Genetic heterogeneity in Peutz-Jeghers syndrome

Abstract

LKB1, the human gene encoding a serine threonine kinase, was recently identified as a susceptibility gene for Peutz-Jeghers syndrome (PJS), a disease characterized by the constellation of intestinal hamartomata, oral mucocutaneous hyperpigmentation, and an increased risk for gastrointestinal as well as extraintestinal malignancies. To date, the majority of individuals with PJS have been found to have genetic alterations in LKB1, most of which result in protein truncation. Additionally, linkage analyses have suggested a modicum of genetic heterogeneity, with the majority of PJS families showing linkage to the LKB1 locus. In this study, we evaluated five kindreds with greater than two affected family members, five PJS probands with only one other affected family member, as well as 23 individuals with sporadic PJS for mutations within the LKB1 gene. Conformation sensitive gel electrophoresis was utilized for the initial screen, followed by direct sequence analysis for characterization. Long-range PCR was used for the detection of larger genetic insertions or deletions. Mutation analysis revealed genetic alterations in LKB1 in two probands who had a family history of PJS. LKB1 mutations were detected in only four of the remaining 23 cases of sporadic PJS. These data suggest the presence of significant genetic heterogeneity for PJS and the involvement of other loci in this syndrome.

Molecular and Clinical Characteristics in 46 Families Affected with Peutz–Jeghers Syndrome

“…Of the 46 PJS families in this study, an LKB1/STK11 mutation was identified in 59%, which is similar to the 50-90% frequency reported in other studies of LKB1/STK11 mutations in individuals with PJS [12,15,20,23]. The identification of LKB1/STK11 mutations in only 50-90% of probands (except for the study by Boardman et al [15]) with PJS is attributable to technical limitations of the testing methods presently used and also to genetic heterogeneity [9,10,15,23].…”

Molecular and Clinical Characteristics in 46 Families Affected with Peutz–Jeghers Syndrome

“…Of the 46 PJS families in this study, an LKB1/STK11 mutation was identified in 59%, which is similar to the 50-90% frequency reported in other studies of LKB1/STK11 mutations in individuals with PJS [12,15,20,23]. The identification of LKB1/STK11 mutations in only 50-90% of probands (except for the study by Boardman et al [15]) with PJS is attributable to technical limitations of the testing methods presently used and also to genetic heterogeneity [9,10,15,23].…”

Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome

“…All are nonconservative amino-acid changes that are highly conserved among human, mouse and Xenopus homologues of LKB1/STK11 and reside within the protein kinase core of LKB1/ STK11 (Collins et al, 2000). Table 2 shows the positions of the mutations observed in our study and in previously published reports (Hemminki et al, 1998;Gruber et al, 1989;Jenne et al, 1998;Mehenni et al, 1998;Nakagawa et al, 1998;Resta et al, 1998;Jiang et al, 1999;Kruse et al, 1999;Wang et al, 1999;Westerman et al, 1999b;Ylikorkala et al, 1999;Boardman et al, 2000;Miyaki et al, 2000;Yoon et al, 2000;Olschwang et al, 2001;Abed et al, 2001). Overall, most mutations reported to date have been frameshift or nonsense mutations and thus result in a truncated protein.…”

“…Olschwang et al (2001) recently reported a high frequency of proximal bile duct adenocarcinomas in PJS who did not carry LKB1/STK11 mutations. Similarly, Boardman et al (2000) reported a high frequency of cancer in this group of patients, although no cases of bile duct cancers were observed. In our study, we had few familial cases not caused by LKB1/STK11 mutations to enable us to compute a separate estimate of risk for noncarriers.…”

Two novel STK11 missense mutations induce phosphorylation of S6K and promote cell proliferation in Peutz‑Jeghers syndrome

“…In total, 3 of the truncation mutations identified in the present study have previously been described (7,24,25), and 1 is novel [c.143_144insA (p.Try49Valfs*114)] (PJS2; Table II). The novel mutation involves an insertion of nucleotide A between nucleotides 143 and 144 in exon 1.…”

Molecular and Clinical Characteristics in 46 Families Affected with Peutz–Jeghers Syndrome

