DÄ internationalArchive50/2018Hematological Malignancies in Adults With a Family Predisposition

Review article

Hematological Malignancies in Adults With a Family Predisposition

Dtsch Arztebl Int 2018; 115(50): 848-54; DOI: 10.3238/arztebl.2018.0848

Bochtler, T; Haag, G; Schott, S; Kloor, M; Krämer, A; Müller-Tidow, C

Background: Some hematological malignancies arise in persons with a hereditary predisposition. The hereditary nature of these diseases often goes unrecognized, particularly when symptoms begin in adulthood.

Methods: This review is based on pertinent publications retrieved by a selective search in PubMed.

Results: Many rare germline mutations have been identified that lead to acute leukemia and myelodysplastic syndromes. They differ from one another with respect to their penetrance, the age of onset of disease, and the clinical manifestations. In view of this heterogeneity, no uniform recommendations have yet been formulated for their diagnosis and treatment. The most common types of hematological malignancy with a hereditary predisposition are traceable to an underlying disturbance of DNA damage response and repair mechanisms and to mutations of hematological transcription factors. With regard to the selection of patients for testing, the consensus is that cytogenetic and molecular-genetic findings that are suspect for a hereditary predisposition, such as CEBPA and RUNX1 mutations, call for further investigation, as do any clinical features that are typical of tumor syndromes, or a positive family history. The knowledge that a hereditary predisposition may be present is highly stressful for patients; testing should only be carried out after the patient has received genetic counseling. The confirmation of a germline mutation always requires a comparison with healthy tissue. A fibroblast culture is recommended as the gold standard for this purpose.

Conclusion: The detection of a hereditary predisposition to hematological neoplasia is often relevant to treatment and follow-up care: for example, it may motivate early allogeneic stem-cell transplantation. Counseling, predictive testing, and follow-up care are available to the patients’ relatives as well.

LNSLNS

The significance of hereditary cancer predisposition syndromes has been established for solid tumors, such as the Lynch syndrome or familial breast and ovarian cancer, and raised awareness of the role of hereditary predisposition in other cancer entities, including hematological malignancies. While for Lynch syndrome or familial breast and ovarian cancer diagnostic and therapeutic algorithms have been established for routine clinical use (Box 1 and 2) (1, 2), potential hereditary predisposition to hematological malignancies, such as acute leukemias or myelodysplastic syndromes (MDS), is frequently overlooked, especially in adults (3). The reasons why an underlying familial predisposition is often not recognized in adult patients with hematological malignancies are manifold. Since most cases of hereditary leukemia or MDS occur in children (4), hemato-oncologists treating adult patients are not very familiar with these diseases. In addition, hematological malignancies are associated with a very complex and heterogenic spectrum of various hereditary genetic changes, so-called hereditary mutations. Since usually only some of the mutation carriers develop clinical manifestations, the family history is often unrevealing. In addition, a comprehensive family history is frequently not taken in the first place (5).

Lynch syndrome (HNPCC)*
Lynch syndrome (HNPCC)*
Box 1
Lynch syndrome (HNPCC)*
Familial breast and ovarian cancer*
Familial breast and ovarian cancer*
Box 2
Familial breast and ovarian cancer*

Molecular genetic and cytogenetic tests, such as sequencing of individual genes or groups of genes (so-called gene panel sequencing), and testing for smaller or larger chromosomal changes have shown that numerous hematological malignancies are associated with hereditary predisposition (6). While the exact proportion of cases of acute leukemia or MDS associated with a hereditary predisposition is still unknown, it is estimated to be 5% to 10%; thus, a hereditary predisposition is not rare at all (3, 79). For patient populations comprising children and young adults, predisposing hereditary mutations have been reported in approximately 10% of cases (3, 810). Among adults, this rate appears to be lower, but, on the other hand, not all hereditary predisposing mutations have yet been identified and new predisposing genetic changes continue to be discovered (11, 12). There still are patients with a family history of cancer who test negative for all of the hereditary mutations identified so far.

It is important to identify genetic predispositions as they may be relevant to the therapeutic approach and detection of a hereditary predisposition provides family members with the opportunity to undergo genetic testing and benefit from improved cancer screening.

