Practical Management Protocol

Purpose
This protocol provide practical recommendations for identifying, assessing, and managing individuals and families at risk for hereditary cancer syndromes. The document is designed to meet the standards required for European accreditation of genetic counseling units.

Genetic Counseling Process

• Pre-test counseling:
• Evaluate personal/family history
• Discuss implications of results for patient and relatives
• Explain possible outcomes (positive, negative, VUS)
• Informed consent is mandatory
• Post-test counseling:
• Interpret results with clinical context
• Coordinate cascade testing for relatives
• Offer psychosocial support as needed

Psychosocial and Ethical Considerations

• Ensure patient autonomy and confidentiality
• Assess psychological readiness for genetic results
• Support family communication strategies
• Follow national legal frameworks for genetic information disclosure

1. Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

1.1 Overview Hereditary Breast and Ovarian Cancer Syndrome is primarily associated with germline mutations in the BRCA1 and BRCA2 genes. Additional moderate-penetrance genes such as PALB2, ATM, and CHEK2 are increasingly recognized as relevant in risk assessment.

1.2 Criteria for Germline Genetic Testing Genetic testing for HBOC should be offered when any of the following criteria are met:

• Individual with breast cancer diagnosed < 50 years
• Triple-negative breast cancer diagnosed < 60 years
• Ovarian, fallopian tube, or primary peritoneal cancer at any age
• Male breast cancer at any age
• Multiple primary breast cancers in the same individual
• Ashkenazi Jewish ancestry with personal or family history of breast/ovarian cancer
• Known pathogenic BRCA1/2 mutation in a relative
• Family history with ≥2 breast cancers (especially if < 50 y), ovarian cancer, pancreatic cancer, or high-grade prostate cancer
• Pancreatic cancer or metastatic/ductal prostate cancer in an individual with any family history of HBOC-associated tumors

1.3 Risk Management Strategies

1.4 Family Screening and Counseling

• Cascade testing should be offered to at-risk family members when a pathogenic variant is identified.
• Testing should ideally begin with the affected individual.
• If no mutation is found but the family history is strong, consider multigene panel testing or re-evaluation with updates in guidelines.

1.5 Follow-Up and Documentation

• All individuals undergoing testing should have pre- and post-test genetic counseling.
• Clear documentation of variants, VUS (variants of uncertain significance), and clinical decisions is essential.
• Consider periodic re-contact as variant classifications and recommendations evolve.

2. Lynch Syndrome (Hereditary Colorectal and Endometrial Cancer)

Overview:
Lynch syndrome is caused by germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or EPCAM deletions. It confers high lifetime risks of colorectal, endometrial, ovarian, gastric, small bowel, urinary tract, and other cancers.

Criteria for Genetic Testing (revised Bethesda / NCCN guidelines):

• Colorectal or endometrial cancer diagnosed before age 50
• Presence of synchronous/metachronous LS-associated tumors
• Tumors with MMR deficiency or MSI-H
• ≥1 first-degree relative with LS-related cancer diagnosed before age 50
• ≥2 first- or second-degree relatives with LS-related cancers regardless of age
• Known MMR mutation in the family

Risk Management Recommendations:

• Risk-reducing hysterectomy and salpingo-oophorectomy may be offered after childbearing is complete.
• Immunotherapy may be an option in MMR-deficient advanced tumors.

3. Hereditary Polyposis Syndromes

Polyposis syndromes are grouped by polyp histology: adenomatous or non-adenomatous. Genetic testing and management depend on clinical and endoscopic findings.

