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Late onset Li-Fraumeni Syndrome with bilateral breast cancer and other malignancies: case report and review of the literature

  • 1Email author,
  • 2,
  • 3,
  • 4,
  • 5,
  • 6,
  • 1 and
  • 6
BMC Cancer201212:217

https://doi.org/10.1186/1471-2407-12-217

©  Kast et al.; licensee BioMed Central Ltd. 2012

Received: 5 December 2011

Accepted: 6 June 2012

Published: 6 June 2012

Open Peer Review reports

Abstract

Background

Li-Fraumeni-Syndrome (LFS) is an autosomal-dominant, inherited tumour predisposition syndrome associated with heterozygous germline mutations in the TP53 gene. Patients with LFS are at a high risk to develop early-onset breast cancer and multiple malignancies, among which sarcomas are the most common. A high incidence of childhood tumours and close to 100% penetrance has been described. Knowledge of the genetic status of the TP53 gene in these patients is critical not only due to the increased risk of malignancies, but also because of the therapeutic implications, since a higher rate of radiation-induced secondary tumours in these patients has been observed.

Case report

We report a patient with LFS harbouring heterozygous, pathogenic TP53 germline mutation, who was affected by four synchronous malignancies at the age of 40: a myxofibrosarcoma of the right upper arm, bilateral breast cancer and a periadrenal liposarcoma. Radiological treatments and a surveillance program were adjusted according to recommendations for LFS patients.

Conclusion

Management of tumour treatment of patients with LFS is different to the general population because of their risk for secondary cancers in the radiation field. Screening procedures should take a possibly elevated risk for radiation induced cancer into account.

Keywords

  • Li-Fraumeni-Syndrome
  • LFS
  • TP53
  • Secondary cancer
  • Treatment

Background

Li-Fraumeni-Syndrome (LFS; OMIM #151623) is a rare autosomal-dominant, inherited tumour predisposition syndrome associated with an increased risk of a variety of malignancies. Recent statistical analyses stress the relevance of four “core” cancers which account for 77% of all associated cancers: breast cancer, sarcomas, brain tumours and adrenocortical carcinoma (ACC) [1]. LFS is characterized by high penetrance [2] and early-onset tumours [3, 4]. The lifetime risk is higher, and age of onset is earlier in women compared to men [5, 6]. Several criteria, classical and Li-Fraumeni-like (LFL), have been developed to identify patients and families with LFS [4, 7–11] (Table 1). LFS is associated with heterozygous germline mutations in the tumor protein p53 (TP53) tumour suppressor gene. Mutations in TP53 are detected in ~80% of individuals fulfilling the classic LFS criteria and ~30% of those fulfilling the LFL criteria (Table 1) [2, 12–14]. In order to increase the sensitivity of detection, the Chompret criteria were adjusted in 2009, for age and tumour spectrum parameters (Table 2). Genetic testing for TP53 is recommended by the National Comprehensive Cancer Network (NCCN, http://www.nccn.org) in accordance with the Chompret criteria, or in any breast cancer patient < 30 years of age testing negative test for BRCA1 and BRCA2 mutations.
Table 1

Description of different criteria for Li-Fraumeni Syndrome (LFS) or Li-Fraumeni-like (LFL) Syndrome

 

Criteria

Description

LFS classic

Li-Fraumeni [4]

Proband diagnosed with sarcoma before 45 years, AND

  

· a first-degree relative with cancer before 45 years, AND

  

· another first- or second-degree relative with any cancer diagnosed under the age of 45 years or with sarcoma at any age

LFL

Chompret original [9]

1. Proband with a ”core cancer” before 36 years, AND at least one first- or second-degree relative with

  

· cancer (other than breast cancer if the proband has breast cancer) under the age of 46 years OR

  

· multiple primaries at any age

  

2. Proband with multiple primary tumours, two of which are “core cancers”, with the initial cancer occurring before 36 years, regardless of the family history

  

3. Proband with adrenocortical carcinoma at any age of onset, regardless of the family history

LFL

Chompret 2009 update [10]

1. Proband with a tumour belonging to the LFS tumour spectrum before 46 years, AND

  

· at least one first- or second-degree relative with cancer (other than breast cancer if the proband has breast cancer) under the age of 56 years OR

  

· a relative with multiple primaries at any age

  

2. Proband with multiple primary tumours (except multiple breast tumours), two of which belong to the LFS spectrum, with the initial cancer occurring before the age of 46 years, regardless of the family history

  

3. Proband with adrenocortical carcinoma or plexus tumour at any age of onset, regardless of the family history

LFL

Birch [6]

Proband with any childhood cancer or sarcoma, brain tumour, or adrenocortical carcinoma diagnosed under 45 years of age, AND

