Can unknown predisposition in familial breast cancer be family-specific?

Henry Lynch, Hongxiu Wen, Yeong C. Kim, Carrie Snyder, Yulia Kinarsky, Pei Xian Chen, Fengxia Xiao, David Goldgar, Kenneth H Cowan, San Ming Wang

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Genetic predisposition plays a key role in the development of familial breast cancer. In spite of strong familial clustering of the disease and extensive efforts made during the past decade; however, progress has been slow in identifying genetic predisposition for the majority of familial breast cancer families. The question arises therefore as to whether current approaches are adequate in identifying the unknown genetic predisposition. We analyzed eight members of a BRCA1-, BRCA2-, p53-, and PTEN-negative breast cancer family, of which five had breast cancer, one is an obligate gene carrier, and two were unaffected. We sequenced the entire coding region of the genome for each member using exome sequencing to identify nonsynonymous variants. We identified 55 nonsynonymous germline variants affecting 49 genes in multiple members of the family, of which 22 are predicted to have damaging effects. We validated 20 of the 22 selected variants in the family by Sanger sequencing. Two variants in KAT6B, an acetal transferase gene, were identified in six family members of which five were affected with breast cancer and one is the unaffected obligate carrier. We further examined the presence of the identified variants in a cohort of 40 additional breast cancer cases from 22 familial breast cancer families, but none of the 22 variants was detected in these cases. Sequencing the entire coding exons in KAT6B detects no variants in these cases. Our results show that genetic predisposition for familial breast cancer can be rich in an affected family, but the predisposition can be family-specific. As such, it will be difficult to detect them by applying population-based approach. Our study supports the concept that focusing on each affected family will be required to determine the genetic predisposition for many familial breast cancer families whose genetic dispositions remain unknown.

Original languageEnglish (US)
Pages (from-to)520-528
Number of pages9
JournalBreast Journal
Volume19
Issue number5
DOIs
StatePublished - Jan 1 2013

Fingerprint

Genetic Predisposition to Disease
Breast Neoplasms
Familial Breast Cancer
Genes
Exome
Acetals
Transferases
Cluster Analysis
Exons
Genome
Population

Keywords

  • exome sequencing
  • familial breast cancer
  • predisposition

ASJC Scopus subject areas

  • Internal Medicine
  • Surgery
  • Oncology

Cite this

Lynch, H., Wen, H., Kim, Y. C., Snyder, C., Kinarsky, Y., Chen, P. X., ... Wang, S. M. (2013). Can unknown predisposition in familial breast cancer be family-specific? Breast Journal, 19(5), 520-528. https://doi.org/10.1111/tbj.12145

Can unknown predisposition in familial breast cancer be family-specific? / Lynch, Henry; Wen, Hongxiu; Kim, Yeong C.; Snyder, Carrie; Kinarsky, Yulia; Chen, Pei Xian; Xiao, Fengxia; Goldgar, David; Cowan, Kenneth H; Wang, San Ming.

In: Breast Journal, Vol. 19, No. 5, 01.01.2013, p. 520-528.

Research output: Contribution to journalArticle

Lynch, H, Wen, H, Kim, YC, Snyder, C, Kinarsky, Y, Chen, PX, Xiao, F, Goldgar, D, Cowan, KH & Wang, SM 2013, 'Can unknown predisposition in familial breast cancer be family-specific?', Breast Journal, vol. 19, no. 5, pp. 520-528. https://doi.org/10.1111/tbj.12145
Lynch H, Wen H, Kim YC, Snyder C, Kinarsky Y, Chen PX et al. Can unknown predisposition in familial breast cancer be family-specific? Breast Journal. 2013 Jan 1;19(5):520-528. https://doi.org/10.1111/tbj.12145
Lynch, Henry ; Wen, Hongxiu ; Kim, Yeong C. ; Snyder, Carrie ; Kinarsky, Yulia ; Chen, Pei Xian ; Xiao, Fengxia ; Goldgar, David ; Cowan, Kenneth H ; Wang, San Ming. / Can unknown predisposition in familial breast cancer be family-specific?. In: Breast Journal. 2013 ; Vol. 19, No. 5. pp. 520-528.
@article{0bfd9bab956d4348a6efe975c859d052,
title = "Can unknown predisposition in familial breast cancer be family-specific?",
abstract = "Genetic predisposition plays a key role in the development of familial breast cancer. In spite of strong familial clustering of the disease and extensive efforts made during the past decade; however, progress has been slow in identifying genetic predisposition for the majority of familial breast cancer families. The question arises therefore as to whether current approaches are adequate in identifying the unknown genetic predisposition. We analyzed eight members of a BRCA1-, BRCA2-, p53-, and PTEN-negative breast cancer family, of which five had breast cancer, one is an obligate gene carrier, and two were unaffected. We sequenced the entire coding region of the genome for each member using exome sequencing to identify nonsynonymous variants. We identified 55 nonsynonymous germline variants affecting 49 genes in multiple members of the family, of which 22 are predicted to have damaging effects. We validated 20 of the 22 selected variants in the family by Sanger sequencing. Two variants in KAT6B, an acetal transferase gene, were identified in six family members of which five were affected with breast cancer and one is the unaffected obligate carrier. We further examined the presence of the identified variants in a cohort of 40 additional breast cancer cases from 22 familial breast cancer families, but none of the 22 variants was detected in these cases. Sequencing the entire coding exons in KAT6B detects no variants in these cases. Our results show that genetic predisposition for familial breast cancer can be rich in an affected family, but the predisposition can be family-specific. As such, it will be difficult to detect them by applying population-based approach. Our study supports the concept that focusing on each affected family will be required to determine the genetic predisposition for many familial breast cancer families whose genetic dispositions remain unknown.",
keywords = "exome sequencing, familial breast cancer, predisposition",
author = "Henry Lynch and Hongxiu Wen and Kim, {Yeong C.} and Carrie Snyder and Yulia Kinarsky and Chen, {Pei Xian} and Fengxia Xiao and David Goldgar and Cowan, {Kenneth H} and Wang, {San Ming}",
year = "2013",
month = "1",
day = "1",
doi = "10.1111/tbj.12145",
language = "English (US)",
volume = "19",
pages = "520--528",
journal = "Breast Journal",
issn = "1075-122X",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Can unknown predisposition in familial breast cancer be family-specific?