3.1 Adenomatous Polyposis Syndromes

Familial Adenomatous Polyposis (FAP)

• Gene: APC
• Phenotype: >100 colorectal adenomas, CHRPE, desmoid tumors, duodenal adenomas, thyroid cancer
• Genetic Testing Criteria: ≥10–20 adenomas, any age; family history of FAP; pathogenic APC variant

Management:

• Colonoscopy or sigmoidoscopy from age 10–12 y every 1–2 years
• Colectomy when polyp burden is unmanageable
• Upper GI endoscopy from age 20–25 y
• Surveillance for desmoid tumors and thyroid nodules

MUTYH-Associated Polyposis (MAP)

• Gene: MUTYH (biallelic mutations)
• Phenotype: 10–100 adenomas, increased CRC risk
• Testing Criteria: ≥10 adenomas, especially with autosomal recessive inheritance
• Management: Similar to attenuated FAP; begin colonoscopy at 25–30 y

Polymerase Proofreading-Associated Polyposis (PPAP)

• Genes: POLE, POLD1
• Phenotype: Multiple adenomas, CRC, endometrial cancer
• Testing Criteria: Multiple adenomas + early-onset or family history of cancer
• Management: Colonoscopy every 1–2 years from age 20–25 y; endometrial screening based on family history

NTHL1-Associated Polyposis

• Gene: NTHL1 (biallelic)
• Phenotype: Adenomas, CRC, breast, endometrial, brain tumors
• Management: Colonoscopy from 25 y every 1–2 years; organ-specific screening based on family history

GREM1 Duplication-Associated Polyposis

• Gene: GREM1
• Seen in: Ashkenazi Jewish population
• Phenotype: Mixed polyps (adenomas/serrated); CRC
• Management: Like attenuated FAP

3.2 Non-Adenomatous Polyposis Syndromes

4. Hereditary Renal Cancer Syndromes

Renal cell carcinoma (RCC) may arise in the context of inherited cancer syndromes. These syndromes are usually autosomal dominant.

4.1 Von Hippel–Lindau (VHL) Syndrome

• Gene: VHL
• Associated tumors: Clear cell RCC, hemangioblastomas (CNS, retina), pheochromocytoma, pancreatic neuroendocrine tumors, endolymphatic sac tumors
• Surveillance: Abdominal MRI from age 15–18 every 1–2 years; annual ophthalmologic and CNS imaging exams
• Gene: FLCN
• Associated tumors: Chromophobe RCC, oncocytic tumors, spontaneous pneumothorax, fibrofolliculomas
• Surveillance: Renal MRI from age 20 every 3 years; lung CT if pneumothorax history
• Gene: FH
• Associated tumors: Papillary type 2 RCC (aggressive), uterine and cutaneous leiomyomas
• Surveillance: Annual renal MRI from age 10; early referral for nephrectomy in small tumors
• Gene: MET
• Tumor type: Papillary type 1 RCC
• Surveillance: Annual abdominal imaging from age 30
• Gene: BAP1
• Tumors: Clear cell RCC, mesothelioma, uveal melanoma
• Surveillance: Annual renal imaging from age 30; dermatologic and ophthalmologic evaluations
• Genes: TSC1, TSC2
• Associated tumors: Angiomyolipomas, SEGA, facial angiofibromas
• Surveillance: Renal MRI from infancy every 1–3 years; CNS imaging
• Gene: PTEN
• Associated tumors: RCC (less common), breast, thyroid, endometrial
• Surveillance: Consider renal imaging starting at age 40 based on individual risk

4.2 Birt–Hogg–Dubé (BHD) Syndrome

4.3 Hereditary Leiomyomatosis and RCC (HLRCC, Reed syndrome)

4.4 Hereditary Papillary Renal Cell Carcinoma (HPRC)

4.5 BAP1 Tumor Predisposition Syndrome

4.6 Tuberous Sclerosis Complex (TSC)

4.7 Cowden Syndrome (PTEN Hamartoma Syndrome)

5. Hereditary Gastric Cancer Syndromes

5.1 Hereditary Diffuse Gastric Cancer (HDGC)

Overview: HDGC is an autosomal dominant cancer syndrome caused primarily by pathogenic variants in the CDH1 gene and, less frequently, in CTNNA1. It is characterized by an increased risk of diffuse-type gastric cancer and lobular breast cancer.