  

· a first- or second-degree relative with a typical LFS-related cancer (“core cancers” and leukaemia) diagnosed at any age, AND

  

· a first- or second-degree relative in the same genetic lineage with any cancer diagnosed under the age of 60 years

LFL

Eeles [7]

Two different tumours that are “core cancers” or leukaemia in first- or second-degree relatives at any age

Li-Fraumeni Syndrome

NCCN-Guidelines since 2010

Classic LFS-Criteria OR LFL according to Chompret 2001/2009 OR

  

Early onset breast cancer: Individual with breast cancer <30 years of age with a negative BRCA1/BRCA2 test, especially if there is a family history of sarcoma, brain tumour, adrenocortical carcinoma or chorid plexus carcinoma

Tumour spectrum: Five “core cancers”: sarcoma, brain tumour, breast cancer or adrenocortical carcinoma plus e.g. leukaemia, lung bronchoalveolar cancer

Abbreviations: NCCN = National Comprehensive Cancer Network.

Table 2

Chronologic synopsis of case report

Year / Month

Sarcoma/Carcinoma

Stage

Therapy

Follow up

2006/08 (40 y)

Myxofibro-sarcoma right upper arm

pT1a, pNx, pMx, G2, R0

Incomplete resection, R1, 2006/08

palpation,

   

Re-Resection, R1, 2006/09

12-mo MRI

   

Re-Re-Resection with musculo-cutaneous flap 2006/11

 

2006/12 (40 y)

Breast cancer right side

ypT2 ypN1a (2/13) yM0 L0 V0 R0 yG3, ER IRS 2, PR IRS 9, Her2neu pos., IRS 3, invasive ductal carcinoma

Neo-adj. CT with 4x FEC, 2007/01-04,

prophylactic

   

Lumpectomy and axillary dissection 2007/05,

mastectomy offered

   

Adj. CT, 4x P 2007/06-08,

3-mo palpation,

   

Herceptin® 2007/09-2008/06

6-mo ultrasound,

   

GnRH Analoga + TAM 07/09-ongoing

12-mo MRI

2006/12 (40 y)

Breast cancer left side

ypT1c ypN1mic (1/17) yM0 L0 V0 R0 yG3, ER IRS 8, PR IRS 12, Her2neu pos. IRS 3, invasive ductal carcinoma

see above

see above

2007/05 (40 y)

Liposarcoma periadrenal left

pT2b pN0 (0/2 LK) pMx L0 V0 G3, Rx, pleomorph sarcoma

Lumbal left adrenalectomy 2007/05,

MRI

   

Radiation therapy (66 Gy) 2007/08-10

 

2008/05 (41 y)

Recurrence Recurrence

ypT2 ypN0 (0/14) ypMx G1 R1(vessel)

CT with 2xIfos 2008/06, followed by Trabectedin, Mini-ICE and Hyperthermia 2009/01-05

 
   

Compartment resection with hemicolectomy, splenectomy, partial diaphragm resection and resection of 11th costa 2009/06

 

2010/06

Recurrence

 

CT with Trabectedin since 2010/06

 

Abbreviations: Neo-adj. = neo-adjuvant, Adj. = adjuvant, CT = Chemotherapy, FEC = 5-FU 500 mg/², Epirubicine 100 mg/m², Cyclophosphamide 500 mg/m², q21d, P = Paclitaxel 175 mg/m², q21d, TAM = Tamoxifen®, Ifos = Ifosfamide, mo = monthly, Mini-ICE = Ifosfamid, Carboplatin, Etoposide.

TP53 encodes a transcription factor implicated in cell-cycle control, apoptosis and genomic stability [15, 16]. Impaired TP53 function may not only influence tumour response to radiotherapy and chemotherapy, but also confers an elevated risk for therapy-induced secondary malignancies and possibly increased sensitivity to low-dose radiation exposure by diagnostic methods [4, 17].

We hereby present a case with LFS and relatively late tumour onset, in which a de novo mutation in TP53 was identified. Response to adjuvant therapy, treatment modification as well as further screening modalities in patients with LFS are discussed.

Case presentation

Myxofibrosarcoma of the right upper arm

In August 2006, a 40-year old female patient was examined for swelling in the lateral side of the right upper arm. Upon resection, the patient was diagnosed with myxofibrosarcoma. A second resection was performed to achieve tumour-free margins and plastic surgery was performed two times on the damaged area for cosmetic purposes.

