Lynch syndrome accounts for the majority of familial endometrial cancers. This paper emphasizes the importance of familial endometrial cancer in the identification of Lynch syndorome. Endometrial cancer is essential as a “sentinel cancer” for