It is common that patients ask their treating physicians whether their relatives are at an increased risk of developing the disease too. In any case, the issue of hereditary predisposition triggers fears and concerns for family members in patients.

The aim of the article is to present those conditions among the numerous hematological malignancies with a hereditary background which typically do not manifest before adulthood and to discuss the diagnostic approaches and the therapeutic consequences.

Methods

This paper is based on review articles, expert opinions as well as retrospective and prospective case series. Preference was given to recent analyses of the last 5 to 10 years. The selective search of the published literature was performed using the PubMed database. No evidence from randomized trials is available for this question. Reference was made to guidelines from scientific specialist societies, where available.

Acute leukemias and myelodysplastic syndromes (MDS)

Various conditions and pathomechanisms are associated with a predisposition to acute leukemias and MDS. These include

  • disorders of DNA repair
  • genetic instability syndromes
  • telomeropathies
  • mutations in signal transduction pathways, transcription factors and tumor suppressor genes
  • immune deficiency syndromes(13).

The disease spectrum extends from syndromic disorders with phenotypic abnormalities to a general cancer predisposition to germline mutations with isolated increases in the risk of acute leukemia and MDS. A selection of the most relevant gene mutations associated with a predisposition to acute leukemia and MDS is compiled in the eTable. Interestingly, the various gene mutations show

  • variable penetrance
  • differences in age at time of onset
  • varying clinical characteristics.

Molecular genetic and cytogenetic tests, such as sequencing of individual genes or groups of genes (so-called gene panel sequencing), and testing for smaller or larger chromosomal changes have shown that numerous hematological malignancies are associated with hereditary predisposition (6). While the exact proportion of cases of acute leukemia or MDS associated with a hereditary predisposition is still unknown, it is estimated to be 5% to 10%; thus, a hereditary predisposition is not rare at all (3, 79). For patient populations comprising children and young adults, predisposing hereditary mutations have been reported in approximately 10% of cases (3, 810). Among adults, this rate appears to be lower, but, on the other hand, not all hereditary predisposing mutations have yet been identified and new predisposing genetic changes continue to be discovered (11, 12). There still are patients with a family history of cancer who test negative for all of the hereditary mutations identified so far.

It is important to identify genetic predispositions as they may be relevant to the therapeutic approach and detection of a hereditary predisposition provides family members with the opportunity to undergo genetic testing and benefit from improved cancer screening.

It is common that patients ask their treating physicians whether their relatives are at an increased risk of developing the disease too. In any case, the issue of hereditary predisposition triggers fears and concerns for family members in patients.

The aim of the article is to present those conditions among the numerous hematological malignancies with a hereditary background which typically do not manifest before adulthood and to discuss the diagnostic approaches and the therapeutic consequences.

Methods

This paper is based on review articles, expert opinions as well as retrospective and prospective case series. Preference was given to recent analyses of the last 5 to 10 years. The selective search of the published literature was performed using the PubMed database. No evidence from randomized trials is available for this question. Reference was made to guidelines from scientific specialist societies, where available.

Acute leukemias and myelodysplastic syndromes (MDS)

Various conditions and pathomechanisms are associated with a predisposition to acute leukemias and MDS. These include

  • disorders of DNA repair
  • genetic instability syndromes
  • telomeropathies
  • mutations in signal transduction pathways, transcription factors and tumor suppressor genes
  • immune deficiency syndromes(13).

The disease spectrum extends from syndromic disorders with phenotypic abnormalities to a general cancer predisposition to germline mutations with isolated increases in the risk of acute leukemia and MDS. A selection of the most relevant gene mutations associated with a predisposition to acute leukemia and MDS is compiled in the eTable. Interestingly, the various gene mutations show

  • variable penetrance
  • differences in age at time of onset
  • varying clinical characteristics.

The most important hereditary predisposition syndromes to hematological malignancies

Disturbed DNA damage response and repair

The development of acute leukemia in patients with Fanconi anemia typically occurs in childhood. The median age at the time Fanconi anemia is first diagnosed is 6.5 years and at the time of occurrence of acute myeloid leukemia (AML) 13 years (14, e1). Even though Fanconi anemia is rarely the cause of AML in adults, it should be included in the differential diagnostic work-up if corresponding clinical signs, such as short stature, café-au-lait spots, congenital heart defects or skeletal abnormalities, are present (9, 1415).

