Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Luis Carvajal-Carmona, Tracy A. O’Mara, Jodie N. Painter, Felicity A. Lose, Joe Dennis, Kyriaki Michailidou, Jonathan P. Tyrer, Shahana Ahmed, Kaltin Ferguson, Catherine S. Healey, Karen Pooley, Jonathan Beesley, Timothy Cheng, Angela Jones, Kimberley Howarth, Lynn Martin, Maggie Gorman, Shirley Hodgson, Study of Endometrial Cancer Genetics Group (NSECG) National Study of Endometrial Cancer Genetics Group (NSECG), Australian National Endometrial Cancer Study Group (ANECS) The Australian National Endometrial Cancer Study Group (ANECS) & 74 others Nicholas Wentzensen, Peter A. Fasching, Alexander Hein, Matthias W. Beckmann, Stefan P. Renner, Thilo Dörk, Peter Hillemanns, Matthias Dürst, Ingo Runnebaum, Diether Lambrechts, Lieve Coenegrachts, Stefanie Schrauwen, Frederic Amant, Boris Winterhoff, Sean C. Dowdy, Ellen L. Goode, Attila Teoman, Helga B. Salvesen, Jone Trovik, Tormund S. Njolstad, Henrica M J Werner, Rodney J. Scott, Katie Ashton, Tony Proietto, Geoffrey Otton, Ofra Wersäll, Miriam Mints, Emma Tham, RENDOCAS, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, John L. Hopper, Melissa C. Southey, Ovarian Cancer Study (AOCS) Australian Ovarian Cancer Study (AOCS), Arif B. Ekici, Matthias Ruebner, Nichola Johnson, Julian Peto, Barbara Burwinkel, Frederik Marme, Hermann Brenner, Aida K. Dieffenbach, Alfons Meindl, Hiltrud Brauch, GENICA Network The GENICA Network, Annika Lindblom, Jeroen Depreeuw, Matthieu Moisse, Jenny Chang-Claude, Anja Rudolph, Fergus J. Couch, Janet E. Olson, Graham G. Giles, Fiona Bruinsma, Julie M. Cunningham, Brooke L. Fridley, Anne Lise Børresen-Dale, Vessela N. Kristensen, Angela Cox, Anthony J. Swerdlow, Nicholas Orr, Manjeet K. Bolla, Qin Wang, Rachel Palmieri Weber, Zhihua Chen, Mitul Shah, Paul D P Pharoah, Alison M. Dunning, Ian Tomlinson, Douglas F. Easton, Amanda B. Spurdle, Deborah J. Thompson

Research output: Contribution to journalArticle

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Abstract

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT–CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10−6 to P = 7.7 × 10−5). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERTP = 1.5 × 10−18, CLPTM1LP = 1.5 × 10−19). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.

Original languageEnglish (US)
Pages (from-to)231-245
Number of pages15
JournalHuman Genetics
Volume134
Issue number2
DOIs
StatePublished - 2015

