Familial cancer syndrome

Retinoblastoma was the first monogenic tumor syndrome to be analyzed. In this case, the starting point for the molecular genetic elucidation of the cause was the identification of deletions on chromosome 13.

Tumor disposition syndromes with skin involvement, also referred to as "tumor-associated genodermatoses", are rare autosomal-dominant hereditary tumor diseases in which certain, often diagnostically groundbreaking skin symptoms occur that indicate tumor activity in various organs.

Clinically significant is that the oncological risk in these tumor syndromes is strongly increased due to mutations in one or more genes compared to the general population, sometimes already from childhood. Thus, preventive measures are necessary, among others, in suspected cases already in childhood.

Equally relevant is that associated skin lesions may precede tumor complexes. In this respect, early detection and classification of these hereditary tumor forms is of high clinical relevance. Often patients, high-risk individuals and asymptomatic plant carriers compared to patients with sporadic cancers, usually require special, more intensive and usually more long-term medical care.

The study of monogenic hereditary tumor disposition syndromes with skin involvement thus provides an important contribution to cancer prevention. This group of diseases is paradigmatic for an extremely successful concept of preventive oncology and personalized medicine.

To date, about 20 monogenic cancer disposition syndromes have been genetically characterized. The mode of inheritance is almost always autosomal dominant. Here, however, the mutations are not characterized by a dominant-negative mechanism (DN) through gain-of-function mut ations (GOF), but by haploinsufficiency based onloss-of-function mutations (LOF). Accordingly, the causative genes are usually not oncogenes but tumor suppressor genes.