Due to its early discovery, the Li-Fraumeni syndrome, which is associated with a germline mutation of the TP53 tumor suppressor gene, became the prototype of a cancer predisposition syndrome (4, 1618). Apart from other types of cancer, such as soft tissue sarcoma and osteosarcoma, breast cancer, central nervous system (CNS) tumors, and adrenocortical carcinoma, it is associated with an increased risk of developing leukemias and lymphomas. Typically, half of those affected have already developed the first cancer by their thirties and forties. Likewise, patients with germline mutation-linked ataxia telangiectasia (ataxia telangiectasia mutated, ATM) tend to develop hematological malignancies (19). Here, short stature and ataxia are the suggestive clinical features.

Acute leukemia associated with telomere disorders typically occurs in adults (3, 15, 20). An example of this type of diseases is dyskeratosis congenita which is associated with acute leukemias, head and neck squamous cell carcinomas and anogenital tumors. In the differential diagnostic work-up, the following clinical signs are suggestive of this condition:

  • short stature
  • skeletal abnormalities
  • pulmonary fibrosis
  • cryptogenic liver cirrhosis
  • abnormal pigmentation
  • leukopenia
  • preceding pancytopenia.

It is conspicuous that all of the hereditary predisposition syndromes from the DNA damage response and repair group are associated not only with an increased risk of hematological malignancies, but also with an increased risk of solid tumors. Interestingly, even in heterozygous carriers of Fanconi anemia or ATM germline mutations an up to three times higher risk of hereditary breast cancer was observed (21, 22, e2e5).

Mutations of hematological transcription factors

Patients with CEBPA germline mutations typically develop acute myeloid leukemia (AML) as young adults with almost complete penetrance (3, 4, 2326). The mean age of onset is reported to be 24 years (1.8–46 years). The prognosis is favorable—as it is for AML with sporadic biallelic CEBPA gene mutations.

Carriers of hereditary RUNX1 mutations have a lifetime risk of developing acute leukemia of only about 35%. The age at which leukemia is first diagnosed in these patients varies widely. Typically, moderate thrombocytopenia is found in carriers of a hereditary RUNX1 mutation from childhood on, a condition referred to as familial platelet disorder with propensity to myeloid malignancy (FPDMM) (2729).

An underlying thrombocytopenia is also observed in germline ETV6-mutated carriers who are at an increased risk of developing acute lymphoblastic or myeloid leukemias (30).

DDX41 germline mutation carriers typically develop a myelodysplastic syndrome (MDS) or AML only at a mean age of 60 years. Characteristically, the prognosis in patients with these conditions is poor, despite unremarkable chromosome analysis (3133).

By contrast, hereditary GATA2 mutation carriers develop MDS or AML typically while they are young. Thus, evaluation for this germline mutation should primarily be performed in young adults with additional clinical signs such as

  • immune deficiency
  • hearing loss
  • pulmonary disease, or
  • lymphedema (4, 34).

Newly discovered hereditary predisposition syndromes include, for example, SAMD9 and SAMD9L mutations which give rise to myeloid malignancies with chromosome 7 involvement in combination with neurological symptoms; in severe case, they manifest as MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy) (11, 12, 35).

Clinical consequences of diagnosed germline mutation

For the following reasons, it is of clinical relevance for patients diagnosed with acute leukemia or MDS to find out about a potential hereditary predisposition:

