Hereditary diffuse gastric cancer syndrome

CDH1 mutations and beyond

Samantha Hansford, Pardeep Kaurah, Hector Li-Chang, Michelle Woo, Janine Senz, Hugo Pinheiro, Kasmintan A. Schrader, David F. Schaeffer, Karey Shumansky, George Zogopoulos, Teresa Almeida Santos, Isabel Claro, Joana Carvalho, Cydney Nielsen, Sarah Padilla, Amy Lum, Aline Talhouk, Katie Baker-Lange, Sue Richardson, Ivy Lewis & 15 others Noralane M. Lindor, Erin Pennell, Andree MacMillan, Bridget Fernandez, Gisella Keller, Henry T. Lynch, Sohrab P. Shah, Parry Guilford, Steven Gallinger, Giovanni Corso, Franco Roviello, Carlos Caldas, Carla Oliveira, Paul D P Pharoah, David G. Huntsman

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

IMPORTANCE: E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. OBJECTIVES: To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. DESIGN, SETTING, AND PARTICIPANTS: Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. MAIN OUTCOMES AND MEASURES: Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. RESULTS: Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. CONCLUSIONS AND RELEVANCE: This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.

Original languageEnglish (US)
Pages (from-to)23-32
Number of pages10
JournalJAMA oncology
Volume1
Issue number1
DOIs
StatePublished - Apr 1 2015

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Stomach Neoplasms
Mutation
Germ-Line Mutation
Breast Neoplasms
Neoplasm Genes
Penetrance
BRCA2 Gene
Genes
Cadherins
Tumor Suppressor Genes
Counseling

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Hansford, S., Kaurah, P., Li-Chang, H., Woo, M., Senz, J., Pinheiro, H., ... Huntsman, D. G. (2015). Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA oncology, 1(1), 23-32. https://doi.org/10.1001/jamaoncol.2014.168

Hereditary diffuse gastric cancer syndrome : CDH1 mutations and beyond. / Hansford, Samantha; Kaurah, Pardeep; Li-Chang, Hector; Woo, Michelle; Senz, Janine; Pinheiro, Hugo; Schrader, Kasmintan A.; Schaeffer, David F.; Shumansky, Karey; Zogopoulos, George; Santos, Teresa Almeida; Claro, Isabel; Carvalho, Joana; Nielsen, Cydney; Padilla, Sarah; Lum, Amy; Talhouk, Aline; Baker-Lange, Katie; Richardson, Sue; Lewis, Ivy; Lindor, Noralane M.; Pennell, Erin; MacMillan, Andree; Fernandez, Bridget; Keller, Gisella; Lynch, Henry T.; Shah, Sohrab P.; Guilford, Parry; Gallinger, Steven; Corso, Giovanni; Roviello, Franco; Caldas, Carlos; Oliveira, Carla; Pharoah, Paul D P; Huntsman, David G.

In: JAMA oncology, Vol. 1, No. 1, 01.04.2015, p. 23-32.

