Cancer in dyskeratosis congenita

Literature review

The medical literature was searched for articles describing cases of DC, using Medline and Web of Science, using the search term “dyskeratosis congenita,” and supplemented after review of the bibliographies of each publication. Cases were also identified in articles from the same sources related to other inherited bone marrow failure syndromes or to aplastic anemia. All languages were included, either read in the original languages by one of the authors or after translation. These cumulative searches have been ongoing by one of the authors (B.P.A.) for more than 30 years. Cases were accepted if the reports provided sufficient phenotypic features for DC to be a likely diagnosis, and/or the cases had mutations in any of the genes that have been associated with DC.^2,8 The subset of Hoyeraal-Hreidarsson syndrome was restricted to those with DC who had cerebellar hypoplasia, and the subset of Revesz syndrome to those with DC and exudative retinopathy. Cases of cancer as defined by the original authors were accepted without verification. Cases of MDS were not included as “cancer” but analyzed separately. Duplicate case reports were identified as much as possible by matching of descriptions in the publications or by prior citations. Where appropriate, all publications of a case are cited, unless the most recent clearly refers to earlier publications of that case. Data for cancer or MDS incidence in the general population came from the United States Cancer Registry Surveillance, Epidemiology and End Results (SEER) database.⁹ Because there was no risk to human subjects, this literature review was not explicitly approved by an institutional review board.

NCI IBMFS DC cohort

The NCI IBMFS cohort was established in 2002. This analysis includes all patients with DC enrolled through 2007 and followed up through 2008. The NCI DC cohort currently consists of 50 patients in 31 families. Diagnoses of DC were made in living participants by examination of medical records, clinical evaluation, documentation of very short telomeres,¹⁰ and/or identification of pathogenic mutations in DC genes where available.² Clinical features which we required to diagnose DC were modified from those of Vulliamy et al⁸ and included any of the diagnostic triad (dysplastic nails, lacy reticular pigmentation, and oral leukoplakia) and/or other characteristic physical findings, with or without hematologic manifestations. Mutations in genes in the telomere biology pathway were documented in 75% of the patients in the NCI DC cohort and included DKC1, TERC, TERT, and TINF2.^11,12 Deceased family members had DC diagnosed based on review of medical records, photographs, and pedigrees. Diagnoses of cancer or MDS were verified through the review of medical records. Follow-up time was from birth, and the analysis was both prospective and retrospective. This part of the study was approved by the Institutional Review Board of the NCI.

Statistics

Information for individual literature cases was initially entered into Lotus 1-2-3 Release 5 (IBM, Armonk, NY) spreadsheets, and then transferred and updated in Microsoft Excel 11.0 (Microsoft, Redmond, WA) spreadsheets. Data included demographics, physical manifestations of DC, age at onset of cancer or MDS, type of cancer, age at death, age at bone marrow transplant, and last age alive. Overall actuarial survival probabilities were calculated using the Kaplan-Meier product limit estimator.¹³ This approach provides estimates of hypothetical probabilities and incidences as if there were no competing risks. Median values and 95% confidence intervals for survivals were estimated using a spline-smoothed estimator of the actuarial curve and bootstrap resampling.¹⁴ The cumulative incidence of development of cancer in the literature cases was calculated as the complement of the Kaplan-Meier product limit estimator (the “1-KM” estimator).¹³ Cases were censored if the patients died or follow-up ended before the development of cancer. The outcomes of interest were solid tumors, AML, MDS, and severe bone marrow failure resulting in BMT or death.

Records for subjects in the NCI DC cohort were accumulated and maintained by Westat (Rockville, MD). In preparation for analysis, the data were cleaned and merged from several source files, and delivered to the NCI in an Excel spreadsheet. The information in the database was similar to that outlined above for the literature cases, with the addition of more details with regard to phenotype, mutated gene, where available, and telomere length. The observed number of cancers was compared with the expected number in the general population (O/E ratio) based on SEER, after adjustment for age, sex, race, and birth cohort.⁹

All statistical tests were 2-sided. P values less than or equal to .05 were considered statistically significant. Sex ratios were compared using the Fisher exact test. Statistics were analyzed using Microsoft Excel, Stata10 (StataCorp, College Station, TX),¹⁵ or MATLAB 20086 software (The MathWorks, Natick, MA).¹⁶

