Rare mutations in RINT1 predispose carriers to breast and lynch syndrome-Spectrum cancers

Daniel J. Park, Kayoko Tao, Florence Le Calvez-Kelm, Tu Nguyen-Dumont, Nivonirina Robinot, Fleur Hammet, Fabrice Odefrey, Helen Tsimiklis, Zhi L. Teo, Louise B. Thingholm, Erin L. Young, Catherine Voegele, Andrew Lonie, Bernard J. Pope, Terrell C. Roane, Russell Bell, Hao Hu, Shankaracharya, Chad D. Huff, Jonathan EllisJun Li, Igor V. Makunin, Esther M. John, Irene L. Andrulis, Mary B. Terry, Mary Daly, Saundra S. Buys, Carrie Snyder, Henry T. Lynch, Peter Devilee, Graham G. Giles, John L. Hopper, Bing Jian Feng, Fabienne Lesueur, Sean V. Tavtigian, Melissa C. Southey, David E. Goldgar

Research output: Contribution to journalArticle

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Abstract

Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case-control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency <0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confi- dence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiplecase breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome-spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7-6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7-21; P = 0.0003).

Original languageEnglish
Pages (from-to)804-815
Number of pages12
JournalCancer Discovery
Volume4
Issue number7
DOIs
StatePublished - 2014

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Hereditary Nonpolyposis Colorectal Neoplasms
Breast
Mutation
Confidence Intervals
Breast Neoplasms
Neoplasms
Incidence
Exome
Heterozygote
Gene Frequency
Databases
Population

All Science Journal Classification (ASJC) codes

  • Oncology
  • Medicine(all)

Cite this

Park, D. J., Tao, K., Le Calvez-Kelm, F., Nguyen-Dumont, T., Robinot, N., Hammet, F., ... Goldgar, D. E. (2014). Rare mutations in RINT1 predispose carriers to breast and lynch syndrome-Spectrum cancers. Cancer Discovery, 4(7), 804-815. https://doi.org/10.1158/2159-8290.CD-14-0212

Rare mutations in RINT1 predispose carriers to breast and lynch syndrome-Spectrum cancers. / Park, Daniel J.; Tao, Kayoko; Le Calvez-Kelm, Florence; Nguyen-Dumont, Tu; Robinot, Nivonirina; Hammet, Fleur; Odefrey, Fabrice; Tsimiklis, Helen; Teo, Zhi L.; Thingholm, Louise B.; Young, Erin L.; Voegele, Catherine; Lonie, Andrew; Pope, Bernard J.; Roane, Terrell C.; Bell, Russell; Hu, Hao; Shankaracharya; Huff, Chad D.; Ellis, Jonathan; Li, Jun; Makunin, Igor V.; John, Esther M.; Andrulis, Irene L.; Terry, Mary B.; Daly, Mary; Buys, Saundra S.; Snyder, Carrie; Lynch, Henry T.; Devilee, Peter; Giles, Graham G.; Hopper, John L.; Feng, Bing Jian; Lesueur, Fabienne; Tavtigian, Sean V.; Southey, Melissa C.; Goldgar, David E.

In: Cancer Discovery, Vol. 4, No. 7, 2014, p. 804-815.

Research output: Contribution to journalArticle

Park, DJ, Tao, K, Le Calvez-Kelm, F, Nguyen-Dumont, T, Robinot, N, Hammet, F, Odefrey, F, Tsimiklis, H, Teo, ZL, Thingholm, LB, Young, EL, Voegele, C, Lonie, A, Pope, BJ, Roane, TC, Bell, R, Hu, H, Shankaracharya, Huff, CD, Ellis, J, Li, J, Makunin, IV, John, EM, Andrulis, IL, Terry, MB, Daly, M, Buys, SS, Snyder, C, Lynch, HT, Devilee, P, Giles, GG, Hopper, JL, Feng, BJ, Lesueur, F, Tavtigian, SV, Southey, MC & Goldgar, DE 2014, 'Rare mutations in RINT1 predispose carriers to breast and lynch syndrome-Spectrum cancers', Cancer Discovery, vol. 4, no. 7, pp. 804-815. https://doi.org/10.1158/2159-8290.CD-14-0212
Park DJ, Tao K, Le Calvez-Kelm F, Nguyen-Dumont T, Robinot N, Hammet F et al. Rare mutations in RINT1 predispose carriers to breast and lynch syndrome-Spectrum cancers. Cancer Discovery. 2014;4(7):804-815. https://doi.org/10.1158/2159-8290.CD-14-0212
Park, Daniel J. ; Tao, Kayoko ; Le Calvez-Kelm, Florence ; Nguyen-Dumont, Tu ; Robinot, Nivonirina ; Hammet, Fleur ; Odefrey, Fabrice ; Tsimiklis, Helen ; Teo, Zhi L. ; Thingholm, Louise B. ; Young, Erin L. ; Voegele, Catherine ; Lonie, Andrew ; Pope, Bernard J. ; Roane, Terrell C. ; Bell, Russell ; Hu, Hao ; Shankaracharya ; Huff, Chad D. ; Ellis, Jonathan ; Li, Jun ; Makunin, Igor V. ; John, Esther M. ; Andrulis, Irene L. ; Terry, Mary B. ; Daly, Mary ; Buys, Saundra S. ; Snyder, Carrie ; Lynch, Henry T. ; Devilee, Peter ; Giles, Graham G. ; Hopper, John L. ; Feng, Bing Jian ; Lesueur, Fabienne ; Tavtigian, Sean V. ; Southey, Melissa C. ; Goldgar, David E. / Rare mutations in RINT1 predispose carriers to breast and lynch syndrome-Spectrum cancers. In: Cancer Discovery. 2014 ; Vol. 4, No. 7. pp. 804-815.
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abstract = "Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case-control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency <0.5{\%}), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95{\%} confi- dence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiplecase breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome-spectrum cancers [standardized incidence ratio (SIR), 3.35; 95{\%} CI, 1.7-6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95{\%} CI, 4.7-21; P = 0.0003).",
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T1 - Rare mutations in RINT1 predispose carriers to breast and lynch syndrome-Spectrum cancers

AU - Park, Daniel J.

AU - Tao, Kayoko

AU - Le Calvez-Kelm, Florence

AU - Nguyen-Dumont, Tu

AU - Robinot, Nivonirina

AU - Hammet, Fleur

AU - Odefrey, Fabrice

AU - Tsimiklis, Helen

AU - Teo, Zhi L.

AU - Thingholm, Louise B.

AU - Young, Erin L.

AU - Voegele, Catherine

AU - Lonie, Andrew

AU - Pope, Bernard J.

AU - Roane, Terrell C.

AU - Bell, Russell

AU - Hu, Hao

AU - Shankaracharya,

AU - Huff, Chad D.

AU - Ellis, Jonathan

AU - Li, Jun

AU - Makunin, Igor V.

AU - John, Esther M.

AU - Andrulis, Irene L.

AU - Terry, Mary B.

AU - Daly, Mary

AU - Buys, Saundra S.

AU - Snyder, Carrie

AU - Lynch, Henry T.

AU - Devilee, Peter

AU - Giles, Graham G.

AU - Hopper, John L.

AU - Feng, Bing Jian

AU - Lesueur, Fabienne

AU - Tavtigian, Sean V.

AU - Southey, Melissa C.

AU - Goldgar, David E.

PY - 2014

Y1 - 2014

N2 - Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case-control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency <0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confi- dence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiplecase breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome-spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7-6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7-21; P = 0.0003).

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