Prevalence of Germline TP53 Mutations in a Prospective Series of Unselected Patients with Adrenocortical Carcinoma
Victoria M. Raymond,* Tobias Else,* Jessica N. Everett, Jessica M. Long, Stephen B. Gruber, and Gary D. Hammer
Divisions of Molecular Medicine and Genetics (V.M.R., J.N.E., J.M.L.) and Metabolism, Endocrinology, and Diabetes (T.E., G.D.H.), Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-5419; and University of Southern California Norris Comprehensive Cancer Center (S.B.G.), Los Angeles, California 90089-9181
Purpose: Adrenocortical carcinoma (ACC) is a hallmark cancer in families with Li Fraumeni syn- drome (LFS) caused by mutations in the TP53 gene. The prevalence of germline TP53 mutations in children diagnosed with ACC ranges from 50-97%. Although existing criteria advocate for TP53 testing in all patients with ACC regardless of age at diagnosis, the overall prevalence of germline mutations in patients diagnosed with ACC has not been well studied.
Patients and Methods: A total of 114 patients with confirmed ACC evaluated in the University of Michigan Endocrine Oncology Clinic were prospectively offered genetic counseling and TP53 genetic testing, regard- less of age at diagnosis or family history. Ninety-four of the 114 patients met with a genetic counselor (82.5%), with 53 of 94 (56.4%) completing TP53 testing; 9.6% (nine of 94) declined testing. The remainder (32 of 94; 34%) expressed interest in testing but did not pursue it for various reasons.
Results: Four of 53 patients in this prospective, unselected series were found to have a TP53 mutation (7.5%). The prevalence of mutations in those diagnosed over age 18 was 5.8% (three of 52). There were insufficient data to estimate the prevalence in those diagnosed under age 18. None of these patients met clinical diagnostic criteria for classic LFS. Three of the families met criteria for Li Fraumeni-like syndrome; one patient met no existing clinical criteria for LFS or Li Fraumeni-like syndrome. Three of the four patients with mutations were diagnosed with ACC after age 45.
Conclusions: Genetic counseling and germline testing for TP53 should be offered to all patients with ACC. Restriction on age at diagnosis or strength of the family history would fail to identify mutation carriers. (J Clin Endocrinol Metab 98: E119-E125, 2013)
A drenocortical carcinoma (ACC) is a rare, aggressive tumor that, when diagnosed in children, prompts a genetic evaluation for Li Fraumeni syndrome (LFS) due to germline TP53 mutations (1). LFS is an autosomal dom- inant cancer predisposition syndrome with elevated risks of premenopausal breast cancer, sarcoma, lymphoma, and ACC (2, 3). Strict criteria exist for the clinical diag- nosis of classic LFS (2) and for the clinical diagnosis of the less stringent Li Fraumeni-like syndrome (4, 5). The
Chompret genetic testing criteria (6, 7) were drafted to guide clinicians on the appropriate patients in whom to offer a genetic evaluation for LFS. The criteria advocate for TP53 genetic testing in all individuals diagnosed with ACC, regardless of age at diagnosis or strength of the fam- ily history. However, this recommendation was based pri- marily on studies of children with ACC and has not been validated by an independent cohort that includes adult ACC patients.
* V.M.R. and T.E. contributed equally to this work.
Abbreviations: ACC, Adrenocortical carcinoma; LFS, Li Fraumeni syndrome; NF1, neuro- fibromatosis type 1; VUS, variant(s) of uncertain significance.
The prevalence of LFS among children with ACC has been reviewed in several series and is estimated to be 50- 80% dependent on the study population (8, 9). A TP53 mutation, p.R337H, with a population frequency of 0.3% in Brazil was found in up to 97% of Brazilian pediatric ACC patients (10). In a U.S. series, Gonzalez et al. (11) reviewed clinical histories of patients referred to a CLIA (Clinical Laboratory Improvement Amendments of 1988) -certified lab for TP53 gene sequencing. Of the 21 patients with ACC, 14 (67%) had identifiable TP53 mutations. Twelve of 14 mutation carriers (80%) were diagnosed under age 18 (range, 0.5-38 yr). Based on the clinical information provided by the referral center, two TP53 mutation carriers met classic LFS criteria, and four pa- tients met Eeles Li Fraumeni-like criteria. Recently, Herr- mann et al. (12) sequenced TP53 in a subset of the adult patients enrolled in the German ACC registry and re- ported a TP53 mutation prevalence of 3.9%. This study was the first to specifically analyze adult-onset ACC; how- ever, their analysis was restricted to an undefined subset of all patients enrolled in the registry (12).