Literature review

A search of Medline in October 2008, using the terms “dyskeratosis + congenita” and restricted to human studies, resulted in 433 citations; addition of “cancer” narrowed it to 161 citations. However, many of those articles were reviews or general discussions and did not include specific cases. In contrast, cumulative records of literature reports maintained by one author (B.P.A.) over 30 years led to the synthesis of 278 reports of 552 cases contributing 10 806 person-years with sufficient information for this analysis (Table 1). Of the 552 patients, 52 had 61 cancers, for a crude rate of 9.4% of reported cases, similar to the crude rate reported by the group in the United Kingdom.⁶

The male:female ratio of all reported cases was 3.1:1; it was 4.2:1 for the cases with cancer (P = .5). The male excess may be biased by the original impression that DC was primarily an X-linked recessive disease, until the genetic proof of autosomal dominant inheritance in 2001.¹⁷ Cases reported through 2000 had a male:female ratio of 3.9:1, while the ratio from 2001 to 2008 was less, at 2.4:1 (P = .001). There was no difference in the male:female ratio of those with cancer compared with those without cancer.

The median age at which cancer was diagnosed was 29 years. The crude death rate in the literature cases was 58% for those who had cancer. The median age at death was higher in the cases with cancer versus those without cancer (29 compared with 17 years), suggesting either biased reporting of such outcomes, or escape from development of earlier fatal complications such as aplastic anemia. The median survival of the entire group, by Kaplan-Meier analysis (which takes into account the survivors as well as the deceased), was 42 years overall (Figure 1A); it was 39 years in those with and 46 in those without cancer (Figure 1A inset), but these ages are not significantly different because of the wide confidence intervals.

Sixty solid tumors were reported in 51 cases; in addition, one patient had AML (Tables 2–4). There were 24 head and neck SCCs (HNSCCs) in 22 patients. The next most frequent cancers were 8 patients with skin SCCs, followed by 6 with anorectal cancer, 4 each with stomach (2 gastric adenocarcinoma and 2 not specified) and lung cancer (2 bronchial, one lung adenocarcinoma, and one not specified), and 3 each with esophageal SCC and Hodgkin disease. Two reports were of colon cancer (one adenocarcinoma, one not specified), 2 pancreatic adenomas, and one each liver adenomas (no mention regarding androgen treatment), retinoblastoma, cervical SCC, and non-Hodgkin lymphoma. The ages of the patients at the time of diagnosis of all of the cancers except the lung and retinoblastoma were substantially younger than the ages expected for sporadic cancers, whether it was the first, second, or third cancer in the patients with DC.

A single cancer was reported after BMT: rectal adenocarcinoma 14 months after transplantation for aplastic anemia, when the patient was 34 years old. Like patients with FA, most of the patients with DC who had multiple tumors had at least one HNSCC.³ Five of the 6 patients with multiple cancers were male, and all of their tumors occurred at 28 to 52 years of age, younger than expected from the general population. Only one case of AML was reported (at age 29 years), as well as 8 cases with various types of MDS (Table 4). These diagnoses were also primarily in adults who were younger than expected in the general population. The reports did not mention evolution to AML in these 8 cases of MDS.

The actuarial risk of cancer (absent any competing risks) was approximately 40% by age 50, and more than 60% by age 68 (Figure 2A); this is slightly lower than the actuarial risk (> 75%) of solid tumors in FA patients by age 45.³ The actuarial risk of MDS in the patients with DC reached a plateau of 3% at 29 years of age (Figure 3A).

Sixty-five patients were reported to have undergone BMT, with several apparent survival plateaus: 64% at 730 days, 35% at 2920 days, 24% at 4015 days; the last death was at 7300 days from pulmonary fibrosis (Figure 4A). These findings might be related to small numbers, heterogeneity of patients, and/or follow-up from periods with different transplantation protocols. Nine of the 30 deaths post-BMT were due to pulmonary fibrosis. Thirty-four patients with sibling donors had an apparent early plateau of 71% survival from day 183 to > 2000, but the last death at 7300 days was in this group. The 18 with alternative donors had a later plateau of 31% at 730 days, but the last patient died at 2920 days, also from pulmonary fibrosis (Figure 4A inset). Although the sibling donor group had a statistically significant longer survival than the alternative donor group (P = .04), the long-term outcome in cases reported in the literature was poor, albeit these involved earlier and now abandoned BMT preparative regimens.⁶³

NCI IBMFS DC cohort

There were 50 patients in 31 families enrolled in the NCI IBMFS DC cohort, contributing 1179 person-years (Tables 5,6), approximately one-tenth the cases and person-years provided by the cases in the literature. At the close of the analytic period, the ages for the NCI cohort ranged from 6 to 52 years (median 18 years) for those alive, and 1 to 63 years (median 29 years) for those who had died before or during the study. The male:female ratio for the total group was 2.8:1, similar to the ratio in the literature cases (P = .7). Cancers were reported in 7 patients (14%), similar to the crude rate of 9%-10% in the literature (P = .3). The median age for cancer was 37 years (range 25-44 years), slightly older than the median of 29 years in the literature cases, but this difference was not statistically significant because of the small numbers of patients (P = .3).