Screening for metastatic disease by computer tomography (CT) showed no pulmonary, bone or hepatic metastases, however a lesion (36 × 23 mm diameter), classified as a benign tumour by CT criteria, was detected adjacent to the left adrenal gland. A control CT scan in December 2006 revealed that this lesion had increased in size. Biopsy of the periadrenal tumour indicated a possible mesenchymal tumour, however malignancy was not confirmed.

Bilateral breast cancer

In addition, suspect bilateral mammary lesions were also diagnosed. Histological examination of biopsies taken from both breast tumours, revealed invasive ductal carcinomas on both sides.

Because of an unfavourable breast-tumour-relation, neo-adjuvant chemotherapy was applied. After four cycles of an anthracycline-containing regimen, restaging revealed no significant change in the breast tumours, however progression of the periadrenal mass which extended in diameter to 67 × 49 mm, was identified by CT scan. Firstly, a bilateral breast-conserving tumour extirpation in combination with bilateral axillary lymphonodectomy was performed. Both carcinomas were positive for oestrogen receptor (ER) and progesterone receptor (PR) expression in the majority of tumour cells, and also overexpressed the human epidermal growth factor receptor (HER2/neu) (Table 2). There were no relevant histological signs of regression 3 months following neo-adjuvant chemotherapy.

Periadrenal liposarcoma

The periadrenal tumour was subsequently resected. Histological diagnosis revealed a poorly differentiated, pleomorphic, periadrenal liposarcoma. The lipogenic nature of tumour was confirmed by immunohistochemical detection of the S100 protein in the tumour cells. Adjuvant chemotherapy with taxanes was recommended following consultation with an interdisciplinary tumour board, because of the nodal positive breast cancer. Post-operative radiation of the periadrenal region due to RX resection of the periadrenal liposarcoma was also scheduled upon completion of the chemotherapy. Treatment with Trastuzumab and endocrine treatment was included according to the receptor status of the bilateral breast cancers. Moreover, radiation therapy after bilateral breast conserving therapy and radiation of the right upper arm was planned.

Genetic counselling and molecular analysis

Family history revealed a paternal uncle who died at 22 years from a malignancy in the splenic region. No further information regarding this tumour was available. Additionally, the paternal grandfather was diagnosed with leukaemia at 70 years. The maternal grandmother died from colorectal cancer diagnosed at 51 years. Criteria for Li-Fraumeni-like syndrome according to Eeles and the updated Chompret criteria were met (Table 1) [8]. Genetic analysis of TP53 was performed by sequencing genomic DNA isolated from peripheral blood leukocytes of our patient. A pathogenic, heterozygous germline mutation (p.Arg282Trp) was identified. Neither parent was shown to be a carrier of this mutation. Paternity was confirmed by using 15 high polymorphic Short-Tandem-Repeats. Taken together, these data indicate that the TP53 mutation in the patient occurred de novo, although a germline mosaicism in one of the parents cannot be excluded. We examined tissue from a different germ layer to identify possible somatic mosaicism in the patient. Analysis of DNA from the oral mucosa revealed the same heterozygous TP53 mutation identified in the leucocytes. Thus, although we cannot rule out somatic mosaicism, this was very unlikely. Predictive testing was performed in the 44 year-old sibling and in both daughters (aged 21 and 18 years) of the patient. All three female subjects were not carriers of the mutation. Analyses of BRCA1 and BRCA2 genes in the index patient did not reveal any pathological findings.

Therapy modification for supposed radiation sensitivity

After confirmation of LFS by molecular analysis, the decision of an interdisciplinary consulting panel was to restrict the planned radiotherapy to the location with the highest priority. This decision was based on the suspected radiosensitivity of individuals harbouring a deleterious mutation in TP53. Thus, radiation was scheduled for the periadrenal region with postoperative RX, however the initially intended radiotherapy of both breasts, as well as of the right upper arm was cancelled.

Surveillance strategies

The patient was offered secondary, bilateral prophylactic mastectomy, to reduce the risk of recurrent breast cancer. Due to the risk of new primary tumours at other sites, the patient refused this option and opted for a close, post-treatment observation regimen. The surveillance program was adjusted to her elevated risk for other primary malignancies and secondary malignancies after radiotherapy. Biannual ultrasound examination of the breast, annual magnetic resonance imaging (MRI) of the breast, and mammography at larger intervals were recommended. Abdominal ultrasound and MRI were predominantly used to monitor the sites of sarcomas.

Recurrent disease of the periadrenal liposarcoma

In June 2008, multiple nodular lesions were detected close to the left kidney by control MRI, inside and adjacent to the former irradiation region. The optimal response to several lines of treatment with chemotherapy was stable disease. A radical resection of the tumour mass was performed in June 2009. Histological analysis confirmed a recurrent, but well-differentiated liposarcoma. The short interval to radiation therapy of the left periadrenal region indicated resistance of the disease to radiation therapy.

