Myelodysplastic Syndrome and Gastrointestinal Carcinomas Characterize the Cancer Risk in Diamond Blackfan Anemia: A Report from the Diamond Blackfan Anemia Registry

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterized by red cell aplasia and congenital anomalies. In our 2012 report the predisposition to cancer was quantified for the first time by the DBA Registry of North America (DBAR), the largest established DBA patient cohort with prospective follow-up since 1991. Five years from the original analysis, this update of the cancer incidence in patients with DBA reveals additional solid tumors, in particular gastrointestinal tumors, and an alarming incidence of myelodysplastic syndrome (MDS).

In this study we report the types, ages, outcomes and hazard rates in DBA patients with neoplasia enrolled in the DBAR. The patients/families and their physicians completed a detailed questionnaire. Information was verified through medical records and telephone interviews. The ratio of observed to expected (O/E) cancers was computed using SEER data, and the cumulative incidence and hazard rate of hematopoietic stem cell transplant (HSCT), acute myeloid leukemia (AML), solid tumors (ST), and MDS by age were calculated.

There were 702 patients with 12,376 person-years of follow-up. Twenty-three had solid tumors, 3 had acute myeloid leukemia (AML), and 8 had MDS. The median age at diagnosis of a solid tumor for the patients who had not received a bone marrow transplant was 35 years (range, 11-63). There were 9 gastrointestinal carcinomas (7 colon, 1 gastroesophageal, and 1 esophageal), 4 osteogenic sarcoma, 2 breast cancer and 2 squamous cell carcinomas (vaginal and oral) and 9 others, with 3 patients having more than one cancer. Cancer incidence in DBA was significantly elevated with an observed-to-expected (O/E) ratio for all cancers combined of 4.75, (95% confidence interval 3.15-6.86); significant O/E ratios were 352 for MDS, 45 for colon carcinoma, excluding rectum, 42 for osteogenic sarcoma, and 29 for AML. Although the sample size is small it appears that the cancer risk by genotype correlates only with the relative incidence of that genotype in the DBAR cohort (RPS19, 7; RPL11, 2; RPL5, 2; RPL35a, 3; and RPS17, 1). By their mid-40s, 24% had received a HSCT, 23% had died, 2% had AML, and 12% had developed a ST; 61% had died or experienced a serious adverse event. The median overall survival was 51 years and the actuarial risk of MDS in the absence of any competing risks was 50% by age 30 years.

Cancer risks in DBA appear to have reached those seen in dyskeratosis congenita (DC) and are still lower than in Fanconi anemia (FA). Furthermore, the type of solid tumors in DBA (gastrointestinal carcinoma and osteogenic sarcoma) vs. FA (head and neck squamous cell carcinoma) are quite different suggesting different mechanisms of carcinogenesis from nucleolar stress vs. genomic instability. Importantly the risk of MDS in DBA is elevated, as it is in FA and DC. This report also confirms the observation that there was no specific association of cancer type or frequency with genotype.