The University of Michigan Endocrine Oncology Pro- gram is a specialized center with expertise in the diagnosis, treatment, and management of ACC, which serves as a referral center for ACC patients nationally and interna- tionally. This multidisciplinary clinic incorporates clini- cians with expertise in endocrinology, endocrine surgery, medical oncology, radiation oncology, pathology, and ge- netics. In 2009, we began routinely offering genetic coun- seling and TP53 testing to clinic patients with the goal of better defining genetic risk in this predominantly adult population with ACC.
Patients and Methods
Patients presenting to the University of Michigan Endocrine On- cology Program between December 1, 2009, and October 31, 2011, with a diagnosis of ACC were included in this analysis. Patients were offered a genetics consultation as part of their visit and met with a genetic counselor who obtained a four-generation cancer genetics pedigree. Based on Chompret genetic testing cri- teria (6), all patients were offered germline TP53 genetic testing with sequencing and large rearrangement analysis with multi- plex ligation probe analysis or gene dosage analysis through a CLIA-certified clinical laboratory.
Families were classified based on published clinical diagnostic criteria. “Typical LFS cancers” and “LFS-related malignancies” for this study include all cancers cited by Tinat et al. (6) as belonging to the LFS tumor spectrum: soft tissue sarcoma, osteosarcoma, brain tumor, breast cancer, ACC, leukemia, lung cancer, and choroid plexus tumor. Criteria are: 1) classic LFS defined as proband with a sarcoma diagnosed before age 45 yr, a first-degree relative with any cancer before age 45 yr, and a first- or second-degree relative with any cancer before age 45 yr or a sarcoma at any age (2); 2) Birch Li Fraumeni-like syndrome, defined as a proband with any child- hood cancer or sarcoma, brain tumor, or ACC diagnosed before age 45 yr, and a first- or second-degree relative with a typical LFS cancer at any age, and a first- or second-degree relative with any cancer before age 60 yr (4, 5); 3) Eeles Li Fraumeni-like syndrome defined as two first- or second-degree relatives with LFS-related malignan- cies at any age (4, 5); or 4) no clinical criteria met. Each family was included in only one of the four diagnostic categories corresponding with the most stringent criteria met.
Permission for research was obtained from the Institutional Review Board at the University of Michigan, Ann Arbor, Mich- igan (HUM00043430).
Results
A total of 114 patients with ACC were evaluated in the University of Michigan Endocrine Oncology Program
| TABLE 1. Characteristics of patients presenting to University of Michigan Endocrine Oncology Program | |||||
|---|---|---|---|---|---|
| No. evaluated in EndoOnc program (% of total population) | No. counseled (% of evaluated) | No. tested for germline TP53 mutation (% of counseled) | No. not tested for germline TP53 mutation (% of counseled) | No. positive for germline TP53 mutation (% of tested) | |
| Gender | |||||
| Female | 72 (63.2) | 61 (84.7) | 33 (54.1) | 28 (45.9) | 3 (9.1) |
| Male | 42 (36.8) | 33 (78.6) | 20 (60.6) | 13 (39.4) | 1 (5.0) |
| Race | |||||
| Caucasian | 100 (87.7) | 82 (82.0) | 48 (58.5) | 34 (41.5) | 3 (6.3) |
| African-American | 9 (7.9) | 8 (88.9) | 4 (50.0) | 4 (50.0) | 1 (25.0) |
| Asian | 3 (2.6) | 2 (66.7) | 0 | 2 (100) | 0 |
| Other | 2 (1.8) | 2 (100) | 1 (50.0) | 1 (50.0) | 0 |
| Total | 114 | 94 (82.5) | 53 (56.4) | 41 (43.6) | 4 (7.5) |
| Mean age (yr) at diagnosis | 45.5 | 44.7 | 45.5 | 43.7 | 42.5 |
| (range) | (3-82) | (3-82) | (3-82) | (17-76) | (3-68) |