“…Of the 46 PJS families in this study, an LKB1/STK11 mutation was identified in 59%, which is similar to the 50-90% frequency reported in other studies of LKB1/STK11 mutations in individuals with PJS [12,15,20,23]. The identification of LKB1/STK11 mutations in only 50-90% of probands (except for the study by Boardman et al [15]) with PJS is attributable to technical limitations of the testing methods presently used and also to genetic heterogeneity [9,10,15,23].…”

Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome

“…All are nonconservative amino-acid changes that are highly conserved among human, mouse and Xenopus homologues of LKB1/STK11 and reside within the protein kinase core of LKB1/ STK11 (Collins et al, 2000). Table 2 shows the positions of the mutations observed in our study and in previously published reports (Hemminki et al, 1998;Gruber et al, 1989;Jenne et al, 1998;Mehenni et al, 1998;Nakagawa et al, 1998;Resta et al, 1998;Jiang et al, 1999;Kruse et al, 1999;Wang et al, 1999;Westerman et al, 1999b;Ylikorkala et al, 1999;Boardman et al, 2000;Miyaki et al, 2000;Yoon et al, 2000;Olschwang et al, 2001;Abed et al, 2001). Overall, most mutations reported to date have been frameshift or nonsense mutations and thus result in a truncated protein.…”

“…Olschwang et al (2001) recently reported a high frequency of proximal bile duct adenocarcinomas in PJS who did not carry LKB1/STK11 mutations. Similarly, Boardman et al (2000) reported a high frequency of cancer in this group of patients, although no cases of bile duct cancers were observed. In our study, we had few familial cases not caused by LKB1/STK11 mutations to enable us to compute a separate estimate of risk for noncarriers.…”

Two novel STK11 missense mutations induce phosphorylation of S6K and promote cell proliferation in Peutz‑Jeghers syndrome

“…In total, 3 of the truncation mutations identified in the present study have previously been described (7,24,25), and 1 is novel [c.143_144insA (p.Try49Valfs*114)] (PJS2; Table II). The novel mutation involves an insertion of nucleotide A between nucleotides 143 and 144 in exon 1.…”

Molecular and Clinical Characteristics in 46 Families Affected with Peutz–Jeghers Syndrome

“…Of the 46 PJS families in this study, an LKB1/STK11 mutation was identified in 59%, which is similar to the 50-90% frequency reported in other studies of LKB1/STK11 mutations in individuals with PJS [12,15,20,23]. The identification of LKB1/STK11 mutations in only 50-90% of probands (except for the study by Boardman et al [15]) with PJS is attributable to technical limitations of the testing methods presently used and also to genetic heterogeneity [9,10,15,23].…”

Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome

“…All are nonconservative amino-acid changes that are highly conserved among human, mouse and Xenopus homologues of LKB1/STK11 and reside within the protein kinase core of LKB1/ STK11 (Collins et al, 2000). Table 2 shows the positions of the mutations observed in our study and in previously published reports (Hemminki et al, 1998;Gruber et al, 1989;Jenne et al, 1998;Mehenni et al, 1998;Nakagawa et al, 1998;Resta et al, 1998;Jiang et al, 1999;Kruse et al, 1999;Wang et al, 1999;Westerman et al, 1999b;Ylikorkala et al, 1999;Boardman et al, 2000;Miyaki et al, 2000;Yoon et al, 2000;Olschwang et al, 2001;Abed et al, 2001). Overall, most mutations reported to date have been frameshift or nonsense mutations and thus result in a truncated protein.…”

“…Olschwang et al (2001) recently reported a high frequency of proximal bile duct adenocarcinomas in PJS who did not carry LKB1/STK11 mutations. Similarly, Boardman et al (2000) reported a high frequency of cancer in this group of patients, although no cases of bile duct cancers were observed. In our study, we had few familial cases not caused by LKB1/STK11 mutations to enable us to compute a separate estimate of risk for noncarriers.…”

Two novel STK11 missense mutations induce phosphorylation of S6K and promote cell proliferation in Peutz‑Jeghers syndrome

“…In total, 3 of the truncation mutations identified in the present study have previously been described (7,24,25), and 1 is novel [c.143_144insA (p.Try49Valfs*114)] (PJS2; Table II). The novel mutation involves an insertion of nucleotide A between nucleotides 143 and 144 in exon 1.…”