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TP53, BRCA1, and BRCA2 Tumor Suppressor Genes Are Not Commonly Mutated in Survivors of Hodgkin’s Disease With Second Primary Neoplasms

Kim E. Nichols, John A. Heath, Debra Friedman, Jaclyn A. Biegel, Arupa Ganguly, Peter Mauch, Lisa Diller

From the Departments of Pediatric Oncology and Human Genetics, Children’s Hospital of Philadelphia; Department of Genetics, University of Pennsylvania, Philadelphia, PA; Departments of Pediatric Oncology and Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Pediatric Hematology/Oncology, Children’s Hospital and Medical Center, Seattle, WA.

Address reprint requests to Lisa Diller, MD, Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: lisa_diller{at}dfci.harvard.edu.

	ABSTRACT

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Purpose: Despite recognition that second malignant neoplasms (SMNs) contribute significantly to mortality after the successful treatment of Hodgkin’s disease (HD), little is known about the molecular events leading to secondary tumors. Factors contributing to second cancer risk include the carcinogenic effects of ionizing radiation and chemotherapy, in combination with possible host susceptibility. To clarify whether host genetic factors contribute to secondary tumorigenesis, we performed mutational analyses of the TP53, BRCA1, and BRCA2 tumor suppressor genes in a cohort of 44 HD patients developing one or more SMN.

Patients and Methods: Family cancer histories and constitutional DNA samples were obtained from 44 HD patients with SMNs identified. Using DNA-based sequencing, we evaluated the TP53 gene in all 44 patients. Nineteen female patients developing one or more secondary breast cancer were also analyzed for mutations in the BRCA1 and BRCA2 breast cancer–susceptibility genes.

Results: Nineteen patients (43%) had more than one SMN, and 12 patients (27%) had a positive family history of cancer. One of 44 patients tested for TP53 harbored a novel homozygous germline abnormality. One of 19 patients tested for BRCA2 carried a previously described heterozygous inactivating mutation. We identified no germline BRCA1 mutations.

Conclusion: Despite features suggestive of genetic predisposition, the TP53, BRCA1, and BRCA2 genes were not frequently mutated in this cohort of HD patients developing SMNs. Larger studies of these genes or investigations of other genes involved in cellular DNA damage response pathways may identify host genetic factors that contribute to secondary tumorigenesis.

	INTRODUCTION

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CURRENT TREATMENT regimens for early-stage Hodgkin’s disease (HD) achieve 20-year disease-free survival rates in excess of 80%.¹ Despite this success, long-term follow-up of HD survivors has revealed an increased incidence of second malignancies, including acute leukemia, non-Hodgkin’s lymphoma, and solid tumors, of which breast, lung, and gastrointestinal carcinomas are the most common.^2–5 Second malignancies occur with an estimated frequency of 10% to 15% after 15 to 25 years^2,6–8 and contribute significantly to both late morbidity and mortality.^4,5 Although radiotherapy, chemotherapy, and immunosuppression are all likely to contribute to the development of second malignant neoplasms (SMNs),^9,10 the occurrence of multiple neoplasms within individual HD patients and an increase in the prevalence of a positive family cancer history¹¹ suggest that an underlying genetic predisposition may also influence second cancer risk in a subset of HD survivors.

Previously, Nichols et al¹¹ and Broeks et al¹² reported that heterozygous inactivating mutations in ATM, the gene defective in ataxia-telangiectasia, do not occur at an excess frequency in HD survivors who develop secondary neoplasms. To further address whether constitutional mutations in other genes regulating the cellular response to DNA damage contribute to the genesis of secondary tumors after HD, we undertook the current investigation. We chose to investigate TP53, the gene mutated in the Li-Fraumeni cancer susceptibility syndrome (LFS),¹³ because TP53 regulates cell cycle checkpoints initiated in response to ionizing radiation and certain DNA-damaging chemotherapeutic agents.¹⁴ Moreover, LFS patients are known to develop multiple neoplasms over time,¹⁵ particularly after exposure to ionizing radiation. In an earlier report, Malkin et al¹⁶ reported a 6.8% incidence of constitutional heterozygous TP53 mutations in patients with secondary cancers. Although this study failed to identify mutations in 11 patients carrying a primary diagnosis of HD, we felt justified in searching for TP53 mutations in our cohort because HD is occasionally seen in LFS kindreds.¹⁷ Additionally, breast, lung, and gastrointestinal tumors, which are commonly seen in LFS, occur at an increased frequency in radiated HD patients.¹⁷ Earlier investigations of TP53 focused largely on exons 5 to 8 and, therefore, might have underestimated the role played by this gene in secondary tumorigenesis.

