The first case report of polymerase proofreading-associated polyposis in POLD1 variant, c.1433G>A p.S478N, in Japan.

Polymerase proofreading-associated polyposis, caused by germline variants in the exonuclease domains of POLD1 and POLE, is a dominantly inherited rare condition characterized by oligo-adenomatous polyposis and increased risk of colorectal cancer, endometrial cancer and brain tumours. We report the first Japanese case of polymerase proofreading-associated polyposis carrying a POLD1 variant. The proband was a Japanese woman who had undergone resections of early colorectal carcinomas repeatedly and a hysterectomy with bilateral oophorectomy for endometrial cancer, all of which were diagnosed within 2 years after the first colectomy at 49 year old. Colonoscopic examinations demonstrated at least 14 non-cancerous polypoid lesions, some of which were histologically confirmed to be adenoma. Multigene panel sequencing identified a missense variant in POLD1 (c.1433G>A). Although her relatives did not undergo genetic testing, her father and paternal grandfather died of brain tumours at 53 and ~30 years of age, respectively.

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

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.

Correction: Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan.

Correction to: Journal of Human Genetics advance online publication, 08 November 2017; https://doi.org/10.1038/s10038-017-0355-1.

Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan.

The hereditary breast and ovarian cancer (HBOC) registration system of Japan was established by the Japanese HBOC Consortium. The first trial was registered in 2015 in four institutions to which some registration committee members belonged. We analyzed the information of 830 Japanese pedigrees, who underwent BRCA1/2 genetic testing, including mutation carriers with BRCA1 (N = 127) and BRCA2 (N = 115), and their families. The mutation-positive rate was 19.7%. Variants of uncertain significance were found in 6.5% of all individuals subjected to genetic testing for BRCA1/2. Compared to the United States, Japan had a higher mutation-positive rate in most categories, except for the groups with male breast cancer. Among the intrinsic subtypes of BRCA1-associated breast cancers, 75.8% were triple-negative. The incidence rate of contralateral breast cancer in BRCA1/2 mutation carriers was 0.99%/year. Among 240 mutation carriers, 26 and 62 patients underwent risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), respectively; the respective frequencies of occult cancer were 7.1 and 3.2%. Metachronous breast cancer after RRM or peritoneal cancer after RRSO was not observed during the follow-up period. The nationwide registration system began last year and the system enables follow-up analysis in Japan.

[The clinical study of familial breast cancer - now and the problems].

The clinical features of familial breast cancer are characterized by early onset, high frequency of bilateral breast cancer, and multiple malignancies of other organs. It is strongly suggested that genetic factors contribute to familial breast cancer. The causative genes now identified are BRCA1 and BRCA2. This disease is called hereditary breast ovarian cancer syndrome (HBOC)because breast cancer and ovarian cancer are clustered in the kindred confirmed BRCA mutation. As for BRCA related breast cancer, early onset and highly frequent bilateral breast cancer are characteristic. In addition, the histological grade is high and the positive rate of estrogen receptors is low in BRCA1-related breast cancer. Gene diagnosis of BRCA is useful when choosing a surgical method, chemotherapy, or a surveillance of mutation carriers. The problem in Japan is that the treatment is very expensive, with poor understanding of HBOC of by clinicians and as yet immature genetic counseling system.