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Risk of cancer in heterozygous relatives of patients with Fanconi anemia

Open ArchivePublished:November 30, 2021DOI:https://doi.org/10.1016/j.gim.2021.08.013

      Abstract

      Purpose

      Fanconi anemia (FA) is a cancer-prone inherited bone marrow failure syndrome caused by biallelic pathogenic variants in one of >22 genes in the FA/BRCA DNA repair pathway. A major concern is whether the risk of cancer is increased in individuals with a single pathogenic FA gene variant.

      Methods

      We evaluated the risk of cancer in the relatives of patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome cohort. We genotyped all available relatives and determined the rates, types of cancer and the age of patients at cancer diagnosis. We calculated the observed-to-expected (O/E) cancer ratios using data from the Surveillance, Epidemiology, and End Results Program adjusted for age, sex, and birth cohort.

      Results

      The risk of cancer was not increased among all FA relatives and FA heterozygotes (O/E ratios of 0.78 and 0.79, respectively). In particular, the risk of cancer was not increased among FANCA or FANCC heterozygotes (O/E ratios of 0.92 and 0.71, respectively). Relatives did not have typical FA cancers, and age at cancer diagnosis was not younger than expected.

      Conclusion

      Understanding the risk of cancer in individuals with single pathogenic FA variants is critical for counseling and management. We did not find increased risk of cancer in these individuals. These findings do not extend to the known cancer predisposition autosomal dominant FA genes, namely BRCA1, BRCA2, PALB2, BRIP1, and RAD51C.