In June 2010, MRI of the abdomen revealed local recurrence. As of February 2012, the patient has been under long-term treatment with trabectedine at a Karnofsky Index of 80%. No distant metastasis, new primaries or recurrences at other sites have since been identified.

Conclusions

In this report, we describe a 40-year old, female patient with four concurrent primary malignant tumours. The simultaneous occurrence of four malignancies is uncommon, and metastases should be excluded. Indeed, all four tumours exhibited morphological features consistent with their histogenesis. Both breast cancers were hormone receptor positive and included intraductal components as precursor lesions for invasive carcinomas. A recent study by Melhem-Bertrandt et al., described an ER positive/HER2 positive phenotype for breast cancer in TP53 germline mutation carriers [18]. This study also observed that in cases of bilaterality, both tumours were HER2 positive. In our patient, examination of the entire myxofibrosarcoma did not reveal any lipogenic morphology, and similarly, the liposarcoma did not exhibit a myxoid or non-lipogenic component. Furthermore, the liposarcoma expressed the S100 protein, which is an established marker for lipogenic differentiation. The typical combination of sarcomas and early-onset breast cancer was indicative of LFS and subsequent genetic analysis confirmed a germline mutation in the TP53 gene. While the patient met some of the wider Li-Fraumeni-like-criteria, she did not meet the classical LFS criteria [4]. The age at onset for the first malignancy was relatively high, as the estimated penetrance at 40 years of age ranges between 77%–100% [5]. The average age for diagnosis of first cancers in TP53 mutation carriers is estimated to be 21.9 years, and this is earlier in females than in males [1, 5]. Predictive testing of minors is recommended since a high prevalence of adrenal gland, soft tissue and brain tumours has been observed in children

Testing of both parents indicated a de novo TP53 mutation in the patient. De novo TP53 mutations have been described in up to 23.5% (4 of 17) of carriers [9, 19]. Recently, de novo TP53 mutations were confirmed in 7% and suspected in up to 20% of a larger cohort with 75 germline mutation carriers [20].

Treatment response to adjuvant therapy and prognosis

Impaired response to chemotherapy and radiation is described in most studies [21–24]. In breast cancer, TP53 status was identified as independent negative prognostic marker [25], however the results remain controversial. The response to treatment ranges from a high rate of pathologic complete remission of breast cancer after neoadjuvant chemotherapy with anthracyclines, to primary tumour resistance and progression as observed in the case of our patient [26–31]. Introduction of wild-type TP53 by gene therapy increased the response to chemotherapy or radiation therapy in preclinical and some early clinical trials [27, 32–34], however the results were not consistent and to date, gene therapy is not within reach for patients with LFS.

Treatment-induced secondary cancers

The risk of developing secondary, radiation-induced malignancies was described as elevated in LFS patients, since the first reports of LFS by Li and Fraumeni [3]. Several case-reports point to the appearance of metachronous cancers in radiation-treated areas in cancer patients with TP53 mutations [35–39].

Data regarding secondary cancers after radiation therapy in young LFS patients is limited, because of the unfavourable prognosis of most core cancers in LFS and the expected time delay in radiation-induced cancers [19]. Interestingly, five long-term in-field relapses or second primary cancers were recently reported in six patients with unilateral breast cancer, following radiation treatment [39]. In a study of 27 LFS patients, nine were treated with radiotherapy. Of these, six patients suffered from one or two successive solid tumours in the radiation field within a period of 3–22 years (median 7 years) after treatment for the first malignancy. One additional cancer was identified in the radiation field of a patient following treatment for a third cancer, after a delay of 7 years [17]. In a separate study, three radiotherapy-treated patients in a series of nine children with adrenocortical tumours and known TP53 mutations, survived more than two years, however these children developed five secondary malignancies in the radiation fields [19]. Preclinical studies support the hypothesis that cells lacking wild-type TP53 function have an increased likelihood of genetic instability due to high rates of inappropriate recombination after radiation-induced DNA damage (reviewed in Cuddihy et al.,[40]). In Trp53-heterozygous or Trp53-null mice, treatment with low-dose irradiation led to shorter latency of tumour development and a higher incidence of malformations [41–43]. Human TP53-deficient cells have been shown to accumulate DNA damage and are susceptible to malignant transformation, whereas TP53-competent cells showed cell-cycle arrest facilitating DNA repair, or apoptosis [44]. These data support the observation that LFS patients are more likely to develop radiotherapy-induced secondary cancers. Finally, it appears that in addition to TP53 variations, the presence of additional genetic alterations are required to predict the individual risk for radiation-induced secondary cancers [45, 46].

