family, H.H. & M. Metals, Inc. Fund for Cancer Research and NCI contract N01-PC-35145 and NO1-CN-43302.

Footnotes

Disclosure of Potential Conflicts of Interest

Under agreements between the Johns Hopkins University, Inostics, PGDx and Qiagen, N.P., B.V., K.W.K. and V.E.V are entitled to a share of the royalties received by the University on sales of products related to genes and technologies described in this manuscript. N.P., B.V., K.W.K. and V.E.V are a co-founders of Inostics and Personal Genome Diagnostics are members of their Scientific Advisory Boards, and own stock in Inostics and PGDx, which is subject to certain restrictions under Johns Hopkins University policy. The terms of these arrangements are managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.

Contributions

N.J.R, V.V., M.G., B.V., N.P., R.H.H., K.W.K. and A.P.K. designed the study; J.Y., G.M.P., M.B., S.G., A.G.S., S.S., M.L.C., J.A., R.S., S.A., J.R.E, M.G., B.V, R.H.H and A.P.K collected and analyzed the familial pancreatic cancer samples; N.J.R., Y.Q., N.P. and K.W.K. performed genomic sequencing. N.J.R, M.G., B.V., N.P., R.H.H., K.W.K and A.P.K analyzed the genetic data; N.J.R., B.V., K.W.K and A.P.K wrote draft manuscripts. All authors contributed to the final version of the paper.

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Supplementary Materials

supplemental tables
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