Genetic Testing Criteria: (based on IGCLC 2020 guidelines):

• ≥2 cases of gastric cancer in a family, with at least one confirmed diffuse type, regardless of age
• One case of diffuse gastric cancer before age 50
• Personal or family history of both diffuse gastric cancer and lobular breast cancer, with one diagnosed before age 70
• Bilateral lobular breast cancer or lobular breast cancer before age 50 with a family history of diffuse gastric cancer
• Known CDH1 or CTNNA1 pathogenic variant in the family

Management:

5.2 Gastric Cancer Associated with Polyposis Syndromes

Overview: Gastric cancer risk may also be elevated in certain polyposis syndromes due to hamartomatous or adenomatous polyps in the stomach.

Management Summary:

• Family history and genotype should guide timing and intensity of surveillance.
• Coordination with gastroenterology is essential for high-risk endoscopic evaluation.
• In GAPPS and HDGC, prophylactic gastrectomy may be indicated due to the risk of invisible or multifocal lesions.

6. Familial Pancreatic Cancer (FPC)

Overview:
FPC is defined as pancreatic ductal adenocarcinoma (PDAC) occurring in ≥2 first-degree relatives without an identified germline mutation. Germline mutations may be found in genes such as BRCA1/2, PALB2, ATM, CDKN2A, STK11, PRSS1, and others.

Criteria for Genetic Testing:

• ≥2 first-degree relatives with PDAC
• PDAC diagnosis <50 years
• Personal/family history of other related cancers (breast, ovarian, melanoma, prostate)
• Known pathogenic germline variant in family

Risk Management:

• Screening with EUS or MRI/MRCP in high-risk individuals (e.g., carriers of pathogenic variants in BRCA2, PALB2, CDKN2A, STK11, etc.)
• Initiate at age 50 or 10 years before the youngest PDAC in the family
• Lifestyle counseling: avoid smoking, maintain healthy weight, manage diabetes

7. Hereditary Prostate Cancer

Overview:
Germline mutations in BRCA2, BRCA1, HOXB13, ATM, CHEK2, and mismatch repair genes are associated with increased prostate cancer (PC) risk, especially for early-onset and aggressive disease.

Criteria for Genetic Testing:

• Metastatic prostate cancer
• High-grade or intraductal carcinoma at any age
• PC diagnosis ≤55 y, or family history of breast, ovarian, pancreatic, or prostate cancer
• Ashkenazi Jewish ancestry with PC

Risk Management:

• Begin PSA screening at age 40 for BRCA2/HOXB13 carriers or earlier if family history is strong
• Annual digital rectal exam and PSA monitoring
• Consider MRI-based screening protocols for high-risk individuals

8. Familial Melanoma

Overview:
Familial melanoma is often linked to mutations in CDKN2A and CDK4, and possibly BAP1. It is characterized by multiple primary melanomas, early age at diagnosis, and a family history of melanoma and/or pancreatic cancer.

Criteria for Genetic Testing:

• ≥2 family members with melanoma
• Multiple primary melanomas in one individual
• Melanoma + pancreatic cancer in the family

Risk Management:

• Dermatologic exam every 6–12 months starting in childhood or early adolescence
• Sun protection education
• Consider pancreatic screening in CDKN2A mutation carriers

9. Hereditary Neuroendocrine Tumor Syndromes

Hereditary neuroendocrine tumors (NETs) encompass a diverse group of syndromes characterized by predisposition to develop tumors arising from neuroendocrine cells. These include medullary thyroid carcinoma, pheochromocytoma/paraganglioma, pancreatic neuroendocrine tumors, and others associated with well-characterized germline mutations.