      Keywords

      Introduction

      Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) and cancer predisposition syndrome
      • Wegman-Ostrosky T.
      • Savage S.A.
      The genomics of inherited bone marrow failure: from mechanism to the clinic.
      caused by biallelic pathogenic variants in 1 of > 22 genes involved in DNA intrastrand crosslink repair.
      • Nalepa G.
      • Clapp D.W.
      Fanconi anaemia and cancer: an intricate relationship.
      FANCB is X-linked recessive, and FANCR (RAD51) is autosomal dominant. The diagnosis of FA is confirmed by increased chromosome breakage in peripheral blood T-cells or skin fibroblasts cultured with DNA-crosslinking agents
      • Alter B.P.
      • Giri N.
      • Savage S.A.
      • et al.
      Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study.
      and/or through genetic testing.
      • Fargo J.H.
      • Rochowski A.
      • Giri N.
      • Savage S.A.
      • Olson S.B.
      • Alter B.P.
      Comparison of chromosome breakage in non-mosaic and mosaic patients with fanconi anemia, relatives, and patients with other inherited bone marrow failure syndromes.
      Many patients with FA are diagnosed in early childhood owing to bone marrow failure and congenital anomalies; however, some are diagnosed in adulthood owing to the development of specific cancers.
      • Wegman-Ostrosky T.
      • Savage S.A.
      The genomics of inherited bone marrow failure: from mechanism to the clinic.
      ,
      • Alter B.P.
      • Giri N.
      • Savage S.A.
      • Rosenberg P.S.
      Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up.
      Patients with FA are at a particularly high risk of developing acute myeloid leukemia (AML), and head and neck and anogenital squamous cell carcinomas.
      • Alter B.P.
      • Giri N.
      • Savage S.A.
      • Rosenberg P.S.
      Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up.
      These cancers often arise in the first 3 decades in patients with FA, much earlier than in the general population.
      Of all FA genes, 5 (FANCD1 [BRCA2], FANCJ [BRIP1], FANCN [PALB2], FANCO [RAD51C], and FANCS [BRCA1]) are also cancer predisposition genes when inherited in a monoallelic autosomal dominant manner.
      • Yadav S.
      • Couch F.J.
      Germline genetic testing for breast cancer risk: the past, present, and future.
      ,
      • Alter B.P.
      • Best A.F.
      Frequency of heterozygous germline pathogenic variants in genes for fanconi anemia in patients with non-BRCA1/BRCA2 breast cancer: a meta-analysis.
      Autosomal recessive inheritance of these genes is associated with rarer forms of FA that constitute only a small percentage of cases reported in the literature.
      • Fiesco-Roa M.O.
      • Giri N.
      • McReynolds L.J.
      • Best A.F.
      • Alter B.P.
      Genotype-phenotype associations in fanconi anemia: a literature review.
      Biallelic pathogenic variants in FANCD1 (BRCA2) and FANCN (PALB2) predispose these patients with FA to embryonic cancers (Wilms tumor, neuroblastoma, brain tumors) which are not seen in other patients with FA.
      • Alter B.P.
      • Rosenberg P.S.
      • Brody L.C.
      Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.
      In 1971, a study of 8 families raised a possibility that the relatives of patients with FA could be at an increased risk of cancer.
      • Swift M.
      Fanconi’s anaemia in the genetics of neoplasia.
      A subsequent study in 1980 that included 25 families failed to identify increased risk of cancer.
      • Swift M.
      • Caldwell R.J.
      • Chase C.
      Reassessment of cancer predisposition of fanconi anemia heterozygotes.
      This was validated by Potter et al
      • Potter N.U.
      • Sarmousakis C.
      • Li F.P.
      Cancer in relatives of patients with aplastic anemia.
      in a study of 125 FA relatives in 1983. These studies were performed before the cloning of the first FA gene FANCC in 1992 and therefore were not informed by confirmed heterozygote status.
      • Strathdee C.A.
      • Duncan A.M.
      • Buchwald M.
      Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9.
      Later, larger studies conducted in FA relatives with Ashkenazi Jewish heritage neither showed an increased risk of cancer in all relatives
      • Baris H.N.
      • Kedar I.
      • Halpern G.J.
      • et al.
      Prevalence of breast and colorectal cancer in Ashkenazi Jewish carriers of fanconi anemia and Bloom syndrome.
      nor in confirmed FANCC heterozygotes (standardized incidence ratio [SIR], 0.026; confidence interval [CI], 0.004-0.084).
      • Laitman Y.
      • Boker-Keinan L.
      • Berkenstadt M.
      • et al.
      The risk for developing cancer in Israeli ATM, BLM, and FANCC heterozygous mutation carriers.
      Another cohort study of 940 FA relatives, many of whom were genotyped, also did not show an elevated risk of cancer.
      • Berwick M.
      • Satagopan J.M.
      • Ben-Porat L.
      • et al.
      Genetic heterogeneity among fanconi anemia heterozygotes and risk of cancer.
      However, they did show increased rates of breast cancer in FANCC heterozygote grandmothers (6/33 relatives: SIR, 2.4; CI, 1.1-5.2).
      • Berwick M.
      • Satagopan J.M.
      • Ben-Porat L.
      • et al.
      Genetic heterogeneity among fanconi anemia heterozygotes and risk of cancer.
      Tischkowitz et al
      • Tischkowitz M.
      • Easton D.F.
      • Ball J.
      • Hodgson S.V.
      • Mathew C.G.
      Cancer incidence in relatives of British Fanconi anaemia patients.
      investigated the incidence of cancer in the relatives of British patients with FA and found no increased risk of cancer (SIR, 0.97; CI, 0.71-1.23).
      The quantification of cancer risk is important for the counseling and surveillance of individuals with a single pathogenic FA gene variant who are members of families known to have FA. This finding can be extended to the general population in whom germline FA variants are frequently identified through the ever-increasing use of genetic testing.
      • Alter B.P.
      • Best A.F.
      Frequency of heterozygous germline pathogenic variants in genes for fanconi anemia in patients with non-BRCA1/BRCA2 breast cancer: a meta-analysis.
      ,
      • Kamps R.
      • Brandão R.D.
      • Bosch B.J.
      • et al.
      Next-generation sequencing in oncology: genetic diagnosis, risk prediction and cancer classification.

      Materials and Methods

      National Cancer Institute IBMFS cohort

      The study included 151 families enrolled in the National Cancer Institute’s Institutional Review Board approved longitudinal retrospective/prospective natural history IBMFS cohort study between 2002 and September 30, 2018. (Clinical Trials Identifier: NCT00027274). Patients with cancer and their unaffected relatives completed family and medical history questionnaires and provided medical records and biospecimens. Relatives included parents, grandparents, siblings, and offspring, regardless of cancer history. The collected data included details regarding cancer diagnoses, age at death or last follow up, and genetic testing. Saliva and/or whole blood was collected for genotyping.

      Pedigree review

      The pathogenic FA variants (single-nucleotide variants, insertions, or deletions) of each allele of the index case were identified through medical record review or sequencing performed as part of the study. All variants were classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines.
      • Richards S.
      • Aziz N.
      • Bale S.
      • et al.
      Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
      The pedigree of each family was reviewed to determine the allele inheritance, obligate heterozygote status, and requirement for additional genotyping. A causative gene was not identified in some families, which were classified as gene-unknown; all index cases in these families had a positive chromosome breakage study.

