Extended Cancer Spectrum in Adults With Telomere Biology Disorders: Insights From a 113‐Patient Single‐Center Cohort

To the Editor,

1.

Telomeres are protective structures at the ends of chromosomes that shorten with cell division [1]. This process is counteracted by the enzyme telomerase, which helps to maintain telomere length (TL) and integrity [2]. Telomerase is a focal point of research in the context of cancer, due to the relationship between telomerase reactivation and tumorigenesis [3]. Impaired telomere function—mediated by germline variants in genes encoding the telomerase complex—can lead to a spectrum of conditions, including telomere biology disorders (TBDs), also known as short telomere syndromes, and cancer predisposition with long telomeres (CPLT), also known as long telomere syndromes [4, 5]. Both conditions have been implicated in the development of cancer [5, 6].

In TBD specifically, research has historically highlighted an increased risk for hematologic malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with observed‐to‐expected ratios (O:E) of 73 and 578, respectively [7, 8]. There have also been well‐documented associations with certain solid tumors in dyskeratosis congenita cohorts, including squamous head and neck carcinomas (HNSCC), skin, and anorectal cancer [9, 10]. Recent research has further demonstrated these associations with the wider spectrum of TBDs, highlighting HNSCC, anorectal, and cervical cancers with respective O:E ratios of 54, 10, and 5 [7, 11]. Proposed mechanisms of cancer in TBD include critically short telomeres triggering DNA damage responses (such as early activation of p53), telomere dysfunction driving chromosomal instability and end‐to‐end chromosome fusions with downstream chromosome breakage and nonreciprocal translocations, and impaired immune surveillance [12, 13, 14]. Despite advancements in TBD, clinically important gaps remain in understanding how TL influences nonhematologic cancers, particularly in the adult‐onset TBD population, where cancer risk remains poorly characterized. We present findings from our adult TBD single‐center cohort to further investigate solid cancer frequency and risk. We also provide granular treatment outcome data that characterize the tolerability of cancer‐directed therapies in TBDs and offer a novel, detailed assessment of cancer outcomes in this population.

The observed cohort consisted of adult patients with strict molecular and phenotypic evidence of TBD. Included patients had at least one cardinal TBD‐defining clinical feature (bone marrow failure, interstitial lung disease, and/or hepatic cirrhosis/portosinusoidal vascular disorder) together with lymphocyte TLs ≤ 10th percentile and a TBD‐associated gene variant classified as a variant of uncertain significance, likely pathogenic, or pathogenic (based on ACMG criteria). Patients without a TBD‐associated gene variant were included only if they had very short lymphocyte TLs (< 1st percentile). Cancer occurrences were compared with data from the Surveillance, Epidemiology, and End Results Program (SEER) of the National Cancer Institute (SEER*Stat Version 9.0.43). The SEER*Stat program was employed to calculate age‐adjusted cancer incidence rates as the comparison group. For the purpose of this analysis, the term “solid tumors” included nodal/extranodal hematological neoplasms, such as lymphoproliferative disorders, given the fact that they are most commonly treated with multiagent systemic chemotherapy regimens analogous to those used for other solid cancers.

There were 113 patients (46 females [41%]; median age at last follow‐up 60 [21–79] years) included in the TBD group: 51 out of 111 tested (46%) with lymphocyte TL < 1st percentile and the remainder with TL ≤ 10th percentile. There were 100 patients with a TBD‐associated variant (88.5% of cohort), including variants in TERT [n = 54], RTEL1 [n = 24], TERC [n = 12], PARN [n = 4], NAF1 [n = 3], TINF2 [n = 2], and NHP2 [n = 1] (Table 1).

TABLE 1.

Cohort characteristics.