9.1 Medullary Thyroid Carcinoma (MTC)

• Gene: RET proto-oncogene
• Associated Syndromes: MEN2A, MEN2B, Familial MTC
• Genetic Testing Indications:
• Any diagnosis of MTC, regardless of age
• Family history of MTC or MEN2 syndromes
• Multiple endocrine neoplasia features
• Risk Management:
• Prophylactic thyroidectomy based on RET mutation risk category (timing varies from infancy to adulthood)
• Annual biochemical screening with serum calcitonin and carcinoembryonic antigen (CEA)
• Annual neck ultrasound
• Genetic counseling for family members

9.2 Pheochromocytoma and Paraganglioma (PPGL)

• Genes: RET, VHL, SDHB, SDHD, SDHC, MAX, TMEM127, FH, and others
• Testing Criteria:
• All cases of PPGL, especially if:
• Diagnosis before 45 years
• Bilateral, multifocal, or extra-adrenal tumors
• Family history of PPGL or related tumors
• Malignant or recurrent tumors
• Management:
• Annual biochemical screening with plasma or urinary metanephrines and catecholamines
• Imaging surveillance (MRI or CT) every 2–3 years for mutation carriers without tumors
• Preoperative management to control hypertension and prevent intraoperative crises
• Genetic counseling for family members

9.3 Multiple Endocrine Neoplasia (MEN) Syndromes

• MEN1 (MEN1 gene mutation):
• Characterized by parathyroid hyperplasia/adenomas, pancreatic neuroendocrine tumors (gastrinomas, insulinomas), and pituitary adenomas.
• Testing criteria: clinical diagnosis of MEN1 or family history.
• Management: regular biochemical screening (calcium, PTH, gastrin, prolactin, insulin), imaging surveillance.
• MEN2 (RET mutations):
• See section 9.1 (MTC and PPGL).

9.4 Syndromic Thyroid and Gastrointestinal Neuroendocrine Tumors

• PTEN Hamartoma Tumor Syndrome (Cowden Syndrome):
• Predisposition to thyroid follicular and papillary carcinoma, and sometimes gastrointestinal carcinoids.
• Testing criteria: personal/family history of Cowden features.
• Management: regular thyroid ultrasound, endoscopic surveillance for gastrointestinal polyps/neoplasms.
• DICER1 Syndrome:
• Predisposes to thyroid neoplasms and rare NETs.
• Testing if clinical suspicion based on tumor spectrum.

9.5 Gastrointestinal Stromal Tumors (GIST)

• Genes: SDH subunits (SDHB, SDHC, SDHD), KIT, PDGFRA
• Associated Syndromes: Carney-Stratakis dyad, Carney triad
• Testing Criteria:
• Young patients with GIST
• Family history of GIST or paragangliomas
• Management:
• Regular imaging and endoscopic surveillance
• Surgical and targeted therapy based on tumor genotype

9.6 Adrenocortical Tumor Syndromes

• Associated Syndromes: Li-Fraumeni Syndrome (TP53 mutations), Beckwith-Wiedemann Syndrome
• Testing Criteria:
• Pediatric/adolescent adrenocortical tumors
• Family history of syndromic cancers
• Management:
• Clinical and imaging follow-up per syndrome protocols
• Avoidance of radiotherapy where possible

Summary Table for Neuroendocrine Tumor Syndromes

9. Hereditary Neuroendocrine Tumor Syndromes

9.1 Medullary Thyroid Carcinoma (MTC)

• Gene: RET
• Syndromes: MEN2A, MEN2B, familial MTC
• Testing Criteria: Any MTC or family history of MEN2
• Management: Prophylactic thyroidectomy based on RET mutation risk level; annual calcitonin and neck ultrasound

9.2 Pheochromocytoma/Paraganglioma (PPGL)

• Genes: RET, VHL, SDHB, SDHD, SDHC, MAX, TMEM127, etc.
• Testing Criteria: All PPGL cases, particularly <45 y or bilateral/multifocal tumors
• Management: Annual BP, plasma metanephrines, MRI every 2–3 years

9.3 MEN1 and MEN2 Syndromes

• MEN1 (gene MEN1): Parathyroid, pancreatic neuroendocrine tumors, pituitary tumors
• MEN2 (gene RET): MTC, pheochromocytoma, parathyroid hyperplasia
• Testing Criteria: Any combination of the above tumors or family history
• Management: Biochemical and imaging surveillance per tumor type from childhood/adolescence

9.4 Syndromic Thyroid Cancer

• Includes PTEN-related (Cowden), DICER1 syndrome
• Requires tailored surveillance based on syndrome