| Median age (yr) at diagnosis | 46.5 | 46.0 | 47.0 | 43.0 | 49.5 |
| Age at diagnosis (yr) | |||||
| ≤17 | 2 (1.8) | 2 (100) | 1 (50.0) | 1 (50.0) | 1 (100) |
| 18-39 | 35 (30.7) | 28 (80.0) | 13 (46.4) | 15 (53.6) | 0 |
| ≥40 | 77 (67.5) | 64 (83.1) | 39 (60.9) | 25 (39.1) | 3 (7.7) |
| TABLE 2. Most stringent LFS clinical diagnostic criteria met by the 94 families who received genetic counseling | ||||||
|---|---|---|---|---|---|---|
| Counseled | Tested for germline TP53 mutation | Not tested for germline TP53 mutation | Positive for germline TP53 mutation | Sensitivity (%) | Specificity (%) | |
| N | 94 | 53 | 41 | 4 | ||
| Classic LFS clinical diagnostic criteria | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 | 100 |
| Birch LFL clinical diagnostic criteria | 12 (12.8) | 8 (15.1) | 4 (9.8) | 0 (0) | 0 | 83.7 |
| Eeles LFL clinical diagnostic criteria | 46 (48.9) | 28 (52.8) | 18 (43.9) | 3 (75.0) | 75 | 49 |
| No clinical diagnostic criteria met | 36 (38.3) | 17 (32.1) | 19 (46.3) | 1 (25.0) | — | — |
| Chompret genetic testing criteria | 94 (100) | 53 (100) | 41 (100) | 4 (100) | 100 | 0 |
during the study period. Forty-two patients were male (36.8%), and 72 were female (63.2%). The majority of patients were Caucasian (87.7%), with a small number being African-American (7.9%) or Asian (2.6%). Average age at ACC diagnosis was 45.5 yr, with a range of 3 to 82 yr at diagnosis. Ninety-eight percent of patients were di- agnosed after age 18 (Table 1).
Of the 114 patients evaluated in the University of Mich- igan Endocrine Oncology Program, 94 (82.5%) opted to meet with a genetic counselor. After completion of a four- generation cancer genetics pedigree, 58 families met cri- teria for clinical diagnoses of Li Fraumeni-like syndrome, 12 met Birch criteria (12.8%), and 46 met Eeles criteria (48.9%). No patients met classic LFS criteria (Table 2).
Fifty-three (56.4%) patients pursued TP53 genetic test- ing, and 9.6% (nine of 94) declined the testing. Thirty-two patients (34%) expressed interest, but did not ultimately pursue testing. Reasons for not pursuing genetic testing included the patients’ desire to consider the option of test- ing, including discussing with family members (34.4%; 11 of 32), wanting to verify insurance coverage, or wanting to pursue genetic testing within their local insurance network (56.3%; 18 of 32). Three patients were denied insurance coverage for TP53 genetic testing (9.4%; three of 32). Average age at diagnosis of the individuals who did (45.5 yr) and did not pursue genetic testing (43.7 yr) did not differ significantly (P = 0.55; t test). Four individuals were positive for a TP53 mutation (7.5%; four of 53).
Patient A: positive for TP53 c.814G>A;p.V272M
This is a missense mutation that is in a highly conserved codon. This mutation has been previously reported in a family with LFS and as a somatic mutation (13). The pa- tient was a Caucasian female diagnosed with stage III ACC at age 68, presenting as Cushing’s syndrome. Biochemical cortisol and dehydroepiandrosterone sulfate excess was confirmed. The patient underwent surgery for a 7.2-cm, 161-g high-grade ACC, with lung metastases being diag- nosed 2.5 months after surgery. After treatment with mi- totane and six cycles of etoposide, doxorubicin, and cis-
platin, the patient experienced disease progression and ultimately died 20 months after initial diagnosis. Her fam- ily history was notable for a father who died at age 86 of a brain tumor, a maternal first cousin who died at age 69 of breast cancer, and a maternal grandmother who died of lung cancer at an advanced age (Fig. 1).