Given the high incidence of secondary breast cancers in female HD survivors, we were also interested in evaluating the known breast cancer susceptibility genes, BRCA1 and BRCA2. Numerous previous studies have shown that BRCA1 and BRCA2 interact with a variety of other proteins involved in surveillance of the genome and efficient DNA repair.¹⁸ Moreover, germline mutations in BRCA1 or BRCA2 increase susceptibility to the damaging influences of ionizing radiation, including increased radiation sensitivity^19,20 and diminished capacity to repair double-strand DNA breaks by homologous recombination.²¹ Clinical studies have shown that HD and non-Hodgkin’s lymphomas occur more often than expected in some breast cancer kindreds,^22–26 suggesting a potential link between BRCA1 or BRCA2 heterozygosity and susceptibility to both HD and secondary breast cancer.

	PATIENTS AND METHODS

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Previously, we identified 52 patients who had been diagnosed with HD between 1969 and 1991 and who had developed one or more SMNs between 1975 and 1998. Full details describing this cohort have been previously reported.¹¹ After our prior analysis of the ATM gene, 44 patients (85%) had adequate quantities of constitutional DNA and RNA remaining to allow for the current investigation. DNA samples from these 44 patients were analyzed for mutations in TP53. DNA samples from the 19 female HD survivors with secondary breast cancer were also evaluated for mutations in BRCA1 and BRCA2. We obtained information regarding personal and family cancer history by patient interview and review of medical records. A positive family cancer history was defined as three first-degree relatives with cancer in addition to the proband, spanning two generations in either the paternal or maternal lineage.

To conserve primary patient DNA samples, we first performed mutational analysis using genomic DNA generated from patient-derived Epstein-Barr virus–transformed lymphoblastoid cell lines (EBV-LCL). Each of the TP53, BRCA1, and BRCA2 exons and approximately 100 nucleotides of adjacent intronic sequences were polymerase chain reaction (PCR) amplified using Taq Platinum DNA polymerase (Invitrogen, Carlsbad, CA; primer sequences available on request). Amplified products were sequenced using an automated fluorescent ABI model 377 sequencer (Applied Biosystems, Foster City, CA). If a mutation in EBV-LCL DNA was detected, sequence analysis was repeated using genomic DNA and cDNA derived from frozen peripheral-blood mononuclear cells. Comparison with relevant current databases was undertaken to determine whether detected mutations had been previously described.^27,28

	RESULTS

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Personal and Family Cancer Histories
Among the 44 patients included in this investigation, we identified 70 SMNs, including 23 breast cancers, 12 basal cell carcinomas (BCCs), five sarcomas, three thyroid cancers, five non-Hodgkin’s lymphomas, five gastrointestinal carcinomas, three female reproductive tract carcinomas, four melanomas, and single cases of lung carcinoma, mesothelioma, squamous cell carcinoma of the skin, prostate carcinoma, and parathyroid adenoma. As shown in Table 1, 19 patients (43%) developed more than one SMN. In 39 patients (89%), second cancers developed within the radiation field. The median dose of radiation received was 34 Gy (range, 15 to 44.7 Gy).

Results of TP53Analysis
As shown in Table 2, evaluation of EBV-LCL genomic DNA, as well as primary lymphocyte cDNA, from one HD patient demonstrated a germline abnormality within the TP53 gene (exon 7, codon 238, nucleotide 713, G to A; cysteine > tyrosine). We could not detect wild-type TP53 sequence at this site, suggesting either hemizygosity or homozygosity for this allele. Because homozygosity of a TP53 germline mutation has not been previously reported, a second sample from this patient’s EBV-LCL was analyzed for TP53 mutations in a separate laboratory. The same nucleotide change was detected, with no evidence for wild-type sequence at codon 238.

In two additional HD patients, we detected heterozygous TP53 mutations using DNA derived from EBV-transformed lymphoblasts (exon 6, codon 216, nucleotide 646, G to A, valine > methionine; and exon 11, codon 382, nucleotide 1146, delA, frameshift). Neither of these mutations, however, was detected after repeat sequence analysis using genomic DNA or cDNA derived from peripheral-blood mononuclear cells. Because it is possible that these mutations arose during the process of EBV transformation, we have not reported them here as positive findings.

Thirty-six patients possessed at least one, and up to a total of seven, known polymorphisms within TP53. Among the TP53 polymorphic variants reported, proteins containing either an arginine (R) or a proline (P) residue at codon 72 have been among the most intensively studied. Recent investigations have shown that these TP53 variants differ biochemically and functionally, suggesting that they may play differential roles during tumorigenesis.^30,31 Therefore, we examined our cohort for the distribution of TP53 R- or P-encoding alleles. We found that 24 patients (55%) were heterozygous at this locus (R/P; exon 4, codon 72, nucleotide 215, G to C; R > P), 18 (41%) were homozygous for R-encoding alleles (R/R), and two (4%) were homozygous for P-encoding alleles (P/P).