9.5 Gastrointestinal Stromal Tumors (GIST)

• Genes: SDH subunits, KIT, PDGFRA
• Associated with: Carney-Stratakis, Carney triad
• Management: Periodic endoscopic and imaging studies

9.6 Adrenocortical Tumor Syndromes

• Associated with: Li-Fraumeni syndrome (TP53), Beckwith-Wiedemann syndrome
• Testing: Pediatric ACT or bilateral tumors

10. Li-Fraumeni Syndrome (LFS)

Overview:
Caused by germline mutations in TP53, LFS confers a high lifetime risk for diverse early-onset cancers: breast cancer, sarcomas, brain tumors, leukemia, adrenocortical carcinoma, and others.

Criteria for Genetic Testing:

• Classic LFS criteria or Chompret criteria (early-onset cancers, multiple primary tumors, family history)

Risk Management (per Toronto Protocol):

• Whole-body MRI annually from infancy/childhood
• Brain MRI annually
• Breast MRI from age 20 (or earlier), consider risk-reducing mastectomy
• Dermatologic, neurologic, and hematologic exams
• Avoid radiation therapy when posible

Conclusion

Hereditary cancer predisposition syndromes represent a complex but critical field in precision oncology and preventive medicine. Early identification through rigorous genetic testing criteria allows for personalized surveillance, risk-reducing interventions, and targeted therapies that can significantly improve patient outcomes and reduce cancer-related morbidity and mortality. A multidisciplinary approach involving genetic counselors, oncologists, surgeons, and primary care providers is essential for effective management. This practical protocol consolidates current evidence-based recommendations for genetic evaluation and risk management, facilitating standardized care in a genetic counseling unit seeking European accreditation. Continuous advances in genomics and evolving guidelines necessitate ongoing education and updates to maintain the highest standard of patient care.

Bibliography

1. Hereditary Breast and Ovarian Cancer (BRCA1/2)
• NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024.
• Kuchenbaecker KB, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017.
2. Lynch Syndrome
• Vasen HF, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013.
• National Comprehensive Cancer Network (NCCN) Guidelines for Lynch Syndrome. Version 2.2024.
3. Hereditary Polyposis Syndromes
• Jasperson KW, et al. Hereditary and familial colon cancer. Gastroenterology. 2010.
• Boardman LA, et al. Hereditary colorectal cancer syndromes: Molecular genetics, genetic counseling, diagnosis and management. Gastroenterol Clin North Am. 2010.
4. Hereditary Renal Cancer Syndromes
• Linehan WM, et al. Hereditary kidney cancer: unique opportunity for disease-based therapy. Cancer. 2010.
• NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer, Version 1.2024.
5. Hereditary Gastric Cancer
• Guilford P, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998.
• Hansford S, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncology. 2015.
6. Familial Pancreatic Cancer
• Klein AP, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Research. 2004.
• Goggins M, et al. Familial pancreatic cancer: genetic advances and clinical implications. Gut. 2017.
7. Hereditary Prostate Cancer
• Castro E, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013.
• NCCN Guidelines for Prostate Cancer Early Detection, Version 2.2024.
8. Familial Melanoma
• Goldstein AM, et al. Familial melanoma: clinical features and genetic counseling. Journal of the American Academy of Dermatology. 2005.
• Hayward NK, et al. Genetics of melanoma predisposition. Pigment Cell Melanoma Res. 2017.
9. Neuroendocrine Tumor Syndromes
• Wells SA Jr, et al. The MEN2 syndromes: Clinical features and management guidelines. Journal of Clinical Endocrinology & Metabolism. 2013.
• Lenders JW, et al. Pheochromocytoma and paraganglioma: clinical and genetic approaches. Endocrine Reviews. 2014.
10. Li-Fraumeni Syndrome
• Malkin D, et al. Germline TP53 mutations in a familial cancer syndrome. Science. 1990.
• Schneider K, et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nature Reviews Clinical Oncology. 2011.