  • It provides the opportunity to involve a specialized center in patient management which should closely cooperate with the patient’s family physician or community-based hematologist. Carriers of a predisposing germline mutation who have not yet developed overt acute leukemia are advised to have complete blood counts performed regularly, usually at six-month intervals. The actual intervals between the blood tests and the need for additional bone marrow biopsies should be determined based on each patient’s individual risk profile (4, 6, 8, 36, 37). In this situation, early detection of a clonal development can facilitate timely planning of allogeneic stem cell transplantation. Specific consensus recommendations have only been prepared for Fanconi anemia and other hereditary anemias (8, e6).
  • Some predisposition syndromes are associated with a special sensitivity to chemotherapy and radiation therapy; it is vital to take this into account when making treatment decisions (4). For example, in patients with Fanconi anemia, standard anthracycline-containing chemotherapy for acute myeloid leukemia or full conditioning prior to allogeneic hematopoietic stem cell transplantation should be avoided because of the disease-specific chromosomal instability which may result in catastrophic adverse events if DNA-damaging substances are administered (3, 14). In patients with Li-Fraumeni syndrome, each chemotherapy or radiation therapy is associated with a high risk for a second primary malignancy (SPM); therefore, treatment decisions should only be made after careful consideration of the risks and benefits of these therapies (18, e7e9).
  • Identification of a germline mutation also helps to pay more attention to non-hematological symptoms, such as pulmonary adverse events in patients with telomere diseases, and to organize interdisciplinary co-treatment of these patients (8).
  • Detection of a germline mutation can be critical for the decision to perform early allogeneic hematopoietic stem cell transplantation (e10, e11). For example, patients with acute leukemia and predisposing germline mutation who are treated with conventional chemotherapy with curative intention are exposed to an increased risk of developing acute leukemia again because of their predisposition. For AML patients with hereditary CEBPA mutation, clonal differences between the initial leukemia and the second leukemia were shown which indicate that these leukemias are independent of each other and the second leukemia is not a disease recurrence (26).
  • With awareness of the germline mutation, potential family donors of allogeneic transplants can be tested for the mutation and transplantation of stem cells from mutation carriers can be avoided (4, 6, 8, 18, 35, 36). This strategy aims at eliminating the risk of donor leukemia after family donor allogeneic stem cell transplantation in case of a common genetic predisposition of the siblings (e12).
  • In addition, for family members it offers the opportunity to receive genetic counselling, predictive genetic testing, and, if necessary, early-diagnosis and screening services. The decision when to start cancer screening should take the mutated gene, the mutation type and the typical age at onset in the family into account (32, 38). The transition from carrier status only to overt hematological disease is often gradual. The germline mutation alone can already be associated with a mild disturbance of hematopoiesis and with cytopenia; for example, the RUNX1 mutation can lead to thrombocytopenia.

The high clinical significance of hereditary predisposition to acute myeloid leukemia is reflected in the WHO classification revised in 2016 which introduced hereditary myeloid malignancies as an independent—still provisional—entity (39).

Patient selection for testing

For hematological malignancies, no standard protocol defining which patients should be selected for testing for potential hereditary mutations has yet been established (37). However, expert consensus has been reached that with patients of the groups listed in the Table the possibility of an underlying germline mutation should be taken into consideration (3, 8, 36). Here, it is important to thoroughly take and document a detailed family history, including the

  • type of malignancy
  • age at first diagnosis
  • precise degree of kinship and lineage.
Possible hereditary predisposition testing selection criteria for patients with acute leukemia or MDS*
Possible hereditary predisposition testing selection criteria for patients with acute leukemia or MDS*
Table
Possible hereditary predisposition testing selection criteria for patients with acute leukemia or MDS*

Myeloproliferative syndromes, lymphomas and plasma cell diseases

Myeloproliferative syndromes

For myeloproliferative syndromes (MPS), such as essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF), familial clustering has been reported too. First-degree relatives of MPS patients are three to seven times more likely to develop MPS themselves (e13, e14). The frequency of familial cases in MPS is estimated to be approximately 8% (e15). The clinical signs and symptoms of familial MPS are identical with those of sporadic MPS, with an age peak at about age 60 years. Likewise, the risks (bleeding, thrombosis, secondary bone marrow fibrosis, transition to AML, and others) and the prognosis are similar (e13, e14). Interestingly, it appears that in familial MPS the underlying JAK2 mutation is not inherited directly, but only the predisposition to develop this mutation (e13).

Lymphoma and plasma cell diseases

For lymphomas, familial clustering has also be described. First-degree relatives of patients with non-Hodgkin lymphoma and Hodgkin lymphoma are slightly more likely to develop lymphoma themselves. With chronic lymphocytic leukemia, this risk is even elevated 8.5 times (e16). Likewise, plasma cell diseases, such as multiple myeloma, show weak familial clustering.

A large proportion of these familial hematological malignancies without identified monogenetic cause appear to have a multifactorial or genetically complex etiology where, besides exogenous factors, numerous genetic risk factors with low or moderate penetrance are involved. The combined genetic factors can only explain part of the risk and remain largely unexplored; therefore, they do not play a role in routine genetic testing as yet.

