HEREDITARY ONCOLOGICAL SYNDROMES

About 10-15% of tumours show this nature. To date, more than 200 hereditary cancer syndromes have been described. Hereditary tumours are most often caused by inherited germline mutations in tumour-suppressor or DNA repair genes. These mutations are therefore a significant risk factor for the development of oncological disease.

If one particular type of tumour typically appears more frequently in the personal and family medical history, we usually think of a particular cancer syndrome. In this case, the disease also develops at a younger age than for similar types of sporadic tumours. Tumours are also more often multifocal or bilateral, or multiple primary tumours may develop in different organs.

Hereditary cancer syndromes tested include:
• hereditary breast and ovarian cancer (HBOC)
• hereditary prostate cancer
• hereditary non-polyposis colorectal cancer (HNPCC - Lynch syndrome)
• Li-Fraumeni syndrome (LFS)
• familial adenomatous polyposis (FAP)
• Peutz-Jeghers syndrome (PJS)
• Cowden syndrome
• Hereditary diffuse gastric cancer (HDGC)
• Familial melanoma syndrome (FAMMM)
• Von Hippel-Lindau syndrome (VHL)
• hereditary leiomyomatosis and renal cell carcinoma (HLRCC)/multiple cutaneous and uterine leiomyomatosis (MCUL)
• familial medullary thyroid carcinoma (MEN2)/Hischprung's disease
• ataxia telangiectasia, familial breast cancer
• Gorlin syndrome

The massively parallel sequencing method enables more efficient (faster and more economical) genetic diagnostics in the field of clinical genetics, especially compared to the previously used Sanger method. Next-generation sequencing can identify new genetic changes, i.e., DNA predispositions that contribute to the development of serious diseases, or to oncogenesis, tumour progression and metastasis.

Today, this technology makes it possible to test a specific group of genes in the so-called gene panel as a standard. Mutations in these genes are associated with hereditary cancers and syndromes (e.g., breast, ovarian, fallopian tube, uterine, gastrointestinal, skin, kidney, pancreatic, and various types of leukaemia). Selected genes are tested by the digital MLPA (Multiple Ligation-dependent Probe Amplification) method, which analyses genomic deletions/duplications of whole exons of analysed genes.

This approach provides a more comprehensive result for the patient; we are able to identify a specific hereditary cancer syndrome and can thus provide the patient's blood relatives with a predictive test for a proven causal mutation in one of the risk genes. Appropriate preventive monitoring is recommended for carriers of the mutation, so that the resulting cancer can be detected early and treated more easily.

Knowledge of the molecular genetic basis of the disease allows presymptomatic diagnosis at the DNA level in families and the development of preventive and therapeutic strategies based on this knowledge. This panel of genes can be screened in individuals after they reach adulthood.

Gene, specification: Genes screened by NGS: APC, ATM, BAP1, BARD1, BLM, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, EPCAM, ERCC2, ERCC3, FANCC, FANCM, FH, FLCN, GREM1, CHEK2, MEN1, MET, MLH1, MLH3, MSH2, MSH6, MUTYH, NBN, NF1, NF2, NTHL1, PALB2, PMS2, POLD1, POLE, PRKAR1A, PTEN, PTCH1, RAD50, RAD51C, RAD51D, RB, RET, SDHB, SLX4, SMAD4, SMARCB1, STK11, SUFU, TP53, UNC13D, VHL, WRN, WT1; FAM175A, CDKN1B, CYLD, DICER1, EXO1, FANCA, FANCB, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, GATA2, HOXB13, KIT, MITF, MRE11, RECQL, RECQL4, RECQL5, SBDS, SCG5, SDHA, SDHAF2, SDHC, SDHD, SMARCA4, SMARCE1, TERT, TGFBR1, TGFBR2, TMEM127. Genes tested by digital MLPA analysis - APC, ATM, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, EPCAM (exon 7-9), CHEK2, SCG5/GREM1 (intron 2SCG5 and the region upstream of GREM1; duplication 15q13.3), MITF(c.952G>A), MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLE (c.1270C>G), PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53

Type of material to be examined: blood

Indicating specialists: medical genetics

All information about the panel can be found on the czecanca.cz website.

