MLH1 germline mutation associated with Lynch syndrome in a family followed for more than 45 years

Tomoyuki Momma,
Kenji GondaEmail author View ORCID ID profile,
Yoshinori Akama,
Eisei Endo,
Daisuke Ujiie,
Shotaro Fujita,
Yuko Maejima,
Shoichiro Horita,
Kenju Shimomura,
Shigehira Saji,
Koji Kono,
Rei Yashima,
Fumiaki Watanabe,
Kokichi Sugano and
Tadashi Nomizu

BMC Medical Genetics201920:67

https://doi.org/10.1186/s12881-019-0792-0

Received: 15 October 2018
Accepted: 25 March 2019
Published: 2 May 2019

Open Peer Review reports

Abstract

Background

Lynch syndrome, is an autosomal dominantly inherited disease that predisposes individuals to a high risk of colorectal cancers, and some mismatch-repair genes have been identified as causative genes. The purpose of this study was to investigate the genomic rearrangement of the gene in a family with Lynch syndrome followed for more than 45 years.

Case presentation

The family with Lynch syndrome is family N, who received colorectal cancer treatment for 45 years. The proband of family N had multiple colorectal and uterine cancers. Because the proband met the diagnostic Amsterdam criteria and was Microsatellite instability (MSI) - positive, we performed genetic testing several times. However, germline mutations in MLH1 and MSH2 genes were not found by long-distance PCR or RT-PCR/direct sequencing analysis within the 45-year follow-up. MLPA analysis showed that the genomes of the proband and proband’s daughter contained a deletion from exon 4 through exon 19 in the MLH1 gene. Her son’s son and her daughter’s son were found to be carriers of the mutation.

Conclusions

For carriers of mismatch-repair gene mutation among families with Lynch syndrome, the onset risk of associated cancers such as uterine cancer is particularly high, including colorectal cancer. The diagnosis of carriers among non-onset relatives is important for disease surveillance.