Research output: Contribution to journalArticle

Hansford, S, Kaurah, P, Li-Chang, H, Woo, M, Senz, J, Pinheiro, H, Schrader, KA, Schaeffer, DF, Shumansky, K, Zogopoulos, G, Santos, TA, Claro, I, Carvalho, J, Nielsen, C, Padilla, S, Lum, A, Talhouk, A, Baker-Lange, K, Richardson, S, Lewis, I, Lindor, NM, Pennell, E, MacMillan, A, Fernandez, B, Keller, G, Lynch, HT, Shah, SP, Guilford, P, Gallinger, S, Corso, G, Roviello, F, Caldas, C, Oliveira, C, Pharoah, PDP & Huntsman, DG 2015, 'Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond', JAMA oncology, vol. 1, no. 1, pp. 23-32. https://doi.org/10.1001/jamaoncol.2014.168
Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA oncology. 2015 Apr 1;1(1):23-32. https://doi.org/10.1001/jamaoncol.2014.168
Hansford, Samantha ; Kaurah, Pardeep ; Li-Chang, Hector ; Woo, Michelle ; Senz, Janine ; Pinheiro, Hugo ; Schrader, Kasmintan A. ; Schaeffer, David F. ; Shumansky, Karey ; Zogopoulos, George ; Santos, Teresa Almeida ; Claro, Isabel ; Carvalho, Joana ; Nielsen, Cydney ; Padilla, Sarah ; Lum, Amy ; Talhouk, Aline ; Baker-Lange, Katie ; Richardson, Sue ; Lewis, Ivy ; Lindor, Noralane M. ; Pennell, Erin ; MacMillan, Andree ; Fernandez, Bridget ; Keller, Gisella ; Lynch, Henry T. ; Shah, Sohrab P. ; Guilford, Parry ; Gallinger, Steven ; Corso, Giovanni ; Roviello, Franco ; Caldas, Carlos ; Oliveira, Carla ; Pharoah, Paul D P ; Huntsman, David G. / Hereditary diffuse gastric cancer syndrome : CDH1 mutations and beyond. In: JAMA oncology. 2015 ; Vol. 1, No. 1. pp. 23-32.
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abstract = "IMPORTANCE: E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. OBJECTIVES: To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. DESIGN, SETTING, AND PARTICIPANTS: Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. MAIN OUTCOMES AND MEASURES: Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. RESULTS: Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19{\%}). By the age of 80 years, the cumulative incidence of gastric cancer was 70{\%} (95{\%} CI, 59{\%}-80{\%}) for males and 56{\%} (95{\%} CI, 44{\%}-69{\%}) for females, and the risk of breast cancer for females was 42{\%} (95{\%} CI, 23{\%}-68{\%}). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11{\%}), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. CONCLUSIONS AND RELEVANCE: This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.",
author = "Samantha Hansford and Pardeep Kaurah and Hector Li-Chang and Michelle Woo and Janine Senz and Hugo Pinheiro and Schrader, {Kasmintan A.} and Schaeffer, {David F.} and Karey Shumansky and George Zogopoulos and Santos, {Teresa Almeida} and Isabel Claro and Joana Carvalho and Cydney Nielsen and Sarah Padilla and Amy Lum and Aline Talhouk and Katie Baker-Lange and Sue Richardson and Ivy Lewis and Lindor, {Noralane M.} and Erin Pennell and Andree MacMillan and Bridget Fernandez and Gisella Keller and Lynch, {Henry T.} and Shah, {Sohrab P.} and Parry Guilford and Steven Gallinger and Giovanni Corso and Franco Roviello and Carlos Caldas and Carla Oliveira and Pharoah, {Paul D P} and Huntsman, {David G.}",
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TY - JOUR

T1 - Hereditary diffuse gastric cancer syndrome

T2 - CDH1 mutations and beyond

AU - Hansford, Samantha

AU - Kaurah, Pardeep

AU - Li-Chang, Hector

AU - Woo, Michelle

AU - Senz, Janine

AU - Pinheiro, Hugo

AU - Schrader, Kasmintan A.

AU - Schaeffer, David F.

AU - Shumansky, Karey

AU - Zogopoulos, George

AU - Santos, Teresa Almeida

AU - Claro, Isabel

AU - Carvalho, Joana

AU - Nielsen, Cydney

AU - Padilla, Sarah

AU - Lum, Amy

AU - Talhouk, Aline

AU - Baker-Lange, Katie

AU - Richardson, Sue

AU - Lewis, Ivy

AU - Lindor, Noralane M.

AU - Pennell, Erin

AU - MacMillan, Andree

AU - Fernandez, Bridget

AU - Keller, Gisella

AU - Lynch, Henry T.

AU - Shah, Sohrab P.

AU - Guilford, Parry

AU - Gallinger, Steven

AU - Corso, Giovanni

AU - Roviello, Franco

AU - Caldas, Carlos

AU - Oliveira, Carla

AU - Pharoah, Paul D P

AU - Huntsman, David G.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - IMPORTANCE: E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. OBJECTIVES: To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. DESIGN, SETTING, AND PARTICIPANTS: Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. MAIN OUTCOMES AND MEASURES: Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. RESULTS: Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. CONCLUSIONS AND RELEVANCE: This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.

AB - IMPORTANCE: E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. OBJECTIVES: To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. DESIGN, SETTING, AND PARTICIPANTS: Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. MAIN OUTCOMES AND MEASURES: Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. RESULTS: Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. CONCLUSIONS AND RELEVANCE: This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.

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