Oncopanel CZECANCA KAPA HyperCap DS Hereditary Cancer Research Panel 1.22 (Roche), where all exons of the genes are sequenced AIP; ALK; APC; APEX1; ATM; ATMIN; ATR; ATRIP; AURKA; AXIN1; BABAM1; BAP1; BARD1; BLM; BMPR1A; BRAP; BRCA1; BRCA2; BRCC3; BRE; BRIP1; BUB1B; C11orf30; C19orf40; casp8; CCND1; CDC73; CDH1; CDK4; CDKN1B; CDKN1C; CDKN2A; CEBPA; CEP57; CLSPN; CSNK1D; CSNK1E; CWF19L2; CYLD; DCLRE1C; DDB2; DHFR; DICER1; DIS3L2; DMBT1; DMC1; DNAJC21; DPYD; EGFR; EPCAM; EPHX1; ERCC1; ERCC2; ERCC3; ERCC4; ERCC5; ERCC6; ESR1; ESR2; EXO1; EXT1; EXT2; EYA2; EZH2; FAM175A; FAM175B; FAN1; FANCA; FANCB; FANCC; FANCD2; FANCE; FANCF; FANCG; FANCI; FANCL; FANCM; FBXW7; FH; FLCN; GADD45A; GATA2; GPC3; GRB7; HELQ; HNF1A; HOXB13; HRAS; HUS1; CHEK1; CHEK2; KAT5; KCNJ5; KIT; LIG1; LIG3; LIG4; LMO1; LRIG1; MAX; MCPH1; MDC1; MDM2; MDM4; MEN1; MET; MGMT; MLH1; MLH3; MMP8; MPL; MRE11A; MSH2; MSH3; MSH5; MSH6; MSR1; MUS81; MUTYH; NAT1; NBN; NCAM1; NELFB; NF1; NF2; NFKBIZ; NHEJ1; NSD1; OGG1; PALB2; PARP1; PCNA; PHB; PHOX2B; PIK3CG; PLA2G2A; PMS1; PMS2; POLB; POLD1; POLE; PPM1D; PREX2; PRF1; PRKAR1A; PRKDC; PTEN; PTCH1; PTTG2; RAD1; RAD17; RAD18; RAD23B; RAD50; RAD51; RAD51AP1; RAD51B; RAD51C; RAD51D; RAD52; RAD54B; RAD54L; RAD9A; RB1; RBBP8; RECQL; RECQL4; RECQL5; RET; RFC1; RFC2; RFC4; RHBDF2; RNF146; RNF168; RNF8; RPA1; RUNX1; SBDS; SDHA; SDHAF2; SDHB; SDHC; SDHD; SETBP1; SETX; SHPRH; SLX4; SMAD4; SMARCA4; SMARCB1; SMARCE1; STK11; SUFU; TCL1A; TELO2; TERF2; TERT; TLR2; TLR4; TMEM127; TOPBP1; TP53; TP53BP1; TSC1; TSC2; TSHR; UBE2A; UBE2B; UBE2I; UBE2V2; UBE4B; UIMC1; VHL; WRN; WT1; XPA; XPC; XRCC1; XRCC2; XRCC3; XRCC4; XRCC5; XRCC6; ZNF350; ZNF365. 

Genes screened by digital MLPA: 

APC, ATM, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, EPCAM (exon 7-9), CHEK2, SCG5/GREM1 (intron 2 SCG5 and the region upstream of GREM1; duplication 15q13.3), MITF (c.952G>A), MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLE (c.1270C>G), PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. 

Molecular genetic testing is performed using the NextSeq massively parallel sequencing technique, CNV analysis and digital MLPAF method. Laboratory molecular genetic testing using oncopanel is performed in one step for the most common hereditary cancer syndromes. It is therefore more comprehensive and can therefore detect risk mutations in genes where we might not expect them based on the structure and type of cancer in the family.

The above suggests that mutations in known genes BRCA1 and BRCA2do not necessarily have to be the only cause of increased risk for breast and ovarian cancer (and other cancers). For this reason, the indication criteria for panel genetic testing are now perceived differently and can be said to be more interconnected. 

The GHC Genetics laboratory is accredited pursuant to ISO 15189:2013.

Cancer testing is performed using the massively parallel sequencing method (next generation sequencing) with the CZECANCA panel. This method is accredited at our laboratory, and we regularly participate in international interlaboratory inspections. We use CE-IVD software and our own bioinformatics procedures for data analysis.