Genetic counselling and testing

In Germany, the German Genetic Diagnostics Act provides the legal framework for hereditary predisposition testing. The purpose of this law is to protect the patient’s right to information self-determination and to prevent discrimination because of genetic features. The diagnostic work-up to determine whether a patient actually has a predisposing germline mutation as well as predictive testing of clinically unaffected relatives must only be performed by specialists in human genetics after a detailed informed consent discussion. This discussion is highly sensitive and has to take ethical aspects into account (e17). For example, knowing about a germline mutation may cause even greater distress and uncertainty for those affected as they already experience because of the disease per se. Furthermore, it should always be critically questioned whether the knowledge of a genetic change contributes to treatment decision-making and whether effective screening and intervention programs are available for the patients and their relatives. The decision for or against genetic testing is particularly difficult for parents as they have to make it for their children. In this group, testing should only be performed in case of known early manifestation. In some cases, genetic counselling is even made more difficult by the fact that the pathogenicity of a detected mutation is unclear. Usually, mutations are classified as pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign (8, 40). The clinical significance of individual mutations may have to be re-evaluated from time to time in the light of new scientific insights.

Diagnostic techniques

Gene mutations are identified using cytogenetic and molecular genetic methods. Besides the gene mutations covered by routine testing, increasingly whole gene groups are tested for, using panel sequencing methods. In patients with suspected hereditary etiology, targeted testing of corresponding genes is performed. If, despite highly suspicious family history, no mutation can be detected with these methods, whole genome sequencing may be performed. An algorithm proposed by scientists at the University of Chicago is presented in the Figure (7).

Algorithm for evaluation of potential hereditary hematological malignancies (HM) by the Chicago Hematopoietic Malignancies Cancer Risk Team (modified according to [7], courtesy of Grune & Stratton, New York)
Algorithm for evaluation of potential hereditary hematological malignancies (HM) by the Chicago Hematopoietic Malignancies Cancer Risk Team (modified according to [7], courtesy of Grune & Stratton, New York)
Figure
Algorithm for evaluation of potential hereditary hematological malignancies (HM) by the Chicago Hematopoietic Malignancies Cancer Risk Team (modified according to [7], courtesy of Grune & Stratton, New York)

Identification of a mutation in cancer cells which is typically found in patients with hereditary cancer and fits to the condition does not allow to draw the conclusion that the patient suffers from a germline disease because the mutation per se does not reveal whether it is a germline mutation or a sporadic mutation only present in the cancer tissue. Thus, testing of healthy material is always required for cross-checking and confirmation.

In patients with hematological diseases, it can usually not be differentiated between hereditary and sporadic mutations by testing of blood samples, because malignant cells are frequently released into the peripheral blood. As an alternative, buccal swab samples can be used; however, this strategy is also associated with a risk of leukocyte contamination. For this reason, some authors regard a fibroblast culture derived from a skin biopsy as the gold standard (3). Alternatively, the use of hair or nail specimens may be considered.

Conclusion

Numerous hematological malignancies can be associated with an underlying hereditary predisposition. In view of the implications for diagnosis and treatment, this possibility should be taken into consideration in older patients, too. Predictive testing may then be offered to asymptomatic family members at risk. Due to the substantial heterogeneity of hereditary predisposition syndromes, randomized controlled trials and consensus recommendations are not available.

Acknowledgement
We extend our thanks to Professor Dr. Claus R. Bartram, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany, for critically reviewing our manuscript.

Conflict of interest statement
Carsten Müller-Tidow is receiving third-party funding for research in the field of hereditary hematological malignancies by the José Carreras Leukaemia Foundation in Germany.

The remaining authors declare no conflict of interest.

Manuscript received on 8 December 2017; revised version accepted on
3 July 2018

Translated from the original German by Ralf Thoene, MD.