      Genotyping

      Targeted panel next-generation sequencing or long-read sequencing was performed on germline DNA extracted from whole blood or saliva to genotype the relatives. Details regarding genotyping are provided in the Supplemental Methods.

      Statistical analysis

      The ratio of observed-to-expected (O/E) cancers was derived from the incidence data of general population from the Surveillance, Epidemiology, and End Results (SEER) Program (SEER 9 Registry; https://seer.cancer.gov), and data were adjusted for age, sex, race, and birth cohort.
      • Alter B.P.
      • Giri N.
      • Savage S.A.
      • Rosenberg P.S.
      Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up.
      The dates of birth and death were imputed for unknown data based on index cases and parental information. Each cancer was counted separately among relatives with multiple cancers.

      Results

      The 151 families in this study included 185 patients with FA and 1038 relatives comprising 61,058 person-years (Table 1). We identified 396 heterozygous relatives who contributed to 20,770 person-years. The median age of relatives was 63 years. Grandparents were the largest group of relatives (n = 564) with a median age of 74 years (Table 1). The cohort included families with 12 of the 22 known FA genes (Supplemental Table 1). A total of 35 families were designated as gene-unknown (see Materials and Methods). The largest number of relatives was 473 in 68 FANCA families with 177 known heterozygotes. There were 120 relatives in 16 FANCC families, including 58 known heterozygotes (Supplemental Table 1).
      Table 1Participants: Ages and person-years
      Participant GroupNo.Person-YearsMedian Age, y (Range)
      Total relatives
      Includes grandparents, parents, siblings, and offspring.
      103861,05863.1 (0.29-107)
      Grandparents56440,72574.1 (19.8-107)
      Parents28515,37351.9 (23.8-96.3)
      Siblings170457022.3 (0.87-73.0)
      Offspring1938921.2 (0.29-42.3)
      Heterozygous relatives
      Heterozygous relatives include individuals who are obligate heterozygotes by pedigree and other relatives who were tested for the variants present in the index case and shown to be heterozygotes for a familial pathogenic FA gene variant.
      39620,77052.3 (0.29-96.3)
      Wild-type relatives85480367.5 (2.26-96.2)
      Genotype-unknown relatives55735,48470.3 (0.87-107)
      a Includes grandparents, parents, siblings, and offspring.
      b Heterozygous relatives include individuals who are obligate heterozygotes by pedigree and other relatives who were tested for the variants present in the index case and shown to be heterozygotes for a familial pathogenic FA gene variant.
      We identified 195 cancers (incident and prevalent) in 1038 relatives, 159 in grandparents, and 30 in parents (Table 2). Cancer diagnosis and types were validated based on medical reports in 23% cases; the remaining cases were validated based on self or proxy reports. In all relatives, we identified an O/E ratio of 0.78 (CI, 0.67-0.90), with O/E ratios of 0.75 and 0.89 in grandparents and parents, respectively. Siblings and offspring had elevated but not statistically significant O/E ratios. A total of 100 cancers were seen in relatives from FANCA families and 20 in relatives from FANCC families with O/E ratios of 0.79 and 0.59, respectively. These analyses did not show an increased risk of cancer in FA relatives (Table 2).
      Table 2Cancer risk in relatives
      Participant GroupObservedExpectedO/E95% CI
      All cancers
       All relatives1952500.780.67-0.90
       Grandparents1592120.750.64-0.88
       Parents3033.90.890.60-1.26
       Siblings54.241.180.38-2.75
       Offspring10.147.220.09-40.2
      All relatives of FANCA families
      Here, all relatives includes all studied from that family group, regardless of the variant status.
      1001270.790.64-0.96
      All relatives of FANCC families
      Here, all relatives includes all studied from that family group, regardless of the variant status.
      2034.00.590.36-0.91
      Wild-type relatives1721.60.790.46-1.26
      Heterozygous: Relatives5156.40.910.67-1.19
      Grandparents2021.10.950.58-1.46
      Parents3033.90.890.60-1.26
      Offspring10.147.280.10-40.5
      FANCA: Relatives2830.40.920.61-1.33
      Grandparents1110.41.060.53-1.90
      Parents1619.00.840.48-1.37
      Offspring10.118.790.11-48.9