• Ataxia teleangiectatica: Autosomal recessive chromosome breakage syndrome with cerebellar ataxia, canities (premature graying), hirsutism, keratosis follicularis, seborrheic eczema, telangiectasias, ephelioid hyperpigmentation and varioliform atrophies of the face, associated with a T-cellular immunodeficiency and an increased risk of neoplasia. This is caused by mutations in the AT gene (the mutated gene is called the ATM gene ).
• Bap1 tumor pred isposition syndrome: BAP1 tumor predisposition syndrome is associated with an increased risk of the "BAP1-inactivated melanocytic tumor" (formerly called atypical Spitz tumor), and the following tumor types (in descending order of frequency): uveal melanoma (UM), malignant mesothelioma (MMe), melanoma (of the skin) (CM), renal cell carcinoma (RCC), basal cell carcinoma (BCC). BAP1 tumor predisposition syndrome is caused by pathogenic variants in the BAP1 gene.
• Bloom syndrome: Rare autosomal recessive inherited syndrome characterized by teleangiectatic erythema in light-exposed areas with possible blistering in childhood, short stature. Pronounced tendency to develop neoplasms (20%) and susceptibility to infections due to a congenital T-cellular immunodeficiency (see immunodeficiencies, T-cellular, primary). Caused by mutations in the BLM gene. Leads to disruption of the DNA helicase RECQL2.
• Bazex-Dupré-Christol syndrome: Rare (currently about 20 families described worldwide) X-linked dominant inherited syndrome with congenital generalized hypotrichosis, diffuse alopecia mainly of the vertex and temporal region, atrophodermia vermiculata with emphasis on the dorsum of the hands and feet and multiple basal cell carcinomas. Mutations in the ACTRT1 gene, which codes for the actin-related protein T1, have been identified. The defective protein leads to activation of the Hedgehog pathway.
• Rombo syndrome: Genodermatosis described in 12 members of a family, probably autosomal dominant inherited, characterized by acrocyanosis and keratosis follicularis appearing at the age of 7-10 years; later development of numerous milia, loss of eyelashes and eyebrows, atrophodermia vermiculata, multiple trichoepitheliomas and basal cell carcinomas. Great similarity (variant?) exists with Bazex-Dupré-Christol syndrome. The gene defect has not yet been analyzed.
• Birt-Hogg-Dubé syndrome: Hereditary, familial or sporadic, very rare syndrome characterized by multiple neoplasms originating from the connective tissue portion of the hair shaft and diseases of various extracutaneous organs, especially lungs and kidneys. Fibrofolliculoma, trichodiscoma (tumors of the hair disc), fibroma molle or perifollicular fibroma (see also hair follicle tumor), basal cell carcinoma have been described. Extracutaneous manifestations: multiple colon adenomas with a high risk of degeneration for colorectal carcinoma, prostate carcinoma, renal cysts, renal angiolipomas, hyperuricemia. Lung: emphysema, bronchiectasis, lung cysts, hamartomas of the lung.
• Carney complex: Carney complex is a rare autosomal dominant syndrome with multiple endocrine neoplasms and lentiginosis caused by defects in the PRKAR1A gene in most patients. The PRKAR1A gene copies for the type 1α regulatory subunit of protein kinase A. Inactivating mutations of PRKAR1A result in aberrant cyclic AMP protein kinase A signaling (Kamilaris CDC et al. 2019) .
• Li-Fraumeni syndrome: Rare tumor predisposition syndrome with an increase in risk for several tumors that occur in childhood and young adulthood. These are: premenopausal breast carcinoma, soft tissue sarcoma, osteosarcoma, brain tumor, adrenocortical carcinoma, leukemia, bronchoalveolar lung carcinoma, and basal cell carcinoma and melanoma (Nieuwenburg SA et al. 2020). This is caused by germline mutations in the TP53 gene on chromosome 17p13.1, which is a gene that halts cell division in the presence of DNA damage.
• Chediak-Higashi syndrome: Rare autosomal recessive variant of oculocutaneous albinoidism with leukocytic immunodeficiency, consecutive susceptibility to infection, hepatosplenomegaly, generalized lymph node enlargement, and impaired melanogenesis. The cause is a mutation in the LYST gene.
• PTEN hamartoma tumor syndromes (this term is used to describe a group of clinically heterogeneous, partially overlapping diseases with autosomal dominant PTEN mutations in the germline and involvement of descendants of all 3 germ layers, manifesting as hamartomas, overgrowth, and benign as well as malignant neoplasms). PTEN hamartoma tumor syndromes include: Cowden syndrome, Lhermitte-Duclos syndrome, Bannayan-Riley-Ruvalcaba syndrome, type2 segmental PTEN hamartoma syndrome, SOLAMEN syndrome).
• Dyskeratosis congenita: rare, hereditary genodermatosis with premature aging characterized by the triad of hypo- or hyperpigmentation, onychodystrophy (starting before 5 years of age) and leukoplakia, in addition to severe systemic involvement (neurological, gastrointestinal, dental, ophthalmological, pulmonological and skeletal changes). The incidence of malignancy is increased in these patients. The cause is mutations in the TERT and DKC1 genes.
• Fanconi anemia: Chronic progressive anemia (mostly hyperchromic-macrocytic) and increased susceptibility to infections. In addition, short stature and other malformations of internal organs. Skin lesions: Hyperpigmentation of the intertrigines, also on the neck and face. Rarer are typical café-au-lait spots. Causes are mainly mutations in the complementation group genes FANCA/FANCB/FANCCand others .
• Nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome): Autosomal-dominantly inherited multisystem disorder with numerous basal cell carcinomas early in life and multiple other malformations (skeletal system, CNS, genitourinary system, heart). Leading symptoms are (prematurely developing) basal cell carcinomas, jaw cysts, pits, calcifications of the falx cerebri and medulloblastomas. The syndrome is caused by a tumor suppressor gene in PTCH1.
• Gardner syndrome: variant of familial adenomatous polyposis (FAP). Gardner syndrome is characterized by multiple colorectal polyps and various types of other cutaneous and extracutaneous tumors. Affected individuals have an almost 100% risk of developing colon cancer. The cause is mutations in the APC gene.
• Palmoplantar keratosis with esophageal carcinoma and mutation in RHBDF2 (Howel-Evans syndrome):

  Syndromic palmoplantar keratosis is an autosomal dominant paraneoplastic syndrome characterized by, callus-like palmoplantar keratosis localized to pressure points, oral leukoplakia, and a 95% lifetime risk for esophageal cancer. Causally, the genodermatosis is due to a mutation in the RHBDF2 gene, which encodes an enzyme that influences regulation of the epidermal growth factor receptor signaling pathway.