Type of material to be examined: blood

Indicating specialists: medical genetics

In addition to the major predisposing BRCA1 and BRCA2 (BReast Cancer Associated) genes, the role of the PALB2 (Partner And Localizer of BRCA2) gene has recently been studied as another candidate gene for genetic testing of patients with hereditary breast cancer in the Czech Republic. In addition, the CHEK2 (CHEckpoint Kinase 2) gene, which is one of the so-called low penetrance genes, is also being monitored. Mutations in these genes cause an increased risk of breast and ovarian cancer, and to a lesser extent other cancers (pancreatic cancer, prostate cancer, CRC, gastric cancer, melanoma) typical of the HBOC syndrome. The lifetime risk for women carrying mutations in both BRCA genes ranges between 40% and 85%. For ovarian cancer, the cumulative risk is 39-65% for BRCA1 gene mutation and 1-37% for BRCA2 one. Male BRCA1 mutation carriers have a lifetime risk of breast cancer of about 1.2%, while BRCA2 mutation carriers have a lifetime risk of about 8%. Genetic counselling is recommended in high-risk individuals to ensure molecular genetic testing of the entire BRCA1,2 gene coding sequence. The test is intended not only for women, but also for men with a risky personal or family medical history who meet the diagnostic clinical criteria for this test. The examination can only be carried out after the age of majority (18 years).

INDICATION CRITERIA 

Sporadic forms: 

• Ovarian, fallopian tube and primary peritoneal carcinoma regardless of age.
• TNBC or medullary breast cancer under the age of 60. 
• Unilateral breast cancer in a woman under 45 years of age (under 50 years if there is no known family medical history).  
• Separate primary breast cancers, first under the age of 50 or both under the age of 60 (bilateral or ipsilateral, synchronous or metachronous).
• Synchronous onset of breast and pancreatic cancer at any age.
• A man with breast cancer at any age. 

Familial occurrence: 

• Family history of ovarian/fallopian tube/peritoneal carcinomas. 
• At least three relatives with breast cancer at any age. 
• Two relatives:  2 related women with breast cancer, at least one under 50 or both under 60.
• Female patient with breast cancer at any age with a direct relative with ovarian cancer, TNBC/medullary breast cancer, pancreatic cancer, male breast cancer, high-grade or primary metastatic pancreatic cancer. 

Indications for prostate cancer testing: 

• History of ≥ 2 cases of prostate cancer in personal or family medical history, at least one at age ≤ 55 years.
• ≥ 3 cases of prostate cancer in close relatives, death due to prostate cancer. 
• Prostate cancer (Gleason score ≥ 7) or primary metastatic prostate cancer and ≥ 1 case of breast cancer, ovarian cancer, endometrial cancer, bowel or gastric cancer, renal cell carcinoma, malignant melanoma, pancreatic cancer, bladder cancer, gallbladder cancer. 

If you have a personal and/or family history of other cancers (colon or small bowel cancer, uterine cancer, kidney cancer, etc.), genetic analysis may also be covered by your health insurance after a risk assessment by a clinical geneticist.

Gene, specification: BRCA1, BRCA2, PALB2, TP53, STK11, CDH1, and PTEN genes By NSG oncopanel testing and digital MLPA, see Panel of genes associated with hereditary cancer - oncopanel   

Type of material to be examined: blood

Indicating specialists: medical genetics

The most common genes are BRCA2, BRCA1 and HOXB13, and carriers of mutations in the CHEK2 and ATM genes are also at increased risk. Hereditary prostate cancer is defined as a disease affecting three or more relatives, or at least two relatives who developed the disease before the age of 55. 

Mutations in the CHEK2 gene are classified as intermediate-risk alleles for hereditary predisposition to prostate (breast and ovarian cancer in women), or thyroid and kidney cancer. In particular, the c.251G>A (p.G84E) mutation of the HOXB13 gene is associated with an increased risk of prostate cancer, especially at younger ages. Carriers of the HOXB13 gene mutation have a risk of prostate cancer ranging from 22% to 52% and appear to have the highest risk in men with a family history of prostate cancer (the normal population risk for prostate cancer is about 10%).