Corresponding author
PD Dr. med. Tilmann Bochtler, Medizinische Klinik V
Hämatologie, Onkologie und Rheumatologie
Universitätsklinikum Heidelberg
Klinische Kooperationseinheit Molekulare Hämatologie/Onkologie
Deutsches Krebsforschungszentrum (DKFZ) Heidelberg
69120 Heidelberg, Germany
Tilmann.Bochtler@med.uni-heidelberg.de

Supplementary material

For eReferences please refer to:
www.aerzteblatt-international.de/ref5018

eTable:
www.aerzteblatt-international.de/18m0848

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Rumi E: Familial chronic myeloproliferative disorders: the state of the art. Hematol Oncol 2008; 26: 131–8 CrossRef MEDLINE
e14.
Landgren O, Goldin LR, Kristinsson SY, Helgadottir EA, Samuelsson J, Bjorkholm M: Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24,577 first-degree relatives of 11,039 patients with myeloproliferative neoplasms in Sweden. Blood 2008; 112: 2199–204 CrossRef MEDLINE PubMed Central
e15.
Rumi E, Passamonti F, Della Porta MG, et al.: Familial chronic myeloproliferative disorders: clinical phenotype and evidence of disease anticipation. J Clin Oncol 2007; 25: 5630–5 CrossRef MEDLINE
e16.
Cerhan JR, Slager SL: Familial predisposition and genetic risk factors for lymphoma. Blood 2015; 126: 2265–73 CrossRef MEDLINE PubMed Central
e17.
Marron JM, Joffe S: Ethical considerations in genomic testing for hematologic disorders. Blood 2017; 130: 460–5 CrossRef MEDLINE PubMed Central
e18.
Qian M, Cao X, Devidas M, et al.: TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. J Clin Oncol 2018; 36: 591–9 CrossRef MEDLINE PubMed Central
e19.
Green CL, Tawana K, Hills RK, et al.: GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations. Br J Haematol 2013; 161: 701–5 CrossRef MEDLINE
e20.
Spinner MA, Sanchez LA, Hsu AP, et al.: GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 2014; 123: 809–21 CrossRef MEDLINE PubMed Central
e21.
Wouters BJ, Lowenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R: Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 2009; 113: 3088–91 CrossRef MEDLINE PubMed Central
e22.
Gaidzik VI, Teleanu V, Papaemmanuil E, et al.: RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features. Leukemia 2016; 30: 2160–8 CrossRef CrossRef MEDLINE
e23.
Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN: EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from lynch syndrome. Genet Med 2009; 11: 42–65 CrossRef MEDLINE PubMed Central
e24.
Kloor M, Huth C, Voigt AY, et al.: Prevalence of mismatch repair-deficient crypt foci in lynch syndrome: a pathological study. Lancet Oncol 2012; 13: 598–606 CrossRef
e25.
Syngal S, Brand RE, Church JM, et al.: ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015; 110: 223–62; quiz 63.
e26.
Jass JR, Smyrk TC, Stewart SM, Lane MR, Lanspa SJ, Lynch HT: Pathology of hereditary non-polyposis colorectal cancer. Anticancer Res 1994; 14: 1631–4 MEDLINE
e27.
Ruschoff J, Roggendorf B, Brasch F, et al.: Molecular pathology in hereditary colorectal cancer. Recommendations of the collaborative German study group on hereditary colorectal cancer funded by the German Cancer Aid (Deutsche Krebshilfe). Pathologe 2004; 25: 178–92.
e28.
Overman MJ, McDermott R, Leach JL, et al.: Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18: 1182–91 CrossRef MEDLINE
e29.
Spier I, Holzapfel S, Steinke V, Aretz S: Genetik gastrointestinaler Tumoren – Welche Folgen haben Keimbahnmutationen? Der Gastroenterologe 2013; 04/2013.
e30.
Rau TT, Dawson H, Hartmann A, Ruschoff J: Hereditary colorectal cancer: an update on genetics and entities in terms of differential diagnosis. Pathologe 2017; 38: 156–63.
e31.
Mavaddat N, Barrowdale D, Andrulis IL, et al.: Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 2012; 21: 134–47 CrossRef MEDLINE PubMed Central
e32.
Hahnen E, Rhiem K, Schmutzler R: Genpanelanalysen: Spannungsfeld zwischen kommerziellem Interesse und Patientennutzen. Dtsch Arztebl 2016; 113: A-2028 VOLLTEXT
e33.