Need for therapy modification in LFS patients

Due to the potentially higher cancer induction rate after radiotherapy, it is important to consider the existence of a germline TP53-mutation, especially if there is a choice between surgery and radiotherapy [47, 48]. After bilateral, breast-conserving resection, the initial plan to apply adjuvant radiation therapy was cancelled due to the detection of a germline TP53 mutation. Greater effort should be taken in the early detection and complete resection of TP53-associated malignancies, since DNA-damaging, standard adjuvant therapies not only have a questionable effect, but also carry the risk for secondary tumours.

Surveillance

Most of the core cancers of LFS are associated with a poor prognosis. Interestingly, the first prospective data on the successful application of a surveillance programme in TP53 mutation carriers was recently published. The key imaging procedure was an annual rapid total body MRI starting in childhood. Compared to the control group, this study demonstrated a potential survival benefit using a comprehensive screening program [49].

Genetic counselling and predictive testing should be offered to patients fulfilling the classic LFS or Li-Fraumeni-like criteria, as well as to their relatives, in order to recommend an intensified cancer screening if LFS is confirmed. While the NCCN guidelines recommend the testing of singular cases suggestive for LFS, even in the absence of family history, others negate the necessity for testing because of low mutation rates (0–7%) and high psychological burden. Numerous publications have explored the testing of early onset breast cancer cases for TP53 germline mutations and found that these represent rare cases [1, 11, 50–57]. For example, no pathologic mutations were found in 95 patients with breast cancer (< 30 years old), despite the fact that several patients displayed a positive family history for breast and ovarian cancer [50]. As the costs of testing decrease in the future and effective prevention strategies may be confirmed, testing patients with early onset breast cancer without a family history of cancer will become even more feasible.

In comparison to other tumour syndromes, such as hereditary breast and ovarian cancer, prophylactic operations do not offer a good prognosis for carriers of a TP53 germline mutation, and each case should be considered individually. Firstly, the life-time breast cancer risk is estimated to be ~22%. This is significantly lower than for carriers of a pathogenic mutation in BRCA1 or BRCA2, who display a life-time risk for breast cancer of ~60–80%. Secondly, in LFS, malignancies emerge in different anatomical sites, whereas BRCA-associated tumours mainly affect the breast and ovaries.

Since some LFS patients seem to carry an elevated risk for radiation-induced malignancies, exposure should be as low as possible, although a general contraindication for any type of radiological diagnostic or treatment cannot be stated. Surveillance strategies should be chosen with regard to the least possible radiation exposure.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Declarations

Acknowledgements

We thank Alexandre Serra and Dorothea Gadzicki for carefully revising the manuscript.

Authors’ Affiliations

(1)
Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Carl Gustav Carus, Fetscherstr, 74, Dresden, Germany
(2)
Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
(3)
Medizinisch Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
(4)
Institut für Pathologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
(5)
MVZ Dr. Reising-Ackermann u, Kollegen, Leipzig, Germany
(6)
Gemeinschaftspraxis für Humangenetik, Dresden, Germany