The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with cancer predisposition and a preventive and therapeutic strategy based on this knowledge. Indication criteria have not been precisely defined, but they are essentially identical to the criteria for molecular genetic testing of HBOC syndrome. Genetic testing may be recommended in the case of three or more relatives or at least two relatives who have developed the disease before the age of 55, especially in combination with pancreatic, breast or ovarian cancer.

Gene, specification:  BRCA2, BRCA1, CHEK2, HOXB13, ATM genes, By NSG oncopanel testing and digital MLPA, see Panel of genes associated with hereditary cancer - oncopanel.

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics

Lynch syndrome-associated tumours are characterized by loss of expression of one of the DNA repair proteins (MMR proteins: MLH1, MSH2, MSH6, PMS2). More than 90% of HNPCC tumours show MSI positivity (microsatellite DNA instability) compared to about 15% of sporadic colorectal tumours.

The presence of p.V600E mutation in the BRAF gene and/or MLH1 promoter methylation in tumour tissue is a suitable marker for their selection. Lynch syndrome is associated with the occurrence of germline pathogenic (causal) mutations affecting the MLH1 (41%), MSH2 (40%), MSH6 (12%), EPCAM and, to a minor extent, PMS2 (7%) genes.

Carriers of pathogenic mutations in these genes have an increased risk of developing colorectal cancer (36-80% in men, 18-76% in women). At the same time, they have an increased risk of other associated cancers - endometrial (20-60%), ovarian, gastric, hepatobiliary, small bowel, renal pelvis, brain and skin.

INDICATION CRITERIA

1. Amsterdam Criteria I
- at least three patients with colorectal cancer in the family, one of them is a first-degree relative of the other two
- at least two generations are affected
- at least one patient was diagnosed before the age of 50 years
- the tumour has been verified by pathologic examination
- familial adenomatous polyposis is excluded

2. Amsterdam Criteria II
- at least three relatives with a HNPCC-associated cancer (colorectal, endometrial, small bowel, ureteral and renal pelvis cancer) in the family, one of them is a first-degree relative of the other two
- at least two generations are affected
- at least one patient was diagnosed before the age of 50 years
- the tumour has been verified by pathologic examination
- familial adenomatous polyposis is excluded

Gene, specification:  MLH1, MSH2, MSH6, PMS2, EPCAM genes, By NSG oncopanel testing and digital MLPA, see Panel of genes associated with hereditary cancer - oncopanel

Type of material to be examined: blood

Indicating specialists: medical genetics

LFS is one of the most serious hereditary cancer syndromes with a high risk of disease in childhood already. Adrenal carcinomas, brain tumours, leukaemia, lymphomas and sarcomas are the most common in children. In adulthood, any solid tumours appear, most often breast tumours, brain tumours, sarcomas, but also skin tumours, gastrointestinal, lung, gynaecological, haematological and other tumours.

The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with a pathogenic mutation of the TP53 gene, and a preventive and therapeutic strategy based on this knowledge.

INDICATIONS FOR EXAMINATION

Criteria for the diagnosis of Li-Fraumeni syndrome

• proband with sarcoma diagnosed at any age less than 45 years and a first-degree relative with any tumour at any age less than 45 years and a first or second degree relative with any tumour at any age less than 45 years, sarcoma at any age 

Chompret criteria for the diagnosis of Li-Fraumeni syndrome

Families meeting at least one of the following criteria:
• proband with sarcoma, brain tumour, breast cancer or adrenocortical carcinoma under 36 years of age
• with at least one first- or second-degree relative with an LFS tumour other than leukaemia (other than breast cancer if the female proband has breast cancer) aged under 46 years, with a relative with multiple primary tumours at any age
• a proband with multiple primary tumours, at least two of which are typical of LFS (other than leukaemia), i.e. sarcoma, brain tumour, breast cancer and/or adrenocortical carcinoma, the first of which occurred under the age of 36 years, regardless of family history
• proband with adrenocortical carcinoma, regardless of age and family history

Modified Chompret criteria (2008)