• Leiomyomatosis hereditary and renal cell carcinoma: The leading symptom of genodermatosis is cutaneous leiomyomas, usually multiple, grouped, also arranged in stripes, 0.2 - 1.0 cm in size, skin-colored to brownish, often painful with pressure (encountered in about 75% of patients). Leiomyomas of the uterus occur in almost all affected women. In addition, renal cell carcinomas are diagnosed in about 15% of affected patients (mostly unilateral, aggressive in course). The cause is mutations in the FH gene.
• Multiple endocrine neoplasia type 1 (MEN1): A multiple endocrine neoplasia with a combination of peptic ulcers, neoplastic changes in the endocrine pancreas, parathyroid gland, anterior pituitary gland and possibly the thyroid gland. Causative mutations are present in the tumor suppressor gene, MEN1.
• Multiple endocrine neoplasia type 2A (MEN2) type 2A: Multiple endocrine neoplasia is an autosomal-dominant disorder characterized by a combination of pheochromocytoma (possibly bilateral), medullary thyroid carcinoma, and possibly parathyroid adenoma, often associated with lichen amyloidosis. Caused by mutations of the RET oncogene, a gene encoding a transmembrane tyrosine kinase located on chromosome 10q11.2.
• Multiple endocrine neoplasia type 3 (MEN3): Combination with conjunctival neuromas, tongue and lip neuromas, pheochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmic abnormalities. It is caused by mutations of the RET oncogene, a gene encoding a transmembrane tyrosine kinase located on chromosome 10q11.2.
• Muir-Torre syndrome: Rare, familial (autosomal dominant inherited) and sporadic tumor syndrome (<300 cases described worldwide) characterized by: multiple benign and malignant skin tumors and carcinomas of internal organs especially colorectal carcinomas. Muir-Torre syndrome is thought to be a (minus) variant of hereditary nonpolyposis colon cancer syndrome/HNPCC/Lynch syndrome with mutations in the same genes, MLH1, MSH2 and MSH6.
• Neurofibromatosis type 1 (neurofibromatosis peripheral): Hereditary, autosomal dominant, neuroectodermal systemic disease also caused by spontaneous mutation. Mutation in gene locus 17q11.2. This NF1 gene locus includes three genes: OMPG (encoding a membrane-bound glycoprotein of oligodendrocyte myelin), EVI2A and EVI2B (encoding viral insertion sequences).
• Neurofibromatosis type 2 (neurofibromatosis central): Neuroectodermal systemic disease. Leading clinical sign is unilateral or bilateral acoustic neuromas (hearing loss often as initial symptom at 20-30 years) occurring in almost all gene carriers; café-au-lait spots are seen in about 50%, neurofibromas in about 20% of cases. Autosomal-dominant inherited defect of the NF2 gene (neurofibromatosis 2 gene).
• Peutz-Jeghers syndrome: Rare, autosomal dominantly inherited polytopic tumor syndrome with a monitoric lentiginosis of the lips, nose and buccal mucosa as well as intestinal hamartous polyps and carcinomas manifesting mainly in the small intestine. Causes are mutations of the Peutz-Jegher syndrome gene (STK11/LKB1), with consecutive disturbance of serine-threonine-protein kinase 11, which modulates cell proliferation.
• Rothmund-Thomson syndrome: RASopathies with poikiloderma in normally intelligent patients, skeletal malformations (saber tibia, small hands and feet, hypoplastic thumbs and dental anomalies), growth retardation, nail dystrophy, hypotrichosis, palmar, rarely palmo-plantar, predominantly papular hyperkeratoses (see also tumor-associated genodermatoses). A variety of benign and malignant hematologic abnormalities have been reported in affected individuals. Photosensitivity is frequently associated with spinocellular carcinomas and basal cell carcinomas. 50% of patients exhibit cataract formation in childhood. There is an increased risk of osteosarcoma. The syndrome is caused by a mutation in the RECQL4 gene .
• Baller-Gerold syndrome: Premature craniosynostosis, abnormalities of the arm and hand bones, hypertelorism, microstomia, and a saddle-shaped dysplastic nose. A few months after birth - signs of poikiloderma. Causally, the syndrome, like Rothmund-Thomson syndrome , is due to a mutation in the RECQL4 gene.
• Tuberous sclerosis: Autosomal-dominant inherited (new mutations are frequent; in about 70%) mutations of the genes TSC1 (tuberous sclerosis gene 1; gene locus 9q34) and TSC2 (tuberous sclerosis gene 2; gene locus 16p13.3) leading to disorders of the proteins hamartin (TSC1) and tuberin (TSC2), respectively. Both proteins lead to inhibition of mTOR (mechanistic target of rapamycin complex 1) and thus to tumor suppression. Mutation of one of these proteins leads to dysfunction of the signaling pathway with consecutive increased cell proliferation and formation of tumors.
• Xeroderma pigmentosum: Autosomal recessive inherited disorder of the nucleotide excision repair system. Mutations are distributed among different genes on different chromosomes. (XP-A: 9q22; XP-B: 2q21, XP-C: 3p25; XP-D: 19q13; XP-E: 11; XP-F: 19q13; XP-G: 13q32; XP-V: 6p12-21). The individual gene segments encode repair proteins involved in different substeps of the nucleotide excision repair system. The risk of developing skin tumors is increased 1000 fold! Furthermore, XB patients have an increased risk of developing internal neoplasms (CNS tumors; sarcomas, leukemias, lung carcinomas) .

In relation to all tumors, a familial accumulation of tumors is observed in up to 30% of patients with malignant diseases, which suggests a hereditary form. The presence of a tumor disposition syndrome is therefore a frequent suspected diagnosis when taking personal and family histories. Approximately 3-5% of all (solid) cancers are based on a monogenic hereditary predisposition; however, depending on the type of tumor and age of onset, the proportion can be significantly higher. For the population area Germany, about 20,000 malignancies occur annually in the context of a tumor disposition syndrome.