      FANCC: Relatives68.480.710.26-1.54
      Grandparents24.390.460.05-1.65
      Parents43.861.040.28-2.65
      FANCD1 (BRCA2)22.580.780.09-2.80
      FANCD211.950.510.01-2.85
      FANCF11.590.630.01-3.49
      FANCG31.741.720.35-5.03
      FANCI40.596.74
      Includes 1 individual with 3 separate cancers.
      1.81-17.2
      FANCJ (BRIP1)11.190.840.01-4.68
       Gene-unknown56.820.730.24-1.71
       Upstream3842.30.900.64-1.23
       Downstream34.670.640.13-1.88
       ID complex52.541.970.63-4.59
      Breast cancer
       Wild-type relatives23.140.640.07-2.30
       Heterozygous: Relatives129.051.330.68-2.32
      Grandparents33.060.980.20-2.87
      Parents95.741.570.72-2.98
      FANCA74.151.690.68-3.47
      FANCC11.720.580.01-3.23
      FANCD1(BRCA2)10.511.980.03-11.0
      FANCD210.342.940.04-16.3
      Gene-unknown21.281.570.18-5.66
      Acute myeloid leukemia
       Wild-type relatives00.1800-20.8
       Heterozygous relatives20.494.110.46-14.8
      Upstream: FANC A, B, C, E, F, and G (L, M, and T are not represented in the cohort).
      Downstream: FANC D1, J, Q, and R (N, O, P, S, U, V, and W are not represented in the cohort); ID Complex: FANC D2 and I.
      CI, confidence interval; ID, (FANCI-FANCD2); O/E, observed-to-expected.
      a Here, all relatives includes all studied from that family group, regardless of the variant status.
      b Includes 1 individual with 3 separate cancers.
      A total of 51 cancers were reported in relatives with a known heterozygous genotype (O/E ratio of 0.91; CI, 0.67-1.19) (Table 2, Supplemental Table 2). Separate analyses of heterozygous grandparents and parents showed O/E ratios of 0.95 and 0.89, respectively. Further stratification of the heterozygous relatives by FA gene produced similar results for FANCA and FANCC (O/E ratios of 0.92 and 0.71, respectively). Analyses of these genotypes by generation did not significantly alter the O/E ratio (Table 2). FANCA, FANCC, FANCD1, FANCD2, FANCG, FANCI, and FANCJ were represented in ≥10 heterozygous relatives, whereas FANCB, FANCE, FANCF, and FANCQ were represented in <10 heterozygous relatives (Supplemental Table 1). FANCG and FANCI heterozygous relatives both had elevated but nonsignificant O/E ratios; however, the number of cancers observed in these groups was low. The high O/E ratio in FANCI heterozygous relatives was due to a single parent with 3 cancers. In this family, both the father and grandfather of the index case had parathyroid and parotid cancers.
      We stratified the analyses by location in the FA/BRCA DNA repair pathway. Most of the cancers (38 of 46, 82.6%) were observed in heterozygotes with variants in upstream genes (O/E ratio of 0.90; CI, 0.64-1.23) (Table 2). There were only 3 cancers observed in the downstream gene group. A total of 5 cancers were observed in the ID (FANCI-FANCD2) complex group, and the O/E was driven by the FANCI heterozygote parent with 3 cancers mentioned earlier. A total of 5 cancers were observed in the relatives of gene-unknown families.
      We observed an elevated but nonsignificant O/E ratio of 1.33 (CI, 0.68-2.23) for breast cancer in heterozygous relatives (Table 2). There was a single case of female breast cancer among 58 FANCC heterozygote relatives (O/E ratio of 0.58; CI, 0.01-3.23). A small number of patients had hematological malignancies (Table 2, Supplemental Table 3). One case of chronic lymphocytic leukemia (CLL) and 1 of chronic myeloid leukemia were observed in wild-type relatives, and 2 cases of AML and 3 cases of CLL were observed in heterozygous relatives with an O/E ratio of 5.47 (CI, 1.10-16.0), which is significant despite the small number of cases. We learned of an additional case of AML in a heterozygous relative after the data collection end date, for a total of 3 AML cases. There was 1 case of aplastic anemia (AA) in a heterozygous relative; no cases of AA or myelodysplastic syndrome (MDS) were observed in wild-type relatives, and 3 cases of AA and 3 of MDS were observed in the relatives of gene-unknown families (Supplemental Table 3).
      Patients with FA are at a risk of excess toxicity when receiving cytotoxic chemotherapies. We could not determine whether relatives had an excess of treatment-related toxicity due to a lack of cancer treatment records. Approximately 50% of relatives with cancer were alive (or assumed alive, no contact) 5 years after their first cancer diagnosis with a range of 0 to 49 years.