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Endometrial Neoplasms
Single Nucleotide Polymorphism
Chromosomes
Neoplasms
Logistic Models
Genetic Promoter Regions
Introns
Haplotypes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk. / Carvajal-Carmona, Luis; O’Mara, Tracy A.; Painter, Jodie N.; Lose, Felicity A.; Dennis, Joe; Michailidou, Kyriaki; Tyrer, Jonathan P.; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S.; Pooley, Karen; Beesley, Jonathan; Cheng, Timothy; Jones, Angela; Howarth, Kimberley; Martin, Lynn; Gorman, Maggie; Hodgson, Shirley; National Study of Endometrial Cancer Genetics Group (NSECG), Study of Endometrial Cancer Genetics Group (NSECG); The Australian National Endometrial Cancer Study Group (ANECS), Australian National Endometrial Cancer Study Group (ANECS); Wentzensen, Nicholas; Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Renner, Stefan P.; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo; Lambrechts, Diether; Coenegrachts, Lieve; Schrauwen, Stefanie; Amant, Frederic; Winterhoff, Boris; Dowdy, Sean C.; Goode, Ellen L.; Teoman, Attila; Salvesen, Helga B.; Trovik, Jone; Njolstad, Tormund S.; Werner, Henrica M J; Scott, Rodney J.; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Wersäll, Ofra; Mints, Miriam; Tham, Emma; RENDOCAS; Hall, Per; Czene, Kamila; Liu, Jianjun; Li, Jingmei; Hopper, John L.; Southey, Melissa C.; Australian Ovarian Cancer Study (AOCS), Ovarian Cancer Study (AOCS); Ekici, Arif B.; Ruebner, Matthias; Johnson, Nichola; Peto, Julian; Burwinkel, Barbara; Marme, Frederik; Brenner, Hermann; Dieffenbach, Aida K.; Meindl, Alfons; Brauch, Hiltrud; The GENICA Network, GENICA Network; Lindblom, Annika; Depreeuw, Jeroen; Moisse, Matthieu; Chang-Claude, Jenny; Rudolph, Anja; Couch, Fergus J.; Olson, Janet E.; Giles, Graham G.; Bruinsma, Fiona; Cunningham, Julie M.; Fridley, Brooke L.; Børresen-Dale, Anne Lise; Kristensen, Vessela N.; Cox, Angela; Swerdlow, Anthony J.; Orr, Nicholas; Bolla, Manjeet K.; Wang, Qin; Weber, Rachel Palmieri; Chen, Zhihua; Shah, Mitul; Pharoah, Paul D P; Dunning, Alison M.; Tomlinson, Ian; Easton, Douglas F.; Spurdle, Amanda B.; Thompson, Deborah J.

In: Human Genetics, Vol. 134, No. 2, 2015, p. 231-245.