Zylka-Menhorn V: Familiärer Brustkrebs: Wie neue Brustkrebsgene zu bewerten sind. Dtsch Arztebl 2017; 114: A-894 VOLLTEXT
e34.
Hartmann A: Pathologie familiärer Tumorsyndrome. Pathologe 2017; 38: 143–8 CrossRef MEDLINE
Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital and Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) Heidelberg, Germany: PD Dr. med. Tilmann Bochtler, Prof. Dr. med. Alwin Krämer
Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany: Prof. Dr. med. Carsten Müller-Tidow
Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany: Dr. med. Georg-Martin Haag
Section Head of Translational Gynecology, University Women’s Hospital Heidelberg, German Cancer Consortium (DKTK), Heidelberg, Germany: Prof. Dr. med. Sarah Schott
Institute of Pathology, Department of Applied Tumor Biology, Heidelberg University Hospital, Heidelberg, Germany: PD Dr. med. Matthias Kloor
Lynch syndrome (HNPCC)*
Lynch syndrome (HNPCC)*
Box 1
Lynch syndrome (HNPCC)*
Familial breast and ovarian cancer*
Familial breast and ovarian cancer*
Box 2
Familial breast and ovarian cancer*
Algorithm for evaluation of potential hereditary hematological malignancies (HM) by the Chicago Hematopoietic Malignancies Cancer Risk Team (modified according to [7], courtesy of Grune & Stratton, New York)
Algorithm for evaluation of potential hereditary hematological malignancies (HM) by the Chicago Hematopoietic Malignancies Cancer Risk Team (modified according to [7], courtesy of Grune & Stratton, New York)
Figure
Algorithm for evaluation of potential hereditary hematological malignancies (HM) by the Chicago Hematopoietic Malignancies Cancer Risk Team (modified according to [7], courtesy of Grune & Stratton, New York)
Key messages
Possible hereditary predisposition testing selection criteria for patients with acute leukemia or MDS*
Possible hereditary predisposition testing selection criteria for patients with acute leukemia or MDS*
Table
Possible hereditary predisposition testing selection criteria for patients with acute leukemia or MDS*
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25.Pabst T, Eyholzer M, Haefliger S, Schardt J, Mueller BU: Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol 2008; 26: 5088–93 CrossRef MEDLINE
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27.Schlegelberger B, Heller PG: RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM). Semin Hematol 2017; 54: 75–80 CrossRef MEDLINE
28.Sood R, Kamikubo Y, Liu P: Role of RUNX1 in hematological malignancies. Blood 2017; 129: 2070–82 CrossRef MEDLINE PubMed Central
29.Hayashi Y, Harada Y, Huang G, Harada H: Myeloid neoplasms with germ line RUNX1 mutation. Int J Hematol 2017; 106: 183–8 CrossRef MEDLINE
30.Feurstein S, Godley LA: Germline ETV6 mutations and predisposition to hematological malignancies. Int J Hematol 2017; 106: 189–95 CrossRef MEDLINE
31.Polprasert C, Schulze I, Sekeres MA, et al.: Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 2015; 27: 658–70 CrossRef MEDLINE
32. Lewinsohn M, Brown AL, Weinel LM, et al.: Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood 2016; 127: 1017–23 CrossRef MEDLINE PubMed Central
33.Maciejewski JP, Padgett RA, Brown AL, Muller-Tidow C: DDX41-related myeloid neoplasia. Semin Hematol 2017; 54: 94–7 CrossRef MEDLINE
34.Wlodarski MW, Hirabayashi S, Pastor V, et al.: Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 2016; 127: 1387–97; quiz 518 CrossRef MEDLINE
35.Davidsson J, Puschmann A, Tedgard U, Bryder D, Nilsson L, Cammenga J: SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies. Leukemia 2018 CrossRef MEDLINE PubMed Central
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38.DiNardo CD: Getting a handle on hereditary CEBPA mutations. Blood 2015; 126: 1156–8 CrossRef MEDLINE
39.Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391–405 CrossRef MEDLINE
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e10.Saida S: Predispositions to leukemia in down syndrome and other hereditary disorders. Curr Treat Options Oncol 2017; 18: 41 CrossRef MEDLINE