Patient B: positive for TP53 c.542G>A;p.R181H
This missense mutation is in a fairly well-conserved codon. It has been reported in a family with LFS, and mu- tations at the same codon have been reported in LFS (13). This patient is a Caucasian female initially diagnosed with bilateral adrenal tumors at age 52. Pathological specimen revealed a high-grade 7-cm left-sided ACC and a contralat- eral pheochromocytoma. The patient did not show any clin- ical symptoms of hormone secretion by the ACC. Eight months after surgery, the patient was diagnosed with liver metastases and underwent initial treatment with eight cycles of mitotane, etoposide, doxorubicin, and cisplatin. Due to
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further progression, she was included in a double-blind trial using a targeted tyrosine kinase inhibitor. Three years later, she was diagnosed with glioblastoma multiforme and un- derwent surgery, followed by treatment with irinotecan, avastin, and carboplatin. She is currently alive with stage IV ACC 4 yr after initial diagnosis. Her medical history is further complicated by a clinical diagnosis of neurofibromatosis type 1 (NF1) diagnosed at age 11, characterized by a history of multiple cutaneous neurofibromas, Lisch nodules, and multiple café au lait macules. After the genetic consultation, this diagnosis was confirmed with identification of a novel missense mutation (c.6881T>G;p.L2294R) in the NF1 gene. Her family history is notable for late-onset pancreatic and colon cancer on the maternal side and a paternal family history of late-onset renal, breast, and colon cancers. No other family members are known to have clinical diagnoses of NF1 (Fig. 2).
Patient C: positive for TP53 c.473G>A;p.R158H
This missense mutation is in a completely conserved codon and has been previously reported in eight families with LFS (13). This Caucasian male was diagnosed with ACC at age 3. The patient initially presented with precocious puberty due to dehydroepiandrosterone sulfate and testosterone ex- cess. He underwent surgery for a 2-cm, 9-g low-grade ACC. He is currently alive without evidence of disease 17 months after initial diagnosis. His medical history is otherwise un- remarkable. His family history is notable for a paternal fam- ily history of prostate and renal cancer. The patient’s mother,
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maternal half-sisters, and paternal half-brother tested nega- tive for the identified TP53 mutation (Fig. 3).
Patient D: positive for a novel variant of uncertain significance in TP53, c.G>T 207bp upstream from exon 1
This African-American female was diagnosed with ACC at age 47. The patient initially presented with symptoms compatible with Cushing syndrome. However, an initial bio- chemical workup was not performed. She underwent initial surgery and had a locoregional recurrence as well as liver metastases 2 yr later. Pathological specimen of repeat surgery revealed a low-grade ACC. After resection, the patient re- ceived 46-Gy adjuvant radiation to the tumor bed. Three years and 8 months later, the patient had a repeat retroper- itoneal recurrence inferior to the kidney, treated with surgery and radiation therapy (50 Gy). She currently is alive without evidence of disease 8 yr and 7 months after initial diagnosis. The medical history is otherwise remarkable for a colon ad- enoma. Her family history is significant for ovarian cancer diagnosed in her mother at age 55, a “bone” cancer diag- nosed in a maternal aunt, endometrial cancer diagnosed in a second maternal aunt, and lung cancer diagnosed in a ma- ternal uncle and maternal grandfather (Fig. 4). Immunohis- tochemistry analysis in the ACC tumor noted absent TP53 expression.
None of the TP53-positive patients met clinical diagnostic criteria for classic LFS. Three patients (A, B, and D) met Eeles Li Fraumeni-like clinical diagnostic criteria (Table 2). The average age at diagnosis did not significantly differ between those positive for germline TP53 mutations (42.5 yr) and those found not to have a mutation (45.6 yr) (P= 0.68; ttest).
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Discussion
ACC is a rare aggressive tumor with a Surveillance Epi- demiology and End Results (SEER) estimated prevalence of 0.72 cases per 1,000,000 individuals (14). ACC has been described in patients with inherited cancer predispo- sition syndromes, most commonly LFS, a rare inherited condition caused by germline mutations in the TP53 gene (15). Individuals with LFS are at highly elevated risk of cancer, with a lifetime risk of almost 100% in women and 73% in men, the gender difference thought to be ac- counted for by the high incidence of female breast cancer in LFS (16).
Additionally, one of the hallmark features of LFS is the diagnosis of pediatric cancers (17). It is estimated that 50-80% of children diagnosed with ACC have a germline TP53 mutation (8). In certain pediatric ACC populations, the risk of TP53 mutations is higher. Ribeiro et al. (10) sequenced the coding region of TP53 in 27 patients with ACC and nine patients with adrenal cortical adenomas in Brazil. The patients average age at diagnosis was 3 yr (range, 4 months to 13.5 yr). Thirty-five of these 36 pa- tients (97%) had an identical TP53 mutation (p.R337H). Latronico et al. (18) examined the prevalence of this p.R337H mutation in Brazilian patients with benign and malignant adrenal tumors and identified the mutation in 14 of 18 children (77.7%) and five of 37 adults (13.5%). These results strongly implicate TP53 p.R337H as the leading cause of ACC in the population in Brazil. How- ever, beyond the p.R337H mutation, the link between
TP53 mutations and adult-onset ACC has not been as well studied.
