Whole exome sequencing and single nucleotide polymorphism array analyses to identify germline alterations in genes associated with testosterone metabolism in a patient with androgen insensitivity syndrome and early-onset colorectal cancer

Vittoria Disciglio, A. Devecchi, O. Palumbo, M. Carella, D. Penso, M. Milione, G. Valle, M. A. Pierotti, M. Vitellaro, L. Bertario, S. Canevari, S. Signoroni, L. De Cecco

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Androgen insensitivity syndrome (AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor (AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer (CRC) have been described. CASE PRESENTATION: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a microRNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers. CONCLUSIONS: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.
Original languageEnglish
Pages (from-to)51
Number of pages1
JournalChinese Journal of Cancer
Volume35
Issue number1
DOIs
Publication statusPublished - 2016

Fingerprint

Androgen-Insensitivity Syndrome
Exome
Single Nucleotide Polymorphism
Testosterone
Colorectal Neoplasms
Genes
Neoplasm Genes
Androgen Receptors
Disorders of Sex Development
Mutation
Germ-Line Mutation
Pedigree
MicroRNAs
Oncogenes
Neoplasms
Chromosomes

Keywords

  • Androgen insensitivity syndrome
  • Androgen receptor
  • Colorectal cancer
  • Single nucleotide polymorphism array
  • Testosterone
  • Whole exome sequencing
  • testosterone
  • adolescent
  • adult
  • Androgen-Insensitivity Syndrome
  • case report
  • chromosome 22
  • Colorectal Neoplasms
  • complication
  • copy number variation
  • DNA sequence
  • exome
  • female
  • genetics
  • germline mutation
  • human
  • male
  • metabolism
  • onset age
  • pedigree
  • single nucleotide polymorphism
  • Adolescent
  • Adult
  • Age of Onset
  • Chromosomes, Human, Pair 22
  • DNA Copy Number Variations
  • Exome
  • Female
  • Germ-Line Mutation
  • Humans
  • Male
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA

Cite this

@article{12f6ea1061ae4d04b5037746f244a0c6,
title = "Whole exome sequencing and single nucleotide polymorphism array analyses to identify germline alterations in genes associated with testosterone metabolism in a patient with androgen insensitivity syndrome and early-onset colorectal cancer",
abstract = "BACKGROUND: Androgen insensitivity syndrome (AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor (AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer (CRC) have been described. CASE PRESENTATION: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a microRNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers. CONCLUSIONS: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.",
keywords = "Androgen insensitivity syndrome, Androgen receptor, Colorectal cancer, Single nucleotide polymorphism array, Testosterone, Whole exome sequencing, testosterone, adolescent, adult, Androgen-Insensitivity Syndrome, case report, chromosome 22, Colorectal Neoplasms, complication, copy number variation, DNA sequence, exome, female, genetics, germline mutation, human, male, metabolism, onset age, pedigree, single nucleotide polymorphism, Adolescent, Adult, Age of Onset, Chromosomes, Human, Pair 22, DNA Copy Number Variations, Exome, Female, Germ-Line Mutation, Humans, Male, Pedigree, Polymorphism, Single Nucleotide, Sequence Analysis, DNA",
author = "Vittoria Disciglio and A. Devecchi and O. Palumbo and M. Carella and D. Penso and M. Milione and G. Valle and Pierotti, {M. A.} and M. Vitellaro and L. Bertario and S. Canevari and S. Signoroni and {De Cecco}, L.",
note = "Export Date: 29 March 2017 Chemicals/CAS: testosterone, 58-22-0; Testosterone",
year = "2016",
doi = "10.1186/s40880-016-0115-1",
language = "English",
volume = "35",
pages = "51",
journal = "Chinese Journal of Cancer",
issn = "1000-467X",
publisher = "Landes Bioscience",
number = "1",

}

TY - JOUR

T1 - Whole exome sequencing and single nucleotide polymorphism array analyses to identify germline alterations in genes associated with testosterone metabolism in a patient with androgen insensitivity syndrome and early-onset colorectal cancer

AU - Disciglio, Vittoria

AU - Devecchi, A.

AU - Palumbo, O.

AU - Carella, M.

AU - Penso, D.

AU - Milione, M.

AU - Valle, G.

AU - Pierotti, M. A.

AU - Vitellaro, M.

AU - Bertario, L.

AU - Canevari, S.

AU - Signoroni, S.

AU - De Cecco, L.

N1 - Export Date: 29 March 2017 Chemicals/CAS: testosterone, 58-22-0; Testosterone

PY - 2016

Y1 - 2016

N2 - BACKGROUND: Androgen insensitivity syndrome (AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor (AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer (CRC) have been described. CASE PRESENTATION: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a microRNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers. CONCLUSIONS: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.

AB - BACKGROUND: Androgen insensitivity syndrome (AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor (AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer (CRC) have been described. CASE PRESENTATION: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a microRNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers. CONCLUSIONS: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.

KW - Androgen insensitivity syndrome

KW - Androgen receptor

KW - Colorectal cancer

KW - Single nucleotide polymorphism array

KW - Testosterone

KW - Whole exome sequencing

KW - testosterone

KW - adolescent

KW - adult

KW - Androgen-Insensitivity Syndrome

KW - case report

KW - chromosome 22

KW - Colorectal Neoplasms

KW - complication

KW - copy number variation

KW - DNA sequence

KW - exome

KW - female

KW - genetics

KW - germline mutation

KW - human

KW - male

KW - metabolism

KW - onset age

KW - pedigree

KW - single nucleotide polymorphism

KW - Adolescent

KW - Adult

KW - Age of Onset

KW - Chromosomes, Human, Pair 22

KW - DNA Copy Number Variations

KW - Exome

KW - Female

KW - Germ-Line Mutation

KW - Humans

KW - Male

KW - Pedigree

KW - Polymorphism, Single Nucleotide

KW - Sequence Analysis, DNA

U2 - 10.1186/s40880-016-0115-1

DO - 10.1186/s40880-016-0115-1

M3 - Article

VL - 35

SP - 51

JO - Chinese Journal of Cancer

JF - Chinese Journal of Cancer

SN - 1000-467X

IS - 1

ER -