Cohort characteristics
Characteristic	Total cohort, n (%)	Patients with solid cancer, n (%)	Patients with MDS/AML, n (%)
Individuals	113	38	14
Sex
Male	67 (59)	25 (66)	10 (71.4)
Female	46 (41)	13 (34)	4 (28.6)
Current age in years, median (range)	60 (21–79)	68 (37–77)	56.5 (38–75)
Race	White—102 (90) Asian—4 (3.5) Black—1 (1.0) Other—2 (2.0) Unknown—1 (1.0) Declined—3 (2.5)	White—37 (97.4) Declined—1 (2.6)	White—12 (85.7) Asian—1 (7.1) Black—1 (7.1)
With lymphocyte TL < 1st percentile, n/n with data (%)	51/111 (46)	12/36 (33)	6/14 (42.9)
With granulocyte TL < 1st percentile, n/n with data (%)	63/107 (59)	17/36 (47)	11/13 (84.6)
Affected TBD‐associated genes (% frequency)	With variant: 100 (88.5% of cohort) No variant: 13 (11.5% of cohort) TERT: 54 (54) RTEL1: 24 (24) TERC: 12 (12) PARN: 4 (4) NAF1: 3 (3) TINF2: 2 (2) NHP2: 1 (1)	With variant: 34 (89.5% of group) No variant: 4 (10.5% of group) TERT: 17 (50) RTEL1: 10 (29.4) PARN: 3 (8.8) TERC: 2 (5.9) NAF1: 1 (2.9) TINF2: 1 (2.9)	With variant: 12 (85.7% of group) No variant: 2 (14.3% of group) TERT: 6 (50) RTEL1: 2 (16.7) TERC: 2 (16.7) PARN: 1 (8.3) NAF1: 1 (8.3)

Outcomes
Parameter	Total, n	Patients with solid cancer, n (%)	Patients with MDS/AML, n (%)
Any transplant (HCT, lung, and liver)	Total: 23	Total: 12	Total: 7
	HCT: 6 a	HCT: 1 a	HCT: 4 a
	Lung: 16	Lung: 10	Lung: 4
	Liver: 2	Liver: 2	Liver: 0
Age at first transplant	53.5 (30–73)	61 (45–65)	47 (38–56)
Age at last follow‐up	57	66	54
Deceased at last follow up	27 (23.9)	10 (26.3)	5 (35.7)

Note: Data are presented as n (%) or median (range); percentages are based on available data. TL < 1st percentile is defined relative to age‐adjusted data; TBD‐associated genes include known telomere biology disorder genes, and transplant categories include HCT, lung, and liver (patients may have > 1 transplant).

Abbreviations: AML, acute myeloid leukemia; HCT, hematopoietic cell transplantation; MDS, myelodysplastic syndrome; TBD, telomere biology disorder; TL, telomere length.

^a One patient also had lung transplant.

In this cohort, there were 82 different nonhematologic cancers (63 nonmelanoma skin cancers [NMSC] and 19 other solid cancers) and 17 total hematological cancers (13 MDS and 4 AML). The NMSC type with the highest relative frequency was BCC [n = 30] followed by invasive SCC [n = 25], and SCC in situ [n = 8]. The solid tumor cancer types with the highest relative frequency were HNSCC [n = 3] and breast [n = 3], followed by lung [n = 2], lymphoma [n = 2], liver [n = 1], pancreas [n = 1], gastric [n = 1], bladder [n = 1], cervical [n = 1], other genital (penile) [n = 1], testicular [n = 1], prostate [n = 1], and melanoma [n = 1] (Table 2). Among 113 patients, 38 developed solid or NMSC (13 females [34%]; median age 68 years [range 37–77]). Of these, 16 patients had 19 solid tumors (7 females [43.8%]; median age 69.5 years [range 37–76]), with 18 tumors occurring before organ transplantation (Table S1).

TABLE 2.

Absolute and relative frequencies of all cancer types in TBD cohort.