      Discussion

      Multiple studies have examined the risk of cancer in relatives of patients with FA, each with its own limitations. Here, we present the largest study of FA relatives to date. We did not find an increased risk of cancer in these individuals. This finding is consistent across all relatives and when focused exclusively on heterozygous relatives. We emphasize that our study does not apply to the well-established cancer predisposition conferred by the heterozygous autosomal dominant inheritance of pathogenic variants in BRCA1, BRCA2, PALB2, or BRIP1.
      In contrast to a previous report of increased breast cancer risk in FANCC grandmothers, we did not find an increased risk of breast cancer in FANCC relatives (all) or, in particular, grandparents.
      • Berwick M.
      • Satagopan J.M.
      • Ben-Porat L.
      • et al.
      Genetic heterogeneity among fanconi anemia heterozygotes and risk of cancer.
      This difference may be because of enrollment biases in each cohort and/or over-representation of predominant or founder variants in different cohorts. The increased risk of cancer in FANCI relatives may be due to limited sample size and would need to be validated (n = 10, 4 cancers) in a larger cohort. We did not identify any other heterozygous FA genes as potential cancer risk genes.
      The cancer types that patients with FA are specifically predisposed to were not observed at increased rates in the relatives. For the 8 FA relatives with typical FA cancers, the cancers occurred at a similar age as seen in the general (non-FA) population, unlike early-onset cancers in patients with FA. Further prospective research is needed to fully evaluate the risk of CLL and AML in FA relatives.
      The strengths of this study include a well-curated cohort and a large number of relatives in whom genotypes could be validated. All included variants are also known to cause disease in the biallelic form. We acknowledge the limitations of our study, including using imputation when no information was available on the vital status and cancer-free status of relatives. We could not validate the genotype status for some relatives owing to a lack of samples, which limited our analysis of validated heterozygotes. The analysis was also limited by a small number of relatives with each specific FA gene except FANCA and FANCC. We could not evaluate treatment efficacy and treatment-related toxicity in the relatives owing to a lack of data.
      Although this study is the largest study of FA relatives to date, it will be further informed by population-wide sequencing efforts that are currently underway. We could only detect a large effect, and the study was limited by a smaller number of relatives in some genes. For FANCA and FANCC we have been able to conclusively show that there is no increased risk of cancer in FA heterozygotes; however, other genotypes require further investigation. In future studies, it would be important to use population-level exome/genome sequencing projects with linked health records, to allow the evaluation of prevalence and penetrance of FA variants and cancer risk in very large cohorts unselected for a history of FA within the family, particularly for the rarer FA genes. These data would also help to answer the question about increased risk of CLL, which could not be resolved in this study.
      The increasingly frequent identification of individuals with a single pathogenic FA gene variant based on genetic testing, regardless of the family history of FA or clinical suspicion, emphasizes the importance of understanding of the cancer risk in these individuals to guide surveillance recommendations. It is important for further studies to evaluate specific rare FA genes and the potential impact of treatment-related toxicity in FA relatives.

      Data Availability

      Data are available upon request to the corresponding author as allowed by study consent.

      Conflict of Interest

      The authors report no conflicts of interest.

      Acknowledgments

      The authors would like to thank all the families who participated and the health care providers who referred patients. The observed-to-expected cancer ratios were provided by Jeremy Miller at Information Management Systems (Silver Spring, MD) through National Institutes of Health contract HHSN26120110000I. DNA sequencing support was provided by the Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc.
      This research was partially funded by the Fanconi Anemia Research Fund through a grant to B.P.A. Funding for the National Cancer Institute inherited bone marrow failure syndrome cohort is through the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute and supported by contract HHSN261201700004C with Westat, Inc.

      Author Information

      Conceptualization: B.P.A., L.J.M.; Data Curation: B.P.A., L.J.M., L.L., M.O.R., A.G.C., N.G.; Formal Analysis: L.J.M.; Funding Acquisition: B.P.A.; Investigation: N.G., L.J.M.; Methodology: B.P.A.; Project Administration: L.L., M.O.R., A.G.C.; Resources: B.P.A., L.L., A.G.C., M.O.R., N.G.; Software: B.P.A., L.J.M.; Supervision: B.P.A.; Validation: B.P.A.; Visualization: L.J.M.; Writing-Original Draft: L.J.M.; Writing-Review and Editing: L.J.M., N.G., L.L., A.G.C., M.O.R., B.P.A.

      Ethics Declaration

      National Institutes of Health Institutional Review Board approved this study and provided oversight in accordance with regulations (NCT00027274). Informed consent was obtained from all participants (or legal guardians of participants).

      Additional Information

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