References

  1. Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, Han JH, Lowstuter K, Longmate J, Sommer SS, et al: Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009, 27 (8): 1250-1256. 10.1200/JCO.2008.16.6959.View ArticlePubMedGoogle Scholar
  2. Nagy R, Sweet K, Eng C: Highly penetrant hereditary cancer syndromes. Oncogene. 2004, 23 (38): 6445-6470. 10.1038/sj.onc.1207714.View ArticlePubMedGoogle Scholar
  3. Li FP, Fraumeni JF: Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?. Ann Intern Med. 1969, 71 (4): 747-752.View ArticlePubMedGoogle Scholar
  4. Li FP, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW: A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988, 48 (18): 5358-5362.PubMedGoogle Scholar
  5. Hwang SJ, Lozano G, Amos CI, Strong LC: Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet. 2003, 72 (4): 975-983. 10.1086/374567.View ArticlePubMedPubMed CentralGoogle Scholar
  6. Wu CC, Shete S, Amos CI, Strong LC: Joint effects of germ-line p53 mutation and sex on cancer risk in Li-Fraumeni syndrome. Cancer Res. 2006, 66 (16): 8287-8292. 10.1158/0008-5472.CAN-05-4247.View ArticlePubMedGoogle Scholar
  7. Birch JM, Hartley AL, Tricker KJ, Prosser J, Condie A, Kelsey AM, Harris M, Jones PH, Binchy A, Crowther D, et al: Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994, 54 (5): 1298-1304.PubMedGoogle Scholar
  8. Eeles RA: Germline mutations in the TP53 gene. Cancer Surv. 1995, 25: 101-124.PubMedGoogle Scholar
  9. Chompret A, Brugieres L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, Hua D, Ligot L, Dondon MG, Bressac-de Paillerets B, et al: P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000, 82 (12): 1932-1937.View ArticlePubMedPubMed CentralGoogle Scholar
  10. Chompret A, Abel A, Stoppa-Lyonnet D, Brugieres L, Pages S, Feunteun J, Bonaiti-Pellie C: Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2001, 38 (1): 43-47. 10.1136/jmg.38.1.43.View ArticlePubMedPubMed CentralGoogle Scholar
  11. Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, Caron O, Bressac-de Paillerets B, Berthet P, Dugast C, et al: 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol. 2009, 27 (26): e108-e109. 10.1200/JCO.2009.22.7967. author reply e110View ArticlePubMedGoogle Scholar
  12. Varley JM: Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat. 2003, 21 (3): 313-320. 10.1002/humu.10185.View ArticlePubMedGoogle Scholar
  13. Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA: Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003, 63 (20): 6643-6650.PubMedGoogle Scholar
  14. Bougeard G, Sesboue R, Baert-Desurmont S, Vasseur S, Martin C, Tinat J, Brugieres L, Chompret A, de Paillerets BB, Stoppa-Lyonnet D, et al: Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet. 2008, 45 (8): 535-538. 10.1136/jmg.2008.057570.View ArticlePubMedGoogle Scholar
  15. Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, et al: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990, 250 (4985): 1233-1238. 10.1126/science.1978757.View ArticlePubMedGoogle Scholar
  16. Lacroix M, Toillon RA, Leclercq G: p53 and breast cancer, an update. Endocr Relat Cancer. 2006, 13 (2): 293-325. 10.1677/erc.1.01172.View ArticlePubMedGoogle Scholar
  17. Hisada M, Garber JE, Fung CY, Fraumeni JF, Li FP: Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. 1998, 90 (8): 606-611. 10.1093/jnci/90.8.606.View ArticlePubMedGoogle Scholar
  18. Melhem-Bertrandt A, Bojadzieva J, Ready KJ, Obeid E, Liu DD, Gutierrez-Barrera AM, Litton JK, Olopade OI, Hortobagyi GN, Strong LC, et al: Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer. 2012, 118 (4): 908-913. 10.1002/cncr.26377.View ArticlePubMedGoogle Scholar
  19. Varley JM, McGown G, Thorncroft M, Santibanez-Koref MF, Kelsey AM, Tricker KJ, Evans DG, Birch JM: Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res. 1997, 57 (15): 3245-3252.PubMedGoogle Scholar
  20. Gonzalez KD, Buzin CH, Noltner KA, Gu D, Li W, Malkin D, Sommer SS: High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet. 2009, 46 (10): 689-693. 10.1136/jmg.2008.058958.View ArticlePubMedGoogle Scholar
  21. Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T: p53 status and the efficacy of cancer therapy in vivo. Science. 1994, 266 (5186): 807-810. 10.1126/science.7973635.View ArticlePubMedGoogle Scholar