• a proband with a tumour belonging to the spectrum of tumours associated with LFS (soft tissue sarcoma, osteosarcoma, brain tumour, premenopausal breast cancer, adrenocortical carcinoma, leukaemia, bronchoalveolar lung cancer) aged less than 46 years and at least one first or second degree relative with a tumour typical of LFS (except breast cancer, if the proband has breast cancer) under the age of 56 years or with multiple tumours
• or a proband with multiple tumours, two of which belong to a narrower spectrum of tumours typical of LFS and the first of which arose under the age of 46 years
• or a patient with adrenocortical carcinoma or a patient with breast cancer under the age of 36 years without a mutation in the BRCA1 or BRCA2 genes, regardless of family history

Birch criteria for the diagnosis of Li-Fraumeni-like syndrome

• a proband with any childhood tumour or sarcoma, brain tumour or adrenocortical tumour diagnosed under the age of 45 years and a first or second-degree relative with a tumour typical of Li-Fraumeni syndrome (sarcoma, breast cancer, brain tumours, adrenocortical tumours, or leukaemia) at any age and a first- or second-degree relative with any tumour under the age of 60 years

Eeles criteria for the diagnosis of Li-Fraumeni‑like syndrome

• two first or second-degree relatives with a tumour typical of Li-Fraumeni syndrome at any age

Gene, specification:  TP53 gene By NSG oncopanel testing and digital MLPA, see Panel of genes associated with hereditary cancer - oncopanel

Type of material to be examined: blood

Indicating specialists: medical genetics

Amyloid adenomatous polyposis together with hereditary non-polyposis colorectal cancer (HNPCC) are among the most studied forms of hereditary colorectal cancer. Approximately 15-20% of colorectal cancers are hereditary. The prevalence of FAP in the Czech population is estimated at 1 : 5000 to 1 : 7500 individuals. The frequency of the disease is maintained in the population by frequent de novo mutations, i.e. without a family history of the disease. A monoallelic mutation in the MUTYH gene puts the carrier at increased risk of CRC, gastric, liver or endometrial cancer in women. A biallelic mutation means a risk of familial adenomatosis (MYH-associated polyposis). In this case, it is an autosomal recessively inherited disease with a lower incidence of polyps at an older age than for FAP caused by mutations in the APC gene. The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with a predisposition in the APC/MUTYH gene, and a preventive and therapeutic strategy based on this knowledge. Predictive genetic testing for a known causal mutation of the APC gene can be performed as early as infancy.

INDICATION CRITERIA
• all forms of diffuse intestinal adenomatous polyposis (familial adenomatous polyposis, Gardner syndrome)

• when FAP is suspected, all first-degree relatives should undergo colonoscopy at the time of clinical diagnosis (parents, siblings, children aged 10 to 15 years sigmoidoscopy)

Gene, specification:  APC, MUTYH genes  By NSG oncopanel testing and digital MLPA, see Panel of genes associated with hereditary cancer - oncopanel

Type of material to be examined: blood

Indicating specialists: medical genetics

Gastrointestinal polyps can lead to chronic bleeding and anaemia, recurrent obstruction and intussusception requiring repeated laparotomies and bowel resections. Mutations in the STK11 gene cause an increased risk of various malignancies, with a cumulative risk of cancer by age 70 of 81%. The cumulative risk of GIT cancer is 66% (small intestine, colon, oesophagus, pancreas). The risk of breast cancer in women under 60 is 32%. The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with a predisposition in the STK11 gene, and a preventive and therapeutic strategy based on this knowledge. If the causative mutation of the STK11 gene is known in the family, predictive genetic testing can be offered in childhood. 

INDICATION CRITERIA ACCORDING TO TOMLINSON AND HOULSTON 

• two or more hamartomatous polyps in the GIT or one hamartomatous polyp and a positive family history of PJS or one hamartomatous polyp and pigmentation 

Gene, specification:  STK11 gene By NSG oncopanel testing and digital MLPA, see Panel of genes associated with hereditary cancer– oncopanel 

Type of material to be examined: blood

Indicating specialists: medical genetics 

The disease can also manifest in the form of Lhermitte-Duclos disease (megalocephaly, epilepsy, dysplastic gangliocytoma of the cerebellum). Skin and mucosal manifestations in the form of hamartomatous lesions including lip and mucosal papilloma, papillomatous papules in the oral cavity, trichilemmomas, hamartomas of the breast and intestine are characteristic (but not always present). The disease is associated with an increased risk of cancer, particularly breast cancer, thyroid cancer, and less commonly urogenital, lung, melanoma tumours, retinal gliomas, skin tumours and brain tumours. The lifetime risk of breast cancer in women is 25-50%, with an average age of diagnosis of 38-46 years; breast cancer in men has also been described. The risk of multifocal and bilateral tumours is increased. The lifetime risk of thyroid carcinoma is about 10%; histologically, thyroid carcinomas are usually follicular, rarely papillary, and never medullary. The risk of endometrial cancer is about 5-10%. The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with a predisposition in the PTEN gene, and a preventive and therapeutic strategy based on this knowledge. 

