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Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X.

Schulz E, Klampfl P, Holzapfel S, Janecke AR, Ulz P, Renner W, Kashofer K, Nojima S, Leitner A, Zebisch A, Wölfler A, Hofer S, Gerger A, Lax S, Beham-Schmid C, Steinke V, Heitzer E, Geigl JB, Windpassinger C, Hoefler G, Speicher MR, Boland CR, Kumanogoh A, Sill H - Nat Commun (2014)

Bottom Line: Here we identify the SEMA4A p.Val78Met germline mutation in an Austrian kindred with FCCTX, using an integrative genomics strategy.In a cohort of 53 patients with FCCTX, we depict two further SEMA4A mutations, p.Gly484Ala and p.Ser326Phe and the single-nucleotide polymorphism (SNP) p.Pro682Ser.Our study shows previously unidentified germline variants in SEMA4A predisposing to FCCTX, which has implications for surveillance strategies of patients and their families.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.

ABSTRACT
Familial colorectal cancer type X (FCCTX) is characterized by clinical features of hereditary non-polyposis colorectal cancer with a yet undefined genetic background. Here we identify the SEMA4A p.Val78Met germline mutation in an Austrian kindred with FCCTX, using an integrative genomics strategy. Compared with wild-type protein, SEMA4A(V78M) demonstrates significantly increased MAPK/Erk and PI3K/Akt signalling as well as cell cycle progression of SEMA4A-deficient HCT-116 colorectal cancer cells. In a cohort of 53 patients with FCCTX, we depict two further SEMA4A mutations, p.Gly484Ala and p.Ser326Phe and the single-nucleotide polymorphism (SNP) p.Pro682Ser. This SNP is highly associated with the FCCTX phenotype exhibiting increased risk for colorectal cancer (OR 6.79, 95% CI 2.63 to 17.52). Our study shows previously unidentified germline variants in SEMA4A predisposing to FCCTX, which has implications for surveillance strategies of patients and their families.

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Pedigrees of families with germline SEMA4A mutations.Families with V78M (a), G484A (b) and S326F (c) mutations are shown. L, individual included in LA; S, individual included in WES; asterisk, SEMA4A mutation carrier; minus, SEMA4A wild type; black symbol, CRC; checkered symbol, colorectal adenoma; dark grey, malignant neoplasm; light grey, benign neoplasm; number in symbol, number of unspecified offspring. AML, acute myeloid leukaemia; BC, breast cancer; CRA, colorectal adenoma; GyT, gynaecologic tumour; OvC, ovarian cancer; PC, prostate cancer; TA, thyroid adenoma; TC, testicular cancer; UC; uterine cancer; UT, uterine tumour. Results of mutational analyses are indicated in tested individuals only. Age at diagnosis (years) is given in parentheses. For multiple colorectal adenomas, age at first presentation or at screening colonoscopy is indicated. An extended pedigree of the family with the V78M mutation including age of the individuals is shown in Supplementary Fig. 1, histopathological characteristics of their colorectal neoplasms are summarized in Table 1.
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f1: Pedigrees of families with germline SEMA4A mutations.Families with V78M (a), G484A (b) and S326F (c) mutations are shown. L, individual included in LA; S, individual included in WES; asterisk, SEMA4A mutation carrier; minus, SEMA4A wild type; black symbol, CRC; checkered symbol, colorectal adenoma; dark grey, malignant neoplasm; light grey, benign neoplasm; number in symbol, number of unspecified offspring. AML, acute myeloid leukaemia; BC, breast cancer; CRA, colorectal adenoma; GyT, gynaecologic tumour; OvC, ovarian cancer; PC, prostate cancer; TA, thyroid adenoma; TC, testicular cancer; UC; uterine cancer; UT, uterine tumour. Results of mutational analyses are indicated in tested individuals only. Age at diagnosis (years) is given in parentheses. For multiple colorectal adenomas, age at first presentation or at screening colonoscopy is indicated. An extended pedigree of the family with the V78M mutation including age of the individuals is shown in Supplementary Fig. 1, histopathological characteristics of their colorectal neoplasms are summarized in Table 1.

Mentions: In the course of a previous study focusing on pedigree analysis of patients with therapy-related myeloid neoplasms1011, we have identified a large Austrian kindred with FCCTX (Family K, Fig. 1a; Supplementary Fig. 1). CRCs in this family were inherited in an autosomal dominant pattern with incomplete penetrance meeting AC-I. In each affected individual, one to six colorectal adenomas and one to two CRCs were diagnosed at a median age of 62.5 years (range, 44–72). The majority of colorectal neoplasms was located in the distal colon and rectum and showed tubular histological features without evidence for an increase of infiltrating lymphocytes (Table 1).


Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X.