Research output: Contribution to journalArticle

Carvajal-Carmona, L, O’Mara, TA, Painter, JN, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Pooley, K, Beesley, J, Cheng, T, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, National Study of Endometrial Cancer Genetics Group (NSECG), SOECGGNSECG, The Australian National Endometrial Cancer Study Group (ANECS), ANECSGANECS, Wentzensen, N, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Dörk, T, Hillemanns, P, Dürst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Scott, RJ, Ashton, K, Proietto, T, Otton, G, Wersäll, O, Mints, M, Tham, E, RENDOCAS, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Australian Ovarian Cancer Study (AOCS), OCSAOCS, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, The GENICA Network, GENICAN, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Børresen-Dale, AL, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Spurdle, AB & Thompson, DJ 2015, 'Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk', Human Genetics, vol. 134, no. 2, pp. 231-245. https://doi.org/10.1007/s00439-014-1515-4
Carvajal-Carmona, Luis ; O’Mara, Tracy A. ; Painter, Jodie N. ; Lose, Felicity A. ; Dennis, Joe ; Michailidou, Kyriaki ; Tyrer, Jonathan P. ; Ahmed, Shahana ; Ferguson, Kaltin ; Healey, Catherine S. ; Pooley, Karen ; Beesley, Jonathan ; Cheng, Timothy ; Jones, Angela ; Howarth, Kimberley ; Martin, Lynn ; Gorman, Maggie ; Hodgson, Shirley ; National Study of Endometrial Cancer Genetics Group (NSECG), Study of Endometrial Cancer Genetics Group (NSECG) ; The Australian National Endometrial Cancer Study Group (ANECS), Australian National Endometrial Cancer Study Group (ANECS) ; Wentzensen, Nicholas ; Fasching, Peter A. ; Hein, Alexander ; Beckmann, Matthias W. ; Renner, Stefan P. ; Dörk, Thilo ; Hillemanns, Peter ; Dürst, Matthias ; Runnebaum, Ingo ; Lambrechts, Diether ; Coenegrachts, Lieve ; Schrauwen, Stefanie ; Amant, Frederic ; Winterhoff, Boris ; Dowdy, Sean C. ; Goode, Ellen L. ; Teoman, Attila ; Salvesen, Helga B. ; Trovik, Jone ; Njolstad, Tormund S. ; Werner, Henrica M J ; Scott, Rodney J. ; Ashton, Katie ; Proietto, Tony ; Otton, Geoffrey ; Wersäll, Ofra ; Mints, Miriam ; Tham, Emma ; RENDOCAS ; Hall, Per ; Czene, Kamila ; Liu, Jianjun ; Li, Jingmei ; Hopper, John L. ; Southey, Melissa C. ; Australian Ovarian Cancer Study (AOCS), Ovarian Cancer Study (AOCS) ; Ekici, Arif B. ; Ruebner, Matthias ; Johnson, Nichola ; Peto, Julian ; Burwinkel, Barbara ; Marme, Frederik ; Brenner, Hermann ; Dieffenbach, Aida K. ; Meindl, Alfons ; Brauch, Hiltrud ; The GENICA Network, GENICA Network ; Lindblom, Annika ; Depreeuw, Jeroen ; Moisse, Matthieu ; Chang-Claude, Jenny ; Rudolph, Anja ; Couch, Fergus J. ; Olson, Janet E. ; Giles, Graham G. ; Bruinsma, Fiona ; Cunningham, Julie M. ; Fridley, Brooke L. ; Børresen-Dale, Anne Lise ; Kristensen, Vessela N. ; Cox, Angela ; Swerdlow, Anthony J. ; Orr, Nicholas ; Bolla, Manjeet K. ; Wang, Qin ; Weber, Rachel Palmieri ; Chen, Zhihua ; Shah, Mitul ; Pharoah, Paul D P ; Dunning, Alison M. ; Tomlinson, Ian ; Easton, Douglas F. ; Spurdle, Amanda B. ; Thompson, Deborah J. / Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk. In: Human Genetics. 2015 ; Vol. 134, No. 2. pp. 231-245.
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title = "Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk",
abstract = "Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT–CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10−6 to P = 7.7 × 10−5). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERTP = 1.5 × 10−18, CLPTM1LP = 1.5 × 10−19). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.",
author = "Luis Carvajal-Carmona and O’Mara, {Tracy A.} and Painter, {Jodie N.} and Lose, {Felicity A.} and Joe Dennis and Kyriaki Michailidou and Tyrer, {Jonathan P.} and Shahana Ahmed and Kaltin Ferguson and Healey, {Catherine S.} and Karen Pooley and Jonathan Beesley and Timothy Cheng and Angela Jones and Kimberley Howarth and Lynn Martin and Maggie Gorman and Shirley Hodgson and {National Study of Endometrial Cancer Genetics Group (NSECG)}, {Study of Endometrial Cancer Genetics Group (NSECG)} and {The Australian National Endometrial Cancer Study Group (ANECS)}, {Australian National Endometrial Cancer Study Group (ANECS)} and Nicholas Wentzensen and Fasching, {Peter A.} and Alexander Hein and Beckmann, {Matthias W.} and Renner, {Stefan P.} and Thilo D{\"o}rk and Peter Hillemanns and Matthias D{\"u}rst and Ingo Runnebaum and Diether Lambrechts and Lieve Coenegrachts and Stefanie Schrauwen and Frederic Amant and Boris Winterhoff and Dowdy, {Sean C.} and Goode, {Ellen L.} and Attila Teoman and Salvesen, {Helga B.} and Jone Trovik and Njolstad, {Tormund S.} and Werner, {Henrica M J} and Scott, {Rodney J.} and Katie Ashton and Tony Proietto and Geoffrey Otton and Ofra Wers{\"a}ll and Miriam Mints and Emma Tham and RENDOCAS and Per Hall and Kamila Czene and Jianjun Liu and Jingmei Li and Hopper, {John L.} and Southey, {Melissa C.} and {Australian Ovarian Cancer Study (AOCS)}, {Ovarian Cancer Study (AOCS)} and Ekici, {Arif B.} and Matthias Ruebner and Nichola Johnson and Julian Peto and Barbara Burwinkel and Frederik Marme and Hermann Brenner and Dieffenbach, {Aida K.} and Alfons Meindl and Hiltrud Brauch and {The GENICA Network}, {GENICA Network} and Annika Lindblom and Jeroen Depreeuw and Matthieu Moisse and Jenny Chang-Claude and Anja Rudolph and Couch, {Fergus J.} and Olson, {Janet E.} and Giles, {Graham G.} and Fiona Bruinsma and Cunningham, {Julie M.} and Fridley, {Brooke L.} and B{\o}rresen-Dale, {Anne Lise} and Kristensen, {Vessela N.} and Angela Cox and Swerdlow, {Anthony J.} and Nicholas Orr and Bolla, {Manjeet K.} and Qin Wang and Weber, {Rachel Palmieri} and Zhihua Chen and Mitul Shah and Pharoah, {Paul D P} and Dunning, {Alison M.} and Ian Tomlinson and Easton, {Douglas F.} and Spurdle, {Amanda B.} and Thompson, {Deborah J.}",
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doi = "10.1007/s00439-014-1515-4",
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TY - JOUR

T1 - Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

AU - Carvajal-Carmona, Luis

AU - O’Mara, Tracy A.