A clinical diagnosis of Cowden syndrome is established when an individual meets any of the following criteria 

• pathognomonic mucocutaneous lesions if there are 
- six or more facial papules, three or more of which must be trichilemmomas, or
- cutaneous facial papules and oral mucosal papillomatosis, or
- oral mucosal papillomatosis and acral keratosis, or
- six or more palmoplantar keratotic lesions 

• one of the following:
- two or more major criteria
- one major and at least three minor criteria 
- at least four minor criteria 

• in families where one member meets the above diagnostic criteria for Cowden syndrome, other relatives are considered for Cowden syndrome if they meet any of the following criteria: 

- pathognomonic criteria or 
- any major criterion with or without minor criteria, or 
- two minor criteria or 
- history of BRRS (Bannayan-Ruvalcaba-Riley syndrome) 

Pathognomonic criteria 

Mucocutaneous lesions: 

• trichilemmomas (in the face)
• acral keratosis 
• papillomatous lesions
• mucosal lesions 

Major criteria
- Lhermitte-Duclos Disease (LDD) - defined in adults as the presence of dysplastic gangliocytoma of the cerebellum
• breast cancer
• thyroid cancer (non‑medullary)
• macrocephaly (head circumference above the 97th percentile)
• endometrial cancer

Minor criteria
• other thyroid lesions (e.g., adenomas, diffuse nodular goitre)
• mental retardation (IQ less than 75)
• hamartomatous intestinal polyps
• fibrocystic breast disease
• lipomas
• fibromas
• tumours of the genitourinary tract (especially renal cell carcinoma)
• malformations of the genitourinary tract
• uterine fibroids

Gene, specification:  PTEN gene By NSG oncopanel testing and digital MLPA, see Panel of genes associated with hereditary cancer– oncopanel 

Type of material to be examined: blood 

Indicating specialists: medical genetics 

Hereditary diffuse gastric cancer (HDGC) is characterized by late diagnosis and poor prognosis. The average age of onset of HDGC is 38 years with a range of 14-69 years. The estimated lifetime risk of developing gastric cancer by age 80 is 67% for men and 83% for women. Many families with HDGC have a germline mutation in the gene encoding E-cadherin (CDH1). The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with predispositions in the CDH1 gene and a preventive and therapeutic strategy based on this knowledge.

INDICATION CRITERIA
• Two cases of gastric cancer in the family, at least one of them being the diffuse type of gastric cancer, diagnosed before the age of 50;
• Three confirmed cases of diffuse gastric cancer in first-degree or second-degree relatives, regardless of age;
• A solitary case in the family of an individual diagnosed with diffuse gastric cancer before 40 years of age;
• A personal or family history of diffuse gastric cancer and lobular breast cancer, one of them diagnosed before 50 years of age.

Gene, specification:  CDH1 gene By NSG oncopanel testing and digital MLPA, see Panel of genes associated with hereditary cancer- oncopanel

Type of material to be examined: blood

Indicating specialists: medical genetics

At the same time, mutations in this gene are found in 0.2-2% of sporadic melanomas. Approximately 1% of hereditary melanomas have a germline mutation in the cyclin-dependent kinase encoded by the CDK4gene. These mutations disrupt the regulation of the central pathway of the cell cycle. Alterations in unknown genes account for the remaining 60%. Mutations in the CDKN2A gene cause about 60% lifetime risk of melanoma in the European population. On average, carriers of this mutation have a 53-fold (30-70-fold) increased risk compared to the general population. In addition to the risk of melanoma, mutation carriers may also have an increased risk of pancreatic cancer by 11-17%. Some studies have also reported a higher risk of breast cancer in mutation carriers. The knowledge of the molecular genetic basis of the disease enables a DNA-based diagnosis in families with the CDKN2A and CDK4predisposing genes, pre-symptomatic diagnosis and a preventive and therapeutic strategy based on this knowledge. Predictive examinations can also be performed in childhood.