AU - Lynch, Henry

AU - Wen, Hongxiu

AU - Kim, Yeong C.

AU - Snyder, Carrie

AU - Kinarsky, Yulia

AU - Chen, Pei Xian

AU - Xiao, Fengxia

AU - Goldgar, David

AU - Cowan, Kenneth H

AU - Wang, San Ming

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Genetic predisposition plays a key role in the development of familial breast cancer. In spite of strong familial clustering of the disease and extensive efforts made during the past decade; however, progress has been slow in identifying genetic predisposition for the majority of familial breast cancer families. The question arises therefore as to whether current approaches are adequate in identifying the unknown genetic predisposition. We analyzed eight members of a BRCA1-, BRCA2-, p53-, and PTEN-negative breast cancer family, of which five had breast cancer, one is an obligate gene carrier, and two were unaffected. We sequenced the entire coding region of the genome for each member using exome sequencing to identify nonsynonymous variants. We identified 55 nonsynonymous germline variants affecting 49 genes in multiple members of the family, of which 22 are predicted to have damaging effects. We validated 20 of the 22 selected variants in the family by Sanger sequencing. Two variants in KAT6B, an acetal transferase gene, were identified in six family members of which five were affected with breast cancer and one is the unaffected obligate carrier. We further examined the presence of the identified variants in a cohort of 40 additional breast cancer cases from 22 familial breast cancer families, but none of the 22 variants was detected in these cases. Sequencing the entire coding exons in KAT6B detects no variants in these cases. Our results show that genetic predisposition for familial breast cancer can be rich in an affected family, but the predisposition can be family-specific. As such, it will be difficult to detect them by applying population-based approach. Our study supports the concept that focusing on each affected family will be required to determine the genetic predisposition for many familial breast cancer families whose genetic dispositions remain unknown.

AB - Genetic predisposition plays a key role in the development of familial breast cancer. In spite of strong familial clustering of the disease and extensive efforts made during the past decade; however, progress has been slow in identifying genetic predisposition for the majority of familial breast cancer families. The question arises therefore as to whether current approaches are adequate in identifying the unknown genetic predisposition. We analyzed eight members of a BRCA1-, BRCA2-, p53-, and PTEN-negative breast cancer family, of which five had breast cancer, one is an obligate gene carrier, and two were unaffected. We sequenced the entire coding region of the genome for each member using exome sequencing to identify nonsynonymous variants. We identified 55 nonsynonymous germline variants affecting 49 genes in multiple members of the family, of which 22 are predicted to have damaging effects. We validated 20 of the 22 selected variants in the family by Sanger sequencing. Two variants in KAT6B, an acetal transferase gene, were identified in six family members of which five were affected with breast cancer and one is the unaffected obligate carrier. We further examined the presence of the identified variants in a cohort of 40 additional breast cancer cases from 22 familial breast cancer families, but none of the 22 variants was detected in these cases. Sequencing the entire coding exons in KAT6B detects no variants in these cases. Our results show that genetic predisposition for familial breast cancer can be rich in an affected family, but the predisposition can be family-specific. As such, it will be difficult to detect them by applying population-based approach. Our study supports the concept that focusing on each affected family will be required to determine the genetic predisposition for many familial breast cancer families whose genetic dispositions remain unknown.

KW - exome sequencing

KW - familial breast cancer

KW - predisposition

UR - http://www.scopus.com/inward/record.url?scp=84884906705&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884906705&partnerID=8YFLogxK

U2 - 10.1111/tbj.12145

DO - 10.1111/tbj.12145

M3 - Article

C2 - 23800003

AN - SCOPUS:84884906705

VL - 19

SP - 520

EP - 528

JO - Breast Journal

JF - Breast Journal

SN - 1075-122X

IS - 5

ER -