e11. Babushok DV, Bessler M, Olson TS: Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults. Leuk Lymphoma 2016; 57: 520–36 CrossRef MEDLINE PubMed Central
e12.Berger G, van den Berg E, Sikkema-Raddatz B, et al.: Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia 2017; 31: 520–2 CrossRef MEDLINE
e13. Rumi E: Familial chronic myeloproliferative disorders: the state of the art. Hematol Oncol 2008; 26: 131–8 CrossRef MEDLINE
e14.Landgren O, Goldin LR, Kristinsson SY, Helgadottir EA, Samuelsson J, Bjorkholm M: Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24,577 first-degree relatives of 11,039 patients with myeloproliferative neoplasms in Sweden. Blood 2008; 112: 2199–204 CrossRef MEDLINE PubMed Central
e15. Rumi E, Passamonti F, Della Porta MG, et al.: Familial chronic myeloproliferative disorders: clinical phenotype and evidence of disease anticipation. J Clin Oncol 2007; 25: 5630–5 CrossRef MEDLINE
e16.Cerhan JR, Slager SL: Familial predisposition and genetic risk factors for lymphoma. Blood 2015; 126: 2265–73 CrossRef MEDLINE PubMed Central
e17.Marron JM, Joffe S: Ethical considerations in genomic testing for hematologic disorders. Blood 2017; 130: 460–5 CrossRef MEDLINE PubMed Central
e18.Qian M, Cao X, Devidas M, et al.: TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. J Clin Oncol 2018; 36: 591–9 CrossRef MEDLINE PubMed Central
e19.Green CL, Tawana K, Hills RK, et al.: GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations. Br J Haematol 2013; 161: 701–5 CrossRef MEDLINE
e20.Spinner MA, Sanchez LA, Hsu AP, et al.: GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 2014; 123: 809–21 CrossRef MEDLINE PubMed Central
e21.Wouters BJ, Lowenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R: Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 2009; 113: 3088–91 CrossRef MEDLINE PubMed Central
e22.Gaidzik VI, Teleanu V, Papaemmanuil E, et al.: RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features. Leukemia 2016; 30: 2160–8 CrossRef CrossRef MEDLINE
e23. Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN: EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from lynch syndrome. Genet Med 2009; 11: 42–65 CrossRef MEDLINE PubMed Central
e24.Kloor M, Huth C, Voigt AY, et al.: Prevalence of mismatch repair-deficient crypt foci in lynch syndrome: a pathological study. Lancet Oncol 2012; 13: 598–606 CrossRef
e25.Syngal S, Brand RE, Church JM, et al.: ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015; 110: 223–62; quiz 63.
e26.Jass JR, Smyrk TC, Stewart SM, Lane MR, Lanspa SJ, Lynch HT: Pathology of hereditary non-polyposis colorectal cancer. Anticancer Res 1994; 14: 1631–4 MEDLINE
e27.Ruschoff J, Roggendorf B, Brasch F, et al.: Molecular pathology in hereditary colorectal cancer. Recommendations of the collaborative German study group on hereditary colorectal cancer funded by the German Cancer Aid (Deutsche Krebshilfe). Pathologe 2004; 25: 178–92.
e28. Overman MJ, McDermott R, Leach JL, et al.: Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18: 1182–91 CrossRef MEDLINE
e29.Spier I, Holzapfel S, Steinke V, Aretz S: Genetik gastrointestinaler Tumoren – Welche Folgen haben Keimbahnmutationen? Der Gastroenterologe 2013; 04/2013.
e30.Rau TT, Dawson H, Hartmann A, Ruschoff J: Hereditary colorectal cancer: an update on genetics and entities in terms of differential diagnosis. Pathologe 2017; 38: 156–63.
e31. Mavaddat N, Barrowdale D, Andrulis IL, et al.: Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 2012; 21: 134–47 CrossRef MEDLINE PubMed Central
e32. Hahnen E, Rhiem K, Schmutzler R: Genpanelanalysen: Spannungsfeld zwischen kommerziellem Interesse und Patientennutzen. Dtsch Arztebl 2016; 113: A-2028 VOLLTEXT
e33.Zylka-Menhorn V: Familiärer Brustkrebs: Wie neue Brustkrebsgene zu bewerten sind. Dtsch Arztebl 2017; 114: A-894 VOLLTEXT
e34.Hartmann A: Pathologie familiärer Tumorsyndrome. Pathologe 2017; 38: 143–8 CrossRef MEDLINE