INDICATION CRITERIA
1. Familial occurrence
• two malignant melanomas in the family in first- and second-degree direct relatives, at least one diagnosed under 50 years of age
• three or more malignant melanomas in the family line without age limitation
• occurrence of two malignant melanomas and breast or pancreatic cancer in direct relatives in the line
2. Sporadic occurrence
• recurrence of malignant melanoma in a patient, first diagnosed under 50 years of age - multiple malignancies in the patient
• breast cancer or pancreatic cancer and malignant melanoma, at least one diagnosed under 50 years of age

Gene, specification:  CDKN2A, CDK4 genes. By NSG oncopanel testing and digital MLPA, see Panel of genes associated with hereditary cancer – oncopanel

Type of material to be examined: blood

Indicating specialists: medical genetics

Von Hippel-Lindau syndrome is caused by a germline mutation in a gene called VHL that encodes a protein whose main function is to control the body's response to hypoxic conditions. If the VHL gene is mutated or lost, the degradation of HIF (Hypoxia Inducible Factor) is disrupted and subsequently also the regulation of other genes that influence processes leading to neoplasia. Thus, an abnormal or missing VHL gene may contribute to cancer. Other possible mechanisms include, for example, disruption of the normal course of the cell cycle or interference with the correct arrangement of fibronectin in the extracellular matrix. The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with a predisposition in the VHL gene and a preventive and therapeutic strategy based on this knowledge. Because of the possible manifestation of the disease in childhood, genetic counselling and testing can be offered at any age. 

INDICATION CRITERIA
• CNS and retinal hemangioblastoma or
• CNS or retinal hemangioblastoma and one of the following:
- multiple renal, pancreatic, or hepatic cysts
- pheochromocytoma
- renal cell carcinoma; or
• indisputable family medical history and simultaneously one of the following
- CNS or retinal hemangioblastoma
- multiple renal, pancreatic or hepatic cysts
- pheochromocytoma
- renal cell carcinoma

Gene, specification: VHL gene By NSG oncopanel testing and MLPA, see Panel of genes associated with hereditary cancer – oncopanel

Type of material to be examined: blood

Indicating specialists: medical genetics

The cause is germline mutations in the FH gene for fumarate hydratase. The determination of fumarate hydratase activity in lymphocytes followed by mutational analysis of the FH gene in individuals with reduced enzyme activity can be used to search for carriers of germline mutations in the FH gene. People with this diagnosis should be monitored for the presence of relevant diseases. The treatment of renal cell carcinoma in this syndrome should be radical in view of its aggressive nature. The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with a predisposition in the FH gene and a preventive and therapeutic strategy based on this knowledge. 

INDICATION CRITERIA 

1 Familial forms 

• Isolated cutaneous leiomyoma in a proband with a family history of cutaneous leiomyomas, uterine leiomyoma/leiomyosarcoma and/or renal cell carcinoma in first-degree relatives; 

• Two or more relatives with isolated renal cell carcinoma, where at least one case is histologically confirmed as papillary carcinoma type II, collecting duct carcinoma or tubulopapillary carcinoma. 

2 Sporadic forms 

• Multiple cutaneous leiomyomas, where at least one was confirmed histologically; 

• Isolated occurrence of cutaneous leiomyoma and concurrent uterine leiomyoma/leiomyosarcoma and/or renal cell carcinoma in a single person of any age; 

• Occurrence of renal cell carcinoma histologically confirmed as papillary carcinoma type II, collecting duct or tubulopapillary type carcinoma; 

Gene, specification: FH gene By NSG oncopanel testing and MLPA, see Panel of genes associated with hereditary cancer – oncopanel 