Eleven patients underwent BMT, 10 for severe aplastic anemia and one for AML that developed 5 years after MDS. Two of those who received transplants for aplastic anemia did not have the diagnosis of DC at the time of the transplantation. None of the 4 who survived transplantation has developed cancer to date, but the follow-up intervals have been short, 11 months to 9 years. The patient who survived 9 years developed significant pulmonary fibrosis 8 years after BMT. Seven patients died from severe bone marrow failure and did not undergo BMT. Five patients had MDS: one with only MDS; one who developed AML and died after BMT; one whose MDS ensued 13 years after cervical cancer; one whose MDS was followed 10 years later by tongue SCC; and one with a face basal cell carcinoma 10 years after MDS but within 1 year of BMT. Twenty-six patients (52%) had no hematologic or malignant complication. The Kaplan-Meier median survival age was 42 years (Figure 1B), the same as in the literature reports (Figure 1A). The median survival was also the same for those with or without cancer (Figure 1B inset).

Seven cases of cancer (5 solid tumors and 2 AML, not including one basal cell carcinoma, which is not tracked by SEER) were observed, compared with 0.6 expected, for an O/E ratio of 11 (95% CI, 4-23; Table 6). All solid tumors were also significantly increased (O/E = 8; 95% CI, 2-20). Large and statistically significant increases were observed for tongue, the only type of HNSCC reported (O/E = 1 154; 95% CI, 232-3372) and AML (O/E = 195; 95% CI, 22-707). Single cases of cervical SCC and non-Hodgkin lymphoma were in excess, but were not statistically significant. The cumulative incidence of cancer was 53% by 44 years of age in the NCI DC cohort (Figure 2B), similar to 38% by 50 years of age and 65% by 68 years of age in the literature cases (Figure 2A).

SEER has been tracking MDS in the general population since 2001. The O/E ratio for this hematologic complication in the NCI DC cohort was 2663 (95% CI, 858-6 215). This extremely high risk, based on only 5 cases, reflects the young age at which MDS occurred in patients with DC: median 35 years (range, 19-61 years) compared with the median age of 70 years in sporadic cases. In fact, MDS was the most frequent complication and had the highest relative risk in our cohort. However, because MDS does not always develop into leukemia, we did not count MDS as a malignancy. One of our patients did have MDS at age 39, and AML at age 44; the AML was included in the cancer tabulation. The cumulative incidence of MDS reached a plateau of 33% by 39 years of age, but the last case occurred at 60 years of age (Figure 3B). Although the plateau age was similar in the literature and the NCI DC cohorts, the cumulative incidence was much higher in the NCI cohort (33% vs 3%). This is the only parameter where the NCI cohort had a higher result than the literature cases, perhaps associated with a referral bias in the NCI cohort, or underreporting in the literature.

A preliminary examination of the correlation of genotype with outcome identified one DKC1 patient with AML and one with MDS; 4 TERC patients with MDS, plus cervical SCC, tongue SCC, and progression to AML in each of 3; one TINF2 patient with diffuse small cell noncleaved lymphoma, and 2 tongue SCCs in patients in whom the gene has not yet been identified. Thus 50% of the 8 patients with mutations in TERC had solid tumors, MDS, or AML, compared with 3 of the 39 with other or unknown mutated genes. Although this is highly statistically significant (P = .009), the numbers are too small to draw a strong conclusion.

Four of the 11 transplanted patients survived, with a 1-year survival probability plateau of 36% at 271 days, lower than the survival in the literature cases at that time point (> 60%), but the numbers are small (Figure 4B). Similar to the cases in the literature, the 3 whose donors were siblings appear to have done better than the 8 with alternative donors, but the numbers are very small (Figure 4B inset), and the difference between sibling and alternative donors in the NCI cohort is not significant (P = .3).