Results of BRCA1 and BRCA2 Analyses
Among the 19 female HD survivors with secondary breast cancer who we tested for BRCA1 and BRCA2 mutations, we found no BRCA1 germline mutations. Although 17 of these patients (89%) possessed recognized BRCA1 gene polymorphisms (range, one to 14 polymorphisms), none of these polymorphisms are known to be associated with an increased risk of breast cancer.²⁵ In contrast, we identified one heterozygous BRCA2 mutation (exon 11, codon 2156 to 2157, deletion of TC; premature stop at codon 2174). This patient, who developed breast cancer at age 29 years, 13 years after the successful treatment of her HD, did not have a positive family cancer history. Eighteen (94.7%) of the 19 patients tested possessed recognized BRCA2 gene polymorphisms (range, one to 10 polymorphisms). As with BRCA1, none of these polymorphisms are known to be associated with an increased risk for breast cancer.²⁵ The estimated carrier frequencies for TP53, BRCA1, and BRCA2 germline mutations from this data were 2.1% (90% CI, 1.2% to 10.4%), 0% (90% CI, 0% to 14.6%), and 5.3% (90% CI, 2.7% to 22.6%), respectively.

	DISCUSSION

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In conclusion, within our cohort of 44 HD survivors with SMNs, we found two patients (4.5%) harboring germline mutations in known DNA damage response genes. The single documented germline TP53 abnormality (TP53 G713A) has not been observed in families with LFS or in the related Li-Fraumeni–like cancer susceptibility syndrome. However, this TP53 alteration has previously been identified as a somatic event in various tumor types, including breast cancers, sarcomas, and hematopoietic malignancies.²⁷ In fact, this abnormality has been estimated to account for approximately 1% to 2% of all identified somatic TP53 mutations.²⁷ The cysteine residue at TP53 codon 238 is known to bind Zn²⁺ and to stabilize the structure of the TP53 DNA binding domain.³² Amino acid substitutions at codon 238 may be associated with abnormal Zn²⁺ binding. We hypothesize that the amino acid alteration noted in this investigation (ie, the exchange of a tyrosine residue for a cysteine residue) would lead to a TP53 protein that functions abnormally, despite the fact that this is a relatively conservative alteration.

To ascertain whether the patient harboring the G713A nucleotide substitution might be hemizygous or homozygous at this locus, we performed additional analyses. Fluorescent in situ hybridization analysis, using the EBV-LCL established from this patient, revealed two intact TP53 alleles, one on each copy of chromosome 17p13. Subsequent Southern blot analysis using a cDNA probe spanning TP53 exons 6 through 8 failed to demonstrate any loss, gain, or rearrangement of genetic material within the genomic region encompassed by these exons.

There are several possible explanations that might account for our finding of what seems to be a homozygous substitution at TP53 nucleotide position 713. First, it is possible that there is a small region of hemizygosity near nucleotide 713 that we were not able to detect using the assays used in this study. Unfortunately, direct sequence analysis of the TP53 gene and PCR analysis of polymorphic intronic markers surrounding exon 7 revealed no other heterozygous variants, suggesting either that these markers were uninformative in this patient or that he was either homozygous or hemizygous at this locus. Second, it is possible that the cancer susceptibility in this family results from a more typical heterozygous TP53 mutation and not from a homozygous nucleotide alteration. To explain our finding in the affected patient, he would have to have undergone a mitotic recombination event early during development during which he lost all or part of his normal TP53 allele and duplicated the mutant nucleotide 713A-encoding allele. Unfortunately, we were not able to further test this possibility because our initial HD study did not allow the collection or testing of DNA samples from relatives of enrolled individuals. Last, it is possible that the G713A alteration exists in the germline as an extremely rare TP53 polymorphism and that the encoded TP53 variant is functionally defective, albeit only mildly.

We recognize that it is not common to see a homozygous germline mutation and that the late age at which the proband developed HD and SMNs is not typical of an inherited cancer syndrome. These features suggest that the effect of the TP53 G713A alteration on malignant transformation must be mild, requiring cooperating oncogenic events. Supporting this possibility are the relatively late onset of cancer in this patient’s father, the absence of pediatric tumors in his family, and the absence of cancer in his mother who was a probable heterozygote. Biallelic homozygous mutations involving other autosomal dominant cancer predisposition genes have been reported,³³ but this is the only case we could identify of homozygosity for a constitutional TP53 mutation.