The oncological disposition is usually based on a highly penetrant germline mutation in a single gene. Inherited is thus the genetic disposition for an increased tumor risk, whereby these are classic hereditary or genetically determined disease patterns that follow the Mendelian laws of inheritance (dominant, recessive). In this respect, the term "tumor disposition syndromes" (TDS) is increasingly used for this group of diseases.

In every tumor, mutations occur during tumorigenesis in the neoplastic tissue, some of which drive tumor development as so-called driver mutations ("every cancer is genetic"). These somatic mutations are usually confined to the tumor and disappear with successful treatment or removal of the neoplasia. In contrast, the genetic alterations causative of TDS are germline mutations (constitutional mutations), usually inherited from one parent and present in all somatic cells of the affected person/carrier. However, germline mutations can also arise newly (de novo) in the affected person or in a germ cell of the parents; frequently, the family history is then unremarkable.

The mutations detected in the genetic analysis of a tumor usually do not allow a reliable differentiation between a somatic mutation occurring only in the tumor itself and a constitutional mutation - for the reliable detection of a germline mutation in the context of the diagnosis of a TDS, the examination of healthy tissue is therefore necessary, usually on the basis of leukocyte DNA of an EDTA blood sample.

If TDS is suspected, it makes sense to present the patient and his family members to a human genetics consultation, where a differential diagnostic assessment is made by means of pedigree analysis and evaluation of clinical information. Depending on the suspected diagnosis, genetic diagnostics can then be initiated, if necessary, and individually appropriate ("risk-adapted") recommendations for screening or early detection examinations can be made in conjunction with other clinical specialties, as well as the identification of other at-risk individuals in the family.

The introduction of new methods of high-throughput sequencing (next-generation sequencing) enables more effective genetic diagnostics, but also poses a challenge for the interpretation of findings and consultation.

Under the new EBM codes (effective July 1, 2016), up to 25 kilobases (kb) of coding region may be sequenced for patients with public health insurance. Therefore, disease-specific gene sets up to 25 kb each are created, which can be used for standard analysis. If no mutation is detected in this gene set, additional genes can be analyzed upon request .

For the molecular genetic analysis 5 ml EDTA blood or 2-5µg DNA are required. Smaller volumes are also sufficient for infants and newborns (1-3 ml ETDA blood). The blood or DNA can be sent by regular mail. Care should be taken to ensure that the samples are packaged in a shatterproof manner. Further information on sending samples can be obtained from the special laboratories. In the meantime, multi-gene analyses ("gene panel") based on high-throughput techniques (next-generation sequencing; NGS) are used almost exclusively for this purpose, in which all known, reliably causative genes of the clinical picture as well as the genes of relevant differential diagnoses are examined simultaneously or as step-by-step diagnostics.

The suspicion of a hereditary tumor disposition syndrome is particularly obvious when there is an accumulation of certain forms of cancer in a family and/or persons are also affected at a younger age. First-degree relatives (children, siblings, parents) of patients with a hereditary tumor disease usually have a high risk of developing this tumor disease; they are therefore referred to as high-risk individuals.

On the one hand, there is a high lifetime risk of tumors of a specific and sometimes broad spectrum, as well as a high risk of recurrence in related family members; on the other hand, efficient cancer prevention is often possible through intensified screening and early detection examinations as well as surgical measures.

Hereditary tumor forms are therefore paradigmatic for an extremely successful concept of preventive oncology and individualized medicine. The physician encounters them in every age group and they sometimes show a pronounced clinical variability, even within a family. Multidisciplinary cooperation between human genetics, pathology and various clinical disciplines is particularly necessary for the professional care of patients and their relatives. Specialized interdisciplinary centers should therefore be involved in diagnostics and coordination of treatment and early detection.

1. Jaju PD et al (2016) Familial skin cancer syndromes: Increased risk of nonmelanotic skin cancers and extracutaneous tumors. J Am Acad Dermatol 74:437-451
2. Kamilaris CDC et al (2019) Carney Complex. Exp Clin Endocrinol Diabetes127:156-164.

3. Nieuwenburg SA et al (2020) Cumulative risk of skin cancer in patients with Li-Fraumeni syndrome. Fam Cancer 19:347-351.

4. Sameer AS et al. (2014) Mismatch repair pathway: molecules, functions, and role in colorectal carcinogenesis. Eur J Cancer Prev 23:246-257.
5. Traver S et al (2015) MCM9 Is Required for Mammalian DNA Mismatch Repair. Mol Cell 59:831-839.
6. Van Maldergem L et al. (2022) In: Adam MP et al. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.