The Chompret criteria (6, 7) advocate for TP53 genetic testing for all patients diagnosed with ACC regardless of age at diagnosis or family history. Despite this recommendation, the overall prevalence of LFS in patients with ACC, including patients with adult-onset ACC, is not well described. A recent study sequenced TP53 in the germline of 103 of the 400 (25.8%) patients with ACC enrolled in the German ACC registry (12). Their analysis specifically focused on an unde- fined subset of patients with adult-onset ACC and identified four patients with germline TP53 mutations (3.9%). The median age at diagnosis in this group was 50 yr, with a range of 18-78 yr. Three of the four positive patients were diag- nosed with ACC under age 40. When analysis was restricted to the 23 ACC patients with an age at diagnosis under 40 yr, the incidence of germline TP53 mutations in this cohort was 13% (three of 23).
Our study is the first to prospectively examine an unse- lected series of patients presenting to a specialized center for ACC with a large national and international referral basis. Patients were offered TP53 genetic testing regardless of age at ACC diagnosis or strength of the family history. The prev- alence of TP53 mutations in this population was 7.4% (four of 53). The average age at diagnosis was 44.7 yr in the entire study cohort and 42.5 yr in those positive for TP53 muta- tions. When pediatric ACC cases were excluded (n = 1), the prevalence of TP53 mutations in the adult population was 5.8% (three of 52). Interestingly, none of these families met classic LFS clinical diagnostic criteria. Three of the four pa- tients met Eeles Li Fraumeni-like syndrome clinical diagnos- tic criteria. Three of four patients were diagnosed at age 47 or later, above the suggested 40-yr-old age restriction pro- posed by Herrmann et al. (12) and above the upper age limit for cancer diagnosis in a proband based on the classic LFS diagnostic criteria (2, 12).
The Chompret criteria have previously been shown to have an “acceptable” sensitivity in identifying patients with LFS. In 105 families identified in The Netherlands who met Chompret criteria, 22 (21%) had TP53 muta- tions (sensitivity, 92%; specificity, 47%) (19). A French series identified TP53 mutations in 67 of 232 families meeting Chompret criteria (sensitivity, 82%; specificity, 58%) (20). A series from the United States identified TP53 mutations in 69 of 195 families who met these criteria (sensitivity, 92%; specificity, 53%) (11). In our prospec- tive series, none of the eight patients meeting Birch criteria for Li Fraumeni-like syndrome had an identifiable TP53 mutation (sensitivity, 0%; specificity, 83.7%). Three of the 28 patients meeting Eeles Li Fraumeni-like criteria had an identifiable TP53 mutation (sensitivity, 75%; specific- ity, 49%). The limitation of using family history alone to
guide TP53 genetic testing is the high de novo rate of germline mutations that has been described as high as 24% (16). Using the Chompret genetic testing criteria, with no age restrictions for diagnosis of ACC, was the best tool for identifying patients with TP53 mutations. Herrmann et al. (12) proposed modifying the Chompret criteria to restrict age at ACC diagnosis to under age 40 yr. Using this age restriction would have failed to identify three of the four mutation carriers in our cohort, arguing against using age restrictions to limit TP53 testing in patients with ACC. When focusing only on those patients diagnosed with ACC at an age greater than 40, three of 39 patients tested positive for a mutation (7.7%).