	Cancer type	All (n)	%	1%–10% percentile TL (n)	%	< 1% percentile TL (n)	%
Solid tumors	Total solid	19	100	14	100	5	100
	Head and neck	3	15.8	3	21.4	—	—
	Breast	3	15.8	3	21.4	—	—
	Lung	2	10.5	1	7.1	1	20
	Lymphoma	2	10.5	2	14.3	—	—
	Liver	1	5.3	—	—	1	20
	Pancreas	1	5.3	—	—	1	20
	Gastric	1	5.3	1	7.1	—	—
	Bladder	1	5.3	—	—	1	20
	Cervical	1	5.3	1	7.1	—	—
	Other genital organ	1	5.3	1	7.1
	Testicular	1	5.3	—	—	1	20
	Prostate	1	5.3	1	7.1	—	—
	Melanoma	1	5.3	1	7.1	—	—
Nonmelanoma skin cancers	Total nonmelanoma skin cancer	63	100	38	100	22	100
	Basal cell carcinoma	30	47.6	16	42.1	12	54.5
	Squamous cell carcinoma, invasive	25	39.7	15	39.5	10	45.5
	Squamous cell carcinoma in situ	8	12.7	7	18.4	—	—
AML/MDS	Total	17	100	10	100	7	100
	MDS	13	86.5	8	80	5	71.4
	AML	4	23.5	2	20	2	28.6

Note: Counts represent cancer occurrences (not individuals) and are presented as n (%), stratified by telomere length (TL) categories (1–10th percentile and < 1st percentile) relative to age‐adjusted norms.

Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; TBD, telomere biology disorder; TL, telomere length.

Using cohort‐matched SEER data, O:E ratios were calculated and age‐adjusted using total person‐years (PY) and cancer‐specific rates (Table 3). The total PY for the cohort from birth (lifetime risk) was 6205. PY was also calculated for first incident cancer after cohort entry (after TBD diagnosis) and was found to be 348. NMSC were excluded due to lack of SEER reporting. Patients with TBD had increased overall cancer incidence at all sites (solid plus hematologic) (O:E 1.72, 95% CI 1.09–2.58, p = 0.021), with a trend toward increased solid tumor incidence (O:E 1.61, 95% CI 0.97–2.51, p = 0.067). When restricted to first incident cancers after cohort entry (time of TBD diagnosis) to address left truncation bias, solid tumor risk remained elevated (O:E 2.67), though not statistically significant (p = 0.06) due to small sample size. There was also significance noted in HNSCC (O:E 7.84, 95% CI 1.62–22.92, p = 0.014) and AML (O:E 39.4, 95% CI 10.7–100.8, p < 0.00001). MDS was categorized differently from the solid cancers and AML, so the analysis was done with a separate SEER comparison group (Site recode ICD‐O‐3 2023 Revision Expanded). TBD patients had significantly increased risk for MDS compared with the general population (O:E 346, 95% CI 184–592, p < 0.00001). Of note, 3 out of the 13 TBD patients with MDS underwent an allogeneic stem cell transplant, one of whom is alive and in ongoing remission after 13 years and two that are deceased after relapse of MDS with leukemic transformation less than 6 months after transplant.

TABLE 3.

Observed over expected ratios for primary solid tumor cancers (events) comparing TBD cohort to NCI SEER data.

	Cancer type or location	Observed	Expected	O:E	CI lower	CI upper	p
Any cancer (lifetime)	All sites (excluding nonmelanoma skin)	23	13.36	1.72	1.09	2.58	0.021
	All solid tumors	19	11.79	1.61	0.97	2.51	0.067
	Oral cavity and pharynx	3	0.38	7.84	1.62	22.92	0.014
	Digestive system	3	2.14	1.40	0.29	4.10	0.72
	Lung	2	1.33	1.50	0.18	5.42	0.72
	Breast	3	2.37	1.27	0.26	3.71	0.84
	Cervical	1	0.21	4.84	0.12	26.95	0.38
	Male genital system (all)	3	1.79	1.67	0.35	4.89	0.51
	Melanoma	1	0.72	1.38	0.04	7.71	1.00
	Bladder a	1	0.41	2.44	0.06	13.62	0.67
	Lymphoma	2	0.71	2.82	0.34	10.17	0.30
	AML	4	0.10	39.4	10.7	100.8	< 0.00001
	MDS b	13	0.04	346	184	592	< 0.00001
First incident cancer after cohort entry or TBD diagnosis	All solid tumors	5	1.87	2.67	0.87	6.23	0.06
	Oral cavity and pharynx	1	0.07	14.48	0.37	80.69	0.11
	Digestive system	2	0.51	3.96	0.48	14.31	0.17
	Lung	1	0.26	3.84	0.10	21.41	0.28
	Bladder a	1	0.11	9.12	0.23	50.80	0.21

Note: Total person‐years (PY) for total cohort (lifetime risk) 6205. Total PY for first incident cancer after cohort entry 348.