AU - Painter, Jodie N.

AU - Lose, Felicity A.

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - Tyrer, Jonathan P.

AU - Ahmed, Shahana

AU - Ferguson, Kaltin

AU - Healey, Catherine S.

AU - Pooley, Karen

AU - Beesley, Jonathan

AU - Cheng, Timothy

AU - Jones, Angela

AU - Howarth, Kimberley

AU - Martin, Lynn

AU - Gorman, Maggie

AU - Hodgson, Shirley

AU - National Study of Endometrial Cancer Genetics Group (NSECG), Study of Endometrial Cancer Genetics Group (NSECG)

AU - The Australian National Endometrial Cancer Study Group (ANECS), Australian National Endometrial Cancer Study Group (ANECS)

AU - Wentzensen, Nicholas

AU - Fasching, Peter A.

AU - Hein, Alexander

AU - Beckmann, Matthias W.

AU - Renner, Stefan P.

AU - Dörk, Thilo

AU - Hillemanns, Peter

AU - Dürst, Matthias

AU - Runnebaum, Ingo

AU - Lambrechts, Diether

AU - Coenegrachts, Lieve

AU - Schrauwen, Stefanie

AU - Amant, Frederic

AU - Winterhoff, Boris

AU - Dowdy, Sean C.

AU - Goode, Ellen L.

AU - Teoman, Attila

AU - Salvesen, Helga B.

AU - Trovik, Jone

AU - Njolstad, Tormund S.

AU - Werner, Henrica M J

AU - Scott, Rodney J.

AU - Ashton, Katie

AU - Proietto, Tony

AU - Otton, Geoffrey

AU - Wersäll, Ofra

AU - Mints, Miriam

AU - Tham, Emma

AU - RENDOCAS,

AU - Hall, Per

AU - Czene, Kamila

AU - Liu, Jianjun

AU - Li, Jingmei

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Australian Ovarian Cancer Study (AOCS), Ovarian Cancer Study (AOCS)

AU - Ekici, Arif B.

AU - Ruebner, Matthias

AU - Johnson, Nichola

AU - Peto, Julian

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Brenner, Hermann

AU - Dieffenbach, Aida K.

AU - Meindl, Alfons

AU - Brauch, Hiltrud

AU - The GENICA Network, GENICA Network

AU - Lindblom, Annika

AU - Depreeuw, Jeroen

AU - Moisse, Matthieu

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Couch, Fergus J.

AU - Olson, Janet E.

AU - Giles, Graham G.

AU - Bruinsma, Fiona

AU - Cunningham, Julie M.

AU - Fridley, Brooke L.

AU - Børresen-Dale, Anne Lise

AU - Kristensen, Vessela N.

AU - Cox, Angela

AU - Swerdlow, Anthony J.

AU - Orr, Nicholas

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Weber, Rachel Palmieri

AU - Chen, Zhihua

AU - Shah, Mitul

AU - Pharoah, Paul D P

AU - Dunning, Alison M.

AU - Tomlinson, Ian

AU - Easton, Douglas F.

AU - Spurdle, Amanda B.

AU - Thompson, Deborah J.

PY - 2015

Y1 - 2015

N2 - Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT–CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10−6 to P = 7.7 × 10−5). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERTP = 1.5 × 10−18, CLPTM1LP = 1.5 × 10−19). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.

AB - Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT–CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10−6 to P = 7.7 × 10−5). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERTP = 1.5 × 10−18, CLPTM1LP = 1.5 × 10−19). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.

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U2 - 10.1007/s00439-014-1515-4

DO - 10.1007/s00439-014-1515-4

M3 - Article

VL - 134

SP - 231

EP - 245

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 2

ER -