With advances in genetic technology, the ability to rec- ognize individuals with underlying inherited cancer pre- disposition syndromes has increased. As genetic testing becomes more fully integrated with healthcare, we are rec- ognizing that few families meet the strict clinical diagnos- tic criteria originally developed to define the cancer syn- drome of interest. For example, a proportion of families with Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome), an inherited colorectal and endome- trial cancer predisposition syndrome, fail to meet the strict clinical diagnostic criteria known as the Amsterdam I/II criteria (21). It is suggested that all patients with colorectal or endometrial cancer be screened for tumor features sug- gestive of Lynch syndrome-associated tumors, regardless of their family history or age at diagnosis (21, 22). Simi- larly, it is recommended that women with estrogen recep- tor-negative, progesterone receptor-negative, and HER2/ neu-negative breast cancers (triple negative breast cancer) be screened for mutations in the BRCA1 and BRCA2 genes responsible for hereditary breast and ovarian cancer syndrome, regardless of the strength of the family history (23). As genetic technology continues to improve, we are less restricted by family history alone to guide genetic risk assessment and can use tumor pathology or tumor fea- tures. The same proves true with LFS. Given the high de novo rate and the variable expressivity and penetrance of TP53 mutations, families with LFS can be overlooked when using only the strength of the family history in the genetic risk assessment. The presence of a deleterious mu- tation in a cancer predisposition gene allows us to rely on genotype rather than strictly family cancer phenotype in making the diagnosis of an inherited cancer predisposition syndrome. Using the diagnosis of a rare LFS-associated cancer allowed for the diagnosis within these families.
Increasing the uptake of genetic testing will identify more variants of uncertain significance (VUS), especially in poorly studied ethnic groups in which the spectrum of germline mutations is less well defined. Determining whether a VUS is a deleterious mutation or a benign poly-
morphism requires many lines of evidence, including ep- idemiological, genetic, and molecular confirmation. This process may span years to decades. Indeed, definitive ev- idence may never occur in a timeframe to impact medical management for the patient of interest. Despite this lim- itation, these VUS cannot be ignored. Molecular informa- tion must be considered in conjunction with the family history to determine appropriate clinical recommenda- tions for the patient and their family. This is the case for patient D, where a novel VUS in TP53 was identified. Given the diagnosis of ACC and the positive family history of cancer, this patient meets the Eeles clinical diagnostic criteria for a diagnosis of Li Fraumeni-like syndrome and is being followed with a working diagnosis of LFS.
This study substantiates the recommendation to test all persons diagnosed with ACC for TP53 mutations regard- less of age at diagnosis or strength of the family cancer history. Relying solely on the Chompret criteria, we were able to demonstrate that the prevalence of TP53 muta- tions in this diverse, prospective cohort, 7.5%, was higher than the 3.9% prevalence in a selected cohort of patients enrolled in the German ACC registry, although not sta- tistically different (P = 0.57) (12). This remains consistent even when restricting the age at diagnosis to greater than age 18 (three of 52; 5.8%; P = 0.70) (Table 1). Given the primarily adult population, there were insufficient data to estimate the prevalence in those patients diagnosed under age 18 (Table 1).
The diagnostic and prognostic value of surveillance screening for tumor development in patients with known mutations in TP53 is supported by recent data from Vil- lani et al. (24) who screened 18 of 33 LFS-positive patients with a specific annual screening protocol and identified 10 tumors in seven asymptomatic patients, suggesting a ben- efit in screening individuals with LFS. Masciari et al. (25) screened 15 patients with TP53 mutations or obligate car- rier status and identified cancer in three asymptomatic individuals using F18-fluorodeoxyglucose-positron emis- sion tomography/computed tomography scans. Although demonstrating a potential screening benefit, there are con- cerns about using F18-fluorodeoxyglucose-positron emis- sion tomography/computed tomography scans as a screening modality for individuals with very elevated risks of cancers. The National Comprehensive Cancer Network has also developed a guideline for screening in patients with LFS (26). Continued collaborative work is necessary to develop the appropriate screening regimen for individ- uals with LFS.
The identification of an inherited risk of genetic TP53 mutations in 7.5% of patients with ACC suggests that incorporating genetic counseling and testing into the treat- ment algorithm of all ACC patients can help guide medical
management of these patients and identify at-risk family members. This should be explored further and in conjunc- tion with the development and evolution of LFS cancer- screening protocols.
Acknowledgments
The authors thank Leon Raskin, Ph.D. (Vanderbilt University Department of Medicine) for his contribution to the molecular analysis of the TP53 variant.
Address all correspondence and requests for reprints to: Vic- toria M. Raymond, 300 North Ingalls, Ann Arbor, Michigan 48109-5419. E-mail: vraymond@umich.edu.
This work was supported by National Institutes of Health/ National Cancer Institute Grants P30 CA014089 (to S.B.G.) and P30 CA046592 (to S.B.G.) and National Institutes of Health Grant T32-DK007245 (to T.E.).
Disclosure Summary: The authors have nothing to declare.
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