  22. Hamada M, Fujiwara T, Hizuta A, Gochi A, Naomoto Y, Takakura N, Takahashi K, Roth JA, Tanaka N, Orita K: The p53 gene is a potent determinant of chemosensitivity and radiosensitivity in gastric and colorectal cancers. J Cancer Res Clin Oncol. 1996, 122 (6): 360-365. 10.1007/BF01220804.View ArticlePubMedGoogle Scholar
  23. Preudhomme C, Fenaux P: The clinical significance of mutations of the P53 tumour suppressor gene in haematological malignancies. Br J Haematol. 1997, 98 (3): 502-511. 10.1046/j.1365-2141.1997.2403057.x.View ArticlePubMedGoogle Scholar
  24. Shelling AN: Role of p53 in drug resistance in ovarian cancer. Lancet. 1997, 349 (9054): 744-745. 10.1016/S0140-6736(05)60195-X.View ArticlePubMedGoogle Scholar
  25. Olivier M, Langerod A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bieche I, et al: The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res. 2006, 12 (4): 1157-1167. 10.1158/1078-0432.CCR-05-1029.View ArticlePubMedGoogle Scholar
  26. Aas T, Borresen AL, Geisler S, Smith-Sorensen B, Johnsen H, Varhaug JE, Akslen LA, Lonning PE: Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med. 1996, 2 (7): 811-814. 10.1038/nm0796-811.View ArticlePubMedGoogle Scholar
  27. Cimoli G, Malacarne D, Ponassi R, Valenti M, Alberti S, Parodi S: Meta-analysis of the role of p53 status in isogenic systems tested for sensitivity to cytotoxic antineoplastic drugs. Biochim Biophys Acta. 2004, 1705 (2): 103-120.PubMedGoogle Scholar
  28. Geisler S, Borresen-Dale AL, Johnsen H, Aas T, Geisler J, Akslen LA, Anker G, Lonning PE: TP53 gene mutations predict the response to neoadjuvant treatment with 5-fluorouracil and mitomycin in locally advanced breast cancer. Clin Cancer Res. 2003, 9 (15): 5582-5588.PubMedGoogle Scholar
  29. Geisler S, Lonning PE, Aas T, Johnsen H, Fluge O, Haugen DF, Lillehaug JR, Akslen LA, Borresen-Dale AL: Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer. Cancer Res. 2001, 61 (6): 2505-2512.PubMedGoogle Scholar
  30. Kandioler-Eckersberger D, Ludwig C, Rudas M, Kappel S, Janschek E, Wenzel C, Schlagbauer-Wadl H, Mittlbock M, Gnant M, Steger G, et al: TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res. 2000, 6 (1): 50-56.PubMedGoogle Scholar
  31. Lanni JS, Lowe SW, Licitra EJ, Liu JO, Jacks T: p53-independent apoptosis induced by paclitaxel through an indirect mechanism. Proc Natl Acad Sci U S A. 1997, 94 (18): 9679-9683. 10.1073/pnas.94.18.9679.View ArticlePubMedPubMed CentralGoogle Scholar
  32. Lu C, El-Deiry WS: Targeting p53 for enhanced radio- and chemo-sensitivity. Apoptosis. 2009, 14 (4): 597-606. 10.1007/s10495-009-0330-1.View ArticlePubMedGoogle Scholar
  33. Peng Z: Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther. 2005, 16 (9): 1016-1027. 10.1089/hum.2005.16.1016.View ArticlePubMedGoogle Scholar
  34. Pan JJ, Zhang SW, Chen CB, Xiao SW, Sun Y, Liu CQ, Su X, Li DM, Xu G, Xu B, et al: Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma. J Clin Oncol. 2009, 27 (5): 799-804. 10.1200/JCO.2008.18.9670.View ArticlePubMedGoogle Scholar
  35. Agir H, MacKinnon C, Tan ST: Li-Fraumeni syndrome: a case with 4 separate primary sarcomas and 5 sequential free flaps in the maxillofacial region. J Oral Maxillofac Surg. 2008, 66 (8): 1714-1719. 10.1016/j.joms.2007.09.015.View ArticlePubMedGoogle Scholar
  36. Limacher JM, Frebourg T, Natarajan-Ame S, Bergerat JP: Two metachronous tumors in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int J Cancer. 2001, 96 (4): 238-242. 10.1002/ijc.1021.View ArticlePubMedGoogle Scholar
  37. Salmon A, Amikam D, Sodha N, Davidson S, Basel-Vanagaite L, Eeles RA, Abeliovich D, Peretz T: Rapid development of post-radiotherapy sarcoma and breast cancer in a patient with a novel germline ‘de-novo’ TP53 mutation. Clin Oncol (R Coll Radiol). 2007, 19 (7): 490-493. 10.1016/j.clon.2007.05.001.View ArticleGoogle Scholar
  38. Nutting C, Camplejohn RS, Gilchrist R, Tait D, Blake P, Knee G, Yao WQ, Ross G, Fisher C, Eeles R: A patient with 17 primary tumours and a germ line mutation in TP53: tumour induction by adjuvant therapy?. Clin Oncol (R Coll Radiol). 2000, 12 (5): 300-304.Google Scholar
  39. Heymann S, Delaloge S, Rahal A, Caron O, Frebourg T, Barreau L, Pachet C, Mathieu MC, Marsiglia H, Bourgier C: Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Radiat Oncol. 2010, 5: 104-10.1186/1748-717X-5-104.View ArticlePubMedPubMed CentralGoogle Scholar
  40. Cuddihy AR, Bristow RG: The p53 protein family and radiation sensitivity: Yes or no?. Cancer Metastasis Rev. 2004, 23 (3–4): 237-257.View ArticlePubMedGoogle Scholar
