Hereditary cancer syndromes

Table 1 Health impact of major hereditary cancer genes: Frequency of pathogenic variants in non-selected subjects and oncological patients

Gene	Frequency of pathogenic variants in population	Contribution in cancer morbidity	Ref.
BRCA1	Approximately 0.1%; > 1% in some founder populations	Breast cancer: 1%-3%; High-grade serous ovarian cancer: 15%-30%	[5,6,45,230-233]
BRCA2	Approximately 0.3%; > 1% in some founder populations	Breast cancer: 1%-3%; High-grade serous ovarian cancer: 7%-12%; Prostate cancer: 2%-4%; Pancreatic cancer: 2%-3%	[5,6,45,99,102,112,232,233]
PALB2	Approximately 0.1%	Breast cancer: Approximately 0.5%-1%	[5,6,45]
CHEK2	0.5%-0.7%	Breast cancer: 0.5%-2%; Moderately elevated frequencies across several cancer types	[5,6,25,113,234,235]
ATM	0.3%-0.5%	Breast cancer: 0.5%-0.8%; Moderately elevated frequencies across several cancer types	[5,6,45,99,102,113]
MLH1, MSH2, MSH6, PMS2, EPCAM	0.02%-0.05% for MLH1, MSH2, MSH6, EPCAM each; approximately 0.1% for PMS2	Colorectal cancer: 1%-6%; Endometrial cancer: 2%-6%	[5,6,76,236-238]
CDH1	< 0.005%	Diffuse gastric cancer: 7%; Lobular breast cancer: 0.3%	[5,6,92]
TP53	< 0.01%	Breast cancer in women < 30 years old: 2%-6%; Pediatric cancers: 8%; Osteosarcoma: 4%	[161,239,240]
HOXB13	0.2%-0.4%	Prostate cancer: Approximately 1%	[112,117,241]

Table 2 Cytotoxic and targeted therapy for tumors arising in carriers of cancer-predisposing alleles

Tumor type	Target	Drugs	Ref.
BRCA1/2-driven carcinomas and their phenocopies	BRCA1/2 inactivation resulting in the deficiency of DNA repair by homologous recombination	Platinum derivatives, Mitomycin C, Bifunctional alkylating agents, PARPi	[190-193,195]
Hypermutated cancers (Lynch syndrome associated microsatellite unstable tumors; POLD1/POLE-deficient cancers; MUTYH-associated colorectal carcinomas; tumors in patients with CMMRD syndrome)	High tumor mutation burden resulting in excessive number of neoantigens	Immune checkpoint inhibitors	[199-206]
RET-associated malignancies	RET tyrosine kinase	RET inhibitors	[207-209]
Neurofibromatosis, type 1	Upregulation of RAS/RAF/MEK pathway due to NF1 inactivation	MEK inhibitors	[210,211]
Basal cell carcinomas in patients with Gorlin syndrome	Hedgehog pathway	SMO inhibitors	[213]
Tumors arising in patients with tuberous sclerosis	mTOR pathway	mTOR inhibitors	[214,215]
Renal cell carcinomas associated with von Hippel-Lindau syndrome	Up-regulation of HIF-2α due to VHL gene inactivation	HIF-2α inhibitors	[216]

HIF-2α: Hypoxia inducible factor-2α; PARPi: Poly (ADP-ribose) polymerase inhibitors; CMMRD: Constitutional mismatch repair deficiency syndrome; MEK: Mitogen-activated protein kinase; SMO: Smoothened; mTOR: Mechanistic target of rapamycin; VHL: von Hippel-Lindau.