Type of material to be examined: blood

Indicating specialists: medical genetics 

MTC is a tumour arising from parafollicular cells of the thyroid gland and accounts for 4-10% of all thyroid tumours. It occurs mostly in a sporadic form (75%), less frequently in a familial form (25%). The familial form is inherited in an autosomal dominant manner and has three variants: familial MTC (FMTC), multiple endocrine neoplasia type 2A (MEN 2A) and multiple endocrine neoplasia type 2B (MEN 2B). Multiple endocrine neoplasia type 2A (MEN 2A) comprises 15-23% of all MTC families. More than 50% of patients have concurrent pheochromocytoma and 15-30% have primary hyperparathyroidism, the disease fully manifests between 25 and 35 years of age. MEN 2A is most commonly associated with mutations in exons 10 and 11. MEN 2B is the least common but most aggressive form of MTC. It comprises approximately 1% of all MTC families and full manifestation of the disease occurs between the ages of 10 and 20. Pheochromocytoma occurs in 50% of these patients, rarely hyperparathyroidism. The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with a predisposition in the RET gene and a preventive and therapeutic strategy based on this knowledge.

INDICATIVE CRITERIA
All patients with pathologically verified MTC (even sporadic MTC) should be genetically screened for the presence of germline mutations in the RET gene, and relatives at risk for the disease should be targeted. RET proto-oncogene screening should also be performed in all individuals with evidence of pheochromocytoma (which may be the first manifestation of MEN 2A) and in patients with Hirschsprung's disease who are at increased risk of MTC.

Gene, specification: VHL gene By NSG oncopanel testing and MLPA, see Panel of genes associated with hereditary cancer – oncopanel

Type of material to be examined: blood

Indicating specialists: medical genetics

The disease is clinically characterized by cerebellar ataxia, oculocutaneous telangiectasias, immune system defects, increased sensitivity to the effects of ionizing radiation and a marked tendency to develop tumours, especially lymphomas and leukaemia. The occurrence of breast cancer in patients with AT is relatively rare, which is mainly due to the significant shortening of life of biallelic mutations carriers. The relationship of ATM mutations to breast cancer is thus based on epidemiological analyses showing a modest but significantly increased lifetime risk of breast cancer in carriers of a monoallelic mutation in the ATM gene. The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with a predisposition in the ATM gene and a preventive and therapeutic strategy based on this knowledge. 

INDICATION CRITERIA 

Genetic testing of the ATM gene is recommended for individuals with clinically suspected ataxia telangiectasia. 

Gene, specification: ATM gene By NSG oncopanel testing and digital MLPA, see Panel of genes associated with hereditary cancer – oncopanel 

Type of material to be examined: blood

Indicating specialists: medical genetics 

Postnatally, bone and dental malformations or mental subnormalities may be present. Almost all patients with Gorlin syndrome will develop a skin tumour (most commonly basal cell carcinoma) during their lifetime, with up to 75% of basal cell carcinomas manifesting by the age of 20. In childhood, about 10% of those affected develop a tumour of the posterior cranial fossa, most commonly medulloblastoma. Jaw cysts are also often present in those affected, and ovarian fibroids in women.

The knowledge of the molecular genetic basis of the disease enables presymptomatic diagnosis at the DNA level in families with predispositions in the PTCH1 gene and a preventive and therapeutic strategy based on this knowledge. Genetic counselling and testing can be offered at any age.

INDICATION CRITERIA
Criteria for the diagnosis of Gorlin syndrome - two major or one major and two minor criteria must be met.

1. Major criteria
• multiple (more than two) basal cell carcinomas, at least one of them under 30 years of age, or more than 10 basal cell nevi
• any odontogenic keratocysts (histologically proven) or polyostotic bone cysts
• palmar or plantar pits (three or more)
• ectopic calcifications, lamellar or early (under 20 years of age) calcification of the falx cerebri
• family history of basal cell nevus syndrome
• congenital skeletal abnormalities: cleft, fusion, curvature or absence of ribs or cleft, wedge-shaped or fused vertebrae

2. Minor criteria
• macrocephaly - head circumference above the 97th percentile with frontal prominence
• congenital malformations: cleft lip and/or palate, polydactyly, hypertelorism, ocular anomalies (cataract, coloboma, microphthalmia)
• other skeletal abnormalities, e.g., Sprengel deformity, chest deformities, syndactyly
• radiological abnormalities, e.g., sella turcica bridging, vertebral anomalies
• cardiac or ovarian fibroma or medulloblastoma

Gene, specification: PTCH1 gene By NSG oncopanel testing and MLPA, see Panel of genes associated with hereditary cancer – oncopanel

Type of material to be examined: blood

Indicating specialists: medical genetics