  41. Kemp CJ, Wheldon T, Balmain A: p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nat Genet. 1994, 8 (1): 66-69. 10.1038/ng0994-66.View ArticlePubMedGoogle Scholar
  42. Kato F, Ootsuyama A, Nomoto S, Kondo S, Norimura T: Threshold effect for teratogenic risk of radiation depends on dose-rate and p53-dependent apoptosis. Int J Radiat Biol. 2001, 77 (1): 13-19. 10.1080/09553000010001899.View ArticlePubMedGoogle Scholar
  43. Baatout S, Jacquet P, Michaux A, Buset J, Vankerkom J, Derradji H, Yan J, von Suchodoletz H, de Saint-Georges L, Desaintes C, et al: Developmental abnormalities induced by X-irradiation in p53 deficient mice. In Vivo. 2002, 16 (3): 215-221.PubMedGoogle Scholar
  44. Boyle JM, Spreadborough A, Greaves MJ, Birch JM, Varley JM, Scott D: The relationship between radiation-induced G(1)arrest and chromosome aberrations in Li-Fraumeni fibroblasts with or without germline TP53 mutations. Br J Cancer. 2001, 85 (2): 293-296. 10.1054/bjoc.2001.1896.View ArticlePubMedPubMed CentralGoogle Scholar
  45. Boyle JM, Spreadborough AR, Greaves MJ, Birch JM, Varley JM, Scott D: Delayed chromosome changes in gamma-irradiated normal and Li-Fraumeni fibroblasts. Radiat Res. 2002, 157 (2): 158-165. 10.1667/0033-7587(2002)157[0158:DCCIGI]2.0.CO;2.View ArticlePubMedGoogle Scholar
  46. Backlund MG, Trasti SL, Backlund DC, Cressman VL, Godfrey V, Koller BH: Impact of ionizing radiation and genetic background on mammary tumorigenesis in p53-deficient mice. Cancer Res. 2001, 61 (17): 6577-6582.PubMedGoogle Scholar
  47. Evans DG, Birch JM, Ramsden RT, Sharif S, Baser ME: Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet. 2006, 43 (4): 289-294.View ArticlePubMedGoogle Scholar
  48. Moule RN, Jhavar SG, Eeles RA: Genotype phenotype correlation in Li-Fraumeni syndrome kindreds and its implications for management. Fam Cancer. 2006, 5 (2): 129-133. 10.1007/s10689-005-4522-8.View ArticlePubMedGoogle Scholar
  49. Villani A, Tabori U, Schiffman J, Shlien A, Beyene J, Druker H, Novokmet A, Finlay J, Malkin D: Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 2011, 12 (6): 559-567. 10.1016/S1470-2045(11)70119-X.View ArticlePubMedGoogle Scholar
  50. Ginsburg OM, Akbari MR, Aziz Z, Young R, Lynch H, Ghadirian P, Robidoux A, Londono J, Vasquez G, Gomes M, et al: The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30. Fam Cancer. 2009, 8 (4): 563-567. 10.1007/s10689-009-9287-z.View ArticlePubMedGoogle Scholar
  51. Arcand SL, Maugard CM, Ghadirian P, Robidoux A, Perret C, Zhang P, Fafard E, Mes-Masson AM, Foulkes WD, Provencher D, et al: Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families. Breast Cancer Res Treat. 2008, 108 (3): 399-408. 10.1007/s10549-007-9608-6.View ArticlePubMedGoogle Scholar
  52. Borresen AL, Andersen TI, Garber J, Barbier-Piraux N, Thorlacius S, Eyfjord J, Ottestad L, Smith-Sorensen B, Hovig E, Malkin D, et al: Screening for germ line TP53 mutations in breast cancer patients. Cancer Res. 1992, 52 (11): 3234-3236.PubMedGoogle Scholar
  53. Lalloo F, Varley J, Ellis D, Moran A, O’Dair L, Pharoah P, Evans DG: Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. Lancet. 2003, 361 (9363): 1101-1102. 10.1016/S0140-6736(03)12856-5.View ArticlePubMedGoogle Scholar
  54. Lalloo F, Varley J, Moran A, Ellis D, O’Dair L, Pharoah P, Antoniou A, Hartley R, Shenton A, Seal S, et al: BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer. 2006, 42 (8): 1143-1150. 10.1016/j.ejca.2005.11.032.View ArticlePubMedGoogle Scholar
  55. Mouchawar J, Korch C, Byers T, Pitts TM, Li E, McCredie MR, Giles GG, Hopper JL, Southey MC: Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res. 2010, 70 (12): 4795-4800. 10.1158/0008-5472.CAN-09-0851.View ArticlePubMedPubMed CentralGoogle Scholar
  56. Prosser J, Elder PA, Condie A, MacFadyen I, Steel CM, Evans HJ: Mutations in p53 do not account for heritable breast cancer: a study in five affected families. Br J Cancer. 1991, 63 (2): 181-184. 10.1038/bjc.1991.44.View ArticlePubMedPubMed CentralGoogle Scholar
  57. Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S, et al: Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006, 295 (12): 1379-1388. 10.1001/jama.295.12.1379.View ArticlePubMedGoogle Scholar

    58. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/12/217/prepub

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