The TP53 codon 72R and 72P variant proteins have been reported to differ in stability and functional activity, and it has been hypothesized that homozygosity or heterozygosity at codon 72 may influence susceptibility to tumorigenesis.³⁴ Compared with codon 72P, the codon 72R-containing TP53 protein has enhanced apoptotic potential^30,31 and is, therefore, considered to be a better suppressor of malignant transformation.³⁰ The codon 72R variant is also more susceptible to human papillomavirus (HPV)-mediated degradation, a characteristic that may contribute to HPV-mediated tumor formation.³⁴ Although initial genetic analyses of patients with HPV-associated skin and cervical tumors had suggested an overrepresentation of homozygous TP53 codon 72R-encoding alleles when compared with the normal population,³⁴ it remains controversial whether heterozygosity or homozygosity at this codon effects host susceptibility to cancer.³⁵ Among our cohort of patients, 18 (41%) were homozygous for R/R alleles, 23 (55%) were R/P heterozygotes, and only two (4%) were homozygous P/P. When compared with other cohorts of comparable ethnic and racial background,^35–37 we find a slight increase in the frequency of R/P heterozygosity (approximate expected frequency = 0.41) and a corresponding decrease in P/P homozygosity (approximate expected frequency = 0.13) in our HD patients with SMN. However, given the small number of patients in our study and the variability of rates of polymorphisms in different geographic and ethnic groups, it is not possible to draw firm conclusions from these data that link heterozygosity or homozygosity at this codon with susceptibility to first or second cancer formation. Larger studies examining constitutional and tumor-derived DNA samples from patients with and without secondary tumors will clarify the contribution of these variant TP53 alleles to therapy-associated secondary tumorigenesis.

Among the 19 female HD survivors with secondary breast cancer, only one patient was found to harbor a heterozygous inactivating mutation in BRCA2, and no patients harbored BRCA1 mutations. Despite their important roles during homologous recombination and repair of DNA strand breaks, inactivating mutations in BRCA1 and BRCA2 are not commonly seen as somatic events in breast tumor samples.^38–40 Moreover, a recent study failed to identify increased loss of heterozygosity at the BRCA1 and BRCA2 loci in secondary breast cancer specimens obtained from women with a previous history of HD, suggesting that inactivation of these genes is not a required step in breast tumor formation after irradiation for HD.⁴¹ Although we identified a number of polymorphisms and unclassified missense variants in both BRCA1 and BRCA2, none of these can be unequivocally classified as disease-associated mutations in the absence of a currently available functional assay.²⁵

Because of the intrinsically higher mortality associated with multiple primary neoplasms,⁴ the number of subjects in this study was small and did not include patients with more rapidly lethal secondary neoplasms. This may have led to a survivor bias with a potentially lower incidence of genetically susceptible subjects. In addition, we may be underestimating the frequency of gene mutations because our methodology would not detect large deletions or insertions and duplications, mutations in the promoter or the 3' untranslated region of the gene, or mutations in those nucleotide sequences that would alter or remove a PCR primer-binding site. Despite these potential limitations, our data represent the most thorough analysis of the contribution of TP53, BRCA1, and BRCA2 germline mutations to therapy-associated secondary tumorigenesis and form the foundation for future genetic investigations.

Radiotherapy and chemotherapy have demonstrated a combined effect in increasing the risk of second solid and hematologic malignancies after HD.⁴ The role of genetic factors, however, has remained less certain. Although our data are consistent with a possible contribution of host genetic factors, as suggested by the large number of patients with a positive family cancer history and the substantial number of patients with multiple second neoplasms, the TP53, BRCA1, and BRCA2 tumor suppressor genes do not seem to play a prominent role during secondary tumorigenesis in this population. It is conceivable that the increased risk of SMNs in HD survivors is a result of inactivating germline mutations in other genes involved in DNA damage repair, such as those encoding specific proteins that interact with TP53, BRCA1, and BRCA2. Alternatively, it remains possible that gene polymorphisms, which exert more subtle effects on protein function, may contribute to second cancer risk in susceptible individuals. Larger studies evaluating these and other candidate genes involved in DNA damage response pathways are warranted.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	ACKNOWLEDGMENTS

 
We thank the patients who participated in this study. We also thank Drs Edward Fox and Sig J. Verselis for their technical assistance with these investigations, and Drs Daniel A. Haber and Anna T. Meadows for their careful review of this manuscript.

	NOTES

 
Supported in part by grants from the David B. Perini Jr Quality of Life Program (L.D.) and the Lee Family Fellowship (K.E.N.), Dana-Farber Cancer Institute, Boston, MA.

Both K.E.N. and J.A.H. contributed equally to this work.

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Submitted December 9, 2002; accepted October 2, 2003.

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