Genetic predisposition to pancreatic cancer

Table 1 Syndromes and genes associated with hereditary predisposition to pancreatic adenocarcinoma, relative and lifetime risk

Settings of hereditary PC	RR of PC (-fold)	Cumulative lifetime risk by age 70 (%)	Genes identified
FPC syndrome			PALLD, CDKN2A, BRCA2, PALB2, ATM,….?
FDR with PC	2-3	2
FDRs with PC	6	8-12
or more FDRs with PC	14-32	40
Hereditary cancer syndromes
PJS	132	36	STK11/LKB1
MPCS/FAMMM	13-47	17	CDKN2A
HBOC	3.5-10	3-8	BRCA1, BRCA2
LS	8.6	< 5	MLH1, MSH2, MSH6
FAP	2-3	< 5	APC
Syndromes of chronic inflammation
HP	50-80	40	PRSS1, SPINK1
CF	5	< 5	CFTR

HP: Hereditary pancreatitis; FAP: Familial adenomatous polyposis; PC: Pancreatic adenocarcinoma; FDR: First-degree relative; PJS: Peutz-Jeghers syndrome; MPCS: Melanoma pancreatic-cancer syndrome; FAMMM: Familial atypical multiple mole melanoma; HBOC: Hereditary breast-ovarian cancer; LS: Lynch syndrome; FPC: Familial PC; CF: Cystic fibrosis; HP: Hereditary pancreatitis.

Table 2 Role of CDKN2A mutations in familial pancreatic adenocarcinoma and melanoma pancreatic-cancer syndrome

Study1	N° of FPC families	CDKN2A mutation found	Type of CDKN2A mutations	% of CDKN2A positive	N° of MPCS	CDKN2A mutation found	% of CDKN2A positive	Type of CDKN2A mutations
Slater et al[61] 2010; Bartsch et al[79] 2002	56	0	-	-	5	2	40	p.Q50X,
								p.E119X
McWilliams et al[80] 2010	119	3	c.-34G>T,p.V95fs,	2.5	39	2	5.3	p.D153spl,
			p.D153spl,					pL16R
Ghiorzo et al[42] 2012	16	5	p.E27X,p.G67R,	31	5	2	40	p.L65P,
			p.G101W,					p.G101W
			c. 201ACTC>CTTT
2Harinck et al[64] 2012	24	3	p.Ser8fs,	12	4	3	75	p.Ala76fs
			p.Ala76fs

¹This table only includes studies that analyze CDKN2A mutations in pancreatic adenocarcinoma (PC) probands from familial PC (FPC) families comparing them with PC probands from Melanoma pancreatic-cancer syndrome (MPCS) families belonging to the same population. The prevalence of CDKN2A mutations in MPCS/FAMMM-PC e families, as analyzed in melanoma probands, is described in the text.

²A melanoma was diagnosed in one FPC family after the proband was found to carry a mutation in CDKN2A.

Table 3 Proposed inclusion criteria for pancreatic adenocarcinoma screening programs in high-risk individuals, identified based on family history and possibly on genetic background

Current (based on family history alone or on genetic background):

Family history:

Three or more relatives in the same lineage affected by PC

Two relatives affected by PC, at least one of which is a FDR of the individual

Hereditary pancreatitis

> 10-fold increased risk as established by PancPRO

Genetic background:

Germline carrier of a mutation in a candidate gene with at least one FDR or SDR affected by PC

Mutation-positive individual in a PJS kindred

Proposed (based on family history and genetic background):

Family history: Identification of a hereditary syndrome or a 10-fold increased risk established by PancPRO

Genetic background: According to testing in candidate genes (CDKN2A, BRCA1-2, ATM, PALB2, STK11, PRSS1, SPINK1…)

Mutation identified: Propose screening to carriers of germline mutation

No mutation identified: Propose screening to all HRIs

In populations with a high prevalence of germline mutations in candidate genes (e.g., CDKN2A founder mutations in Italy or the Netherlands)

The same as above + test candidate genes according to specific genetic background, even in the absence of all criteria for hereditary syndromes or of a PancPRO score > 10

PC: Pancreatic adenocarcinoma; FDR: First-degree relative; PJS: Peutz-Jeghers syndrome; HRIs: High-risk individuals.