Schulz E, Klampfl P, Holzapfel S, Janecke AR, Ulz P, Renner W, Kashofer K, Nojima S, Leitner A, Zebisch A, Wölfler A, Hofer S, Gerger A, Lax S, Beham-Schmid C, Steinke V, Heitzer E, Geigl JB, Windpassinger C, Hoefler G, Speicher MR, Boland CR, Kumanogoh A, Sill H - Nat Commun (2014)

Pedigrees of families with germline SEMA4A mutations.Families with V78M (a), G484A (b) and S326F (c) mutations are shown. L, individual included in LA; S, individual included in WES; asterisk, SEMA4A mutation carrier; minus, SEMA4A wild type; black symbol, CRC; checkered symbol, colorectal adenoma; dark grey, malignant neoplasm; light grey, benign neoplasm; number in symbol, number of unspecified offspring. AML, acute myeloid leukaemia; BC, breast cancer; CRA, colorectal adenoma; GyT, gynaecologic tumour; OvC, ovarian cancer; PC, prostate cancer; TA, thyroid adenoma; TC, testicular cancer; UC; uterine cancer; UT, uterine tumour. Results of mutational analyses are indicated in tested individuals only. Age at diagnosis (years) is given in parentheses. For multiple colorectal adenomas, age at first presentation or at screening colonoscopy is indicated. An extended pedigree of the family with the V78M mutation including age of the individuals is shown in Supplementary Fig. 1, histopathological characteristics of their colorectal neoplasms are summarized in Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214414&req=5

f1: Pedigrees of families with germline SEMA4A mutations.Families with V78M (a), G484A (b) and S326F (c) mutations are shown. L, individual included in LA; S, individual included in WES; asterisk, SEMA4A mutation carrier; minus, SEMA4A wild type; black symbol, CRC; checkered symbol, colorectal adenoma; dark grey, malignant neoplasm; light grey, benign neoplasm; number in symbol, number of unspecified offspring. AML, acute myeloid leukaemia; BC, breast cancer; CRA, colorectal adenoma; GyT, gynaecologic tumour; OvC, ovarian cancer; PC, prostate cancer; TA, thyroid adenoma; TC, testicular cancer; UC; uterine cancer; UT, uterine tumour. Results of mutational analyses are indicated in tested individuals only. Age at diagnosis (years) is given in parentheses. For multiple colorectal adenomas, age at first presentation or at screening colonoscopy is indicated. An extended pedigree of the family with the V78M mutation including age of the individuals is shown in Supplementary Fig. 1, histopathological characteristics of their colorectal neoplasms are summarized in Table 1.
Mentions: In the course of a previous study focusing on pedigree analysis of patients with therapy-related myeloid neoplasms1011, we have identified a large Austrian kindred with FCCTX (Family K, Fig. 1a; Supplementary Fig. 1). CRCs in this family were inherited in an autosomal dominant pattern with incomplete penetrance meeting AC-I. In each affected individual, one to six colorectal adenomas and one to two CRCs were diagnosed at a median age of 62.5 years (range, 44–72). The majority of colorectal neoplasms was located in the distal colon and rectum and showed tubular histological features without evidence for an increase of infiltrating lymphocytes (Table 1).

Bottom Line: Here we identify the SEMA4A p.Val78Met germline mutation in an Austrian kindred with FCCTX, using an integrative genomics strategy.In a cohort of 53 patients with FCCTX, we depict two further SEMA4A mutations, p.Gly484Ala and p.Ser326Phe and the single-nucleotide polymorphism (SNP) p.Pro682Ser.Our study shows previously unidentified germline variants in SEMA4A predisposing to FCCTX, which has implications for surveillance strategies of patients and their families.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.

ABSTRACT
Familial colorectal cancer type X (FCCTX) is characterized by clinical features of hereditary non-polyposis colorectal cancer with a yet undefined genetic background. Here we identify the SEMA4A p.Val78Met germline mutation in an Austrian kindred with FCCTX, using an integrative genomics strategy. Compared with wild-type protein, SEMA4A(V78M) demonstrates significantly increased MAPK/Erk and PI3K/Akt signalling as well as cell cycle progression of SEMA4A-deficient HCT-116 colorectal cancer cells. In a cohort of 53 patients with FCCTX, we depict two further SEMA4A mutations, p.Gly484Ala and p.Ser326Phe and the single-nucleotide polymorphism (SNP) p.Pro682Ser. This SNP is highly associated with the FCCTX phenotype exhibiting increased risk for colorectal cancer (OR 6.79, 95% CI 2.63 to 17.52). Our study shows previously unidentified germline variants in SEMA4A predisposing to FCCTX, which has implications for surveillance strategies of patients and their families.

Show MeSH
Related in: MedlinePlus