Abbreviations: AML, acute myeloid leukemia; CI, confidence interval; HCT, hematopoietic cell transplantation; MDS, myelodysplastic syndrome; NCI, National Cancer Institute; O:E, observed‐to‐expected ratio; PY, person‐years; SEER, Surveillance, Epidemiology, and End Results; TBD, telomere biology disorder.

^a Only primary cancer to occur AFTER any transplant (HCT, lung, and liver).

^b Not reported in SIR data, so a separate age‐adjusted control group was used.

NMSC was the most common malignancy burden in the cohort, with 63 total NMSC events in 26 individuals. A substantial proportion of these patients experienced recurrence of NMSC, regardless of prior transplant history (10 of 26 individuals had previously undergone transplant).

From an outcomes perspective, among the 16 patients with TBD who developed solid tumors (excluding NMSC), surgical resection was the most frequently utilized treatment modality and was often associated with durable disease control, particularly in localized solid tumors. In contrast, systemic therapy commonly required dose modification or early discontinuation; five patients required dose reductions and two were unable to complete therapy due to hematological toxicity. Severe treatment‐related cytopenias (CTCAE Grade ≥ 3) were frequent, including Grade 3/4 neutropenia [n = 5], Grade 3/4 thrombocytopenia [n = 5], Grade 3 anemia [n = 3], and pancytopenia [n = 3], with febrile neutropenia observed in multiple cases [n = 2]. Radiation therapy was feasible but associated with significant complications in some patients, including mandibular osteoradionecrosis [n = 1], fibrosis (muscles of mastication, neck soft tissue, salivary glands) [n = 2], trismus [n = 1], xerostomia [n = 1], mucositis [n = 3], and vocal cord paralysis [n = 1]. Despite these treatment‐related toxicities, several patients achieved prolonged progression‐free (median 84 months, range 4–336 months) and overall survival (median 96 months, range 6–336 months) following curative‐intent local therapy, mainly in surgically treated cancers (breast, cervical, testicular, prostate, early head & neck), with several remissions > 10 years and a longest disease‐free survival of 28 years. All outcomes data can be found in Tables S2 and S3.

Our findings highlight the increased vulnerability of patients with TBD to a spectrum of cancers. Consistent with prior reports, we observed an elevated risk of solid cancers compared with the general population [11]. There was a predominance of HNSCC, reflected by elevated frequency and overall risk. We also noted a high frequency of cutaneous cancers (in patients with and without a transplant history). This may further strengthen the case for routine otolaryngologic and dermatologic screening and surveillance in TBD care pathways.

When stratified by TL, we observed that shorter telomeres (< 1%) appeared to be enriched for more severe visceral cancers (i.e., liver, pancreas, testicular, lung, and bladder) as well as AML/MDS (AML proportion increases in very short telomere group). HNSCC tended to cluster in the 1–10th percentile TL group. These observations taken together with similar published cohorts could imply more aggressive phenotype or a different overall cancer risk depending on telomere attrition severity [4, 15, 16, 17]. Interestingly, we identified a lack of colon and prostate cancers, known to be frequent in the general population (0 colon cancer cases, 1 prostate case [O:E 0.62, 95% CI 0.02–3.48, p = 0.72]) [18].

Notably, our cohort specifically focuses on cancer risk in patients with adult‐onset TBD, an important distinction from much of the existing literature which historically is largely derived from pediatric TBD or dyskeratosis congenita cohorts. In contrast, adult‐onset TBD encompasses a different spectrum of clinical manifestations (isolated pulmonary fibrosis, subtle mucocutaneous signs, etc.), frequently diagnosed after organ failure (lung, liver, and bone marrow), and often driven by heterozygous variants in TERT, RTEL1, and TERC with variable or incomplete penetrance as seen in our cohort [19]. Adult TBD patients have different phenotypic and genotypic landscapes, complicating disease recognition. This underscores the importance of maintaining a high index of suspicion in relevant clinical contexts.

Finally, our cohort provides detailed outcome data that suggests that standard oncologic treatments are feasible but associated with substantial hematologic and treatment‐related toxicities. We observed that (1) there was a marked intolerance to systemic chemotherapy, and multiple patients had CTCAE Grade 3–4 cytopenias [n = 6, 37.5%] and required treatment dose reductions/modifications [n = 5, 31%]; (2) resection‐based management frequently resulted in long‐term cancer control, particularly for early‐stage solid tumors; (3) and there were multiple chronic toxicities related to radiation therapy [total n = 3, 19%]. Specifically, the cohort received a range of standard chemotherapy regimens, including R‐CHOP, FOLFIRINOX, FOLFOX, and platinum–taxane‐based therapy, with both curative and palliative intent (Table S3). Dose modifications and treatment delays occurred particularly in the palliative setting and were primarily driven by hematologic toxicity. CTCAE Grade ≥ 3 events often required supportive interventions such as transfusions and growth factor support. In several cases, severe toxicity led to treatment discontinuation or inability to proceed to subsequent therapy. These observations underscore the vulnerability of TBD patients to myelosuppressive chemotherapy, prompting consideration of dose adjustments, frequent blood count monitoring, and consideration of surgical solutions when appropriate.

We recognize several limitations. This single‐institution TBD cohort is limited in size and diversity, which may affect statistical power. However, it allowed detailed, granular characterization of solid malignancies at the individual patient level. We also do not currently have full somatic mutation data for each patient, which would further help characterize cancer in TBD by genotype and be an important area of future study.

Our data reinforce that cancer risk in TBD extends beyond hematologic malignancy to multiple organ domains, with enrichment in mucosal squamous tumors (including skin, cervical, penile, and HNSCC). While prior work has emphasized hematologic ties, further investigation is necessary to understand the solid cancers that disproportionately affect this population, especially in adult‐onset TBDs. These insights may inform clinical management strategies and refine cancer screening guidelines for TBD patients.

The Supporting Information includes detailed clinical data for patients included in our study. Table S1 summarizes patient demographics, cancer types, ages at diagnosis, and follow‐up. Table S2 provides individual‐level cancer treatment characteristics, treatment‐related toxicities, complications, responses, and survival outcomes. Table S3 presents detailed chemotherapy treatment information, including regimens, dosing modifications, treatment delays, toxicities, supportive care measures, and reasons for treatment modification or discontinuation.

Author Contributions

M.A.F. analyzed the data, wrote, and edited the paper. T.L.L., C.M.F., R.A.S., J.A.F., L.J.O., K.B.M., E.M.C., D.A.S., and A.A.M. all contributed to the design of the research study and data collection. M.M.P. and A.F. designed the study, contributed to the data collection, analyzed the data, wrote, and edited the paper.

Funding

The authors have nothing to report.

Ethics Statement

This study was approved by the Institutional Review Board and conducted in accordance with applicable ethical standards.

Consent

Written informed consent was obtained from all participants, as applicable.

Conflicts of Interest

M.M.P. has received research funding from Kura Oncology, Stemline pharmaceuticals, Polaris, Epigenetix, and Solu Therapeutics. He has served on the advisory board for AstraZeneca, GSK, and CITI/SOBI. A.A.M. has received research funding to the institution from BMS, Solu Therapeutics, Gilead, Medexus, and Novartis. The other authors declare no conflicts of interest.

Supporting information

Table S1: Patients with solid tumors in the TBD cohort.

Table S2: Cancer treatment characteristics and outcomes in patients with solid tumors.

Table S3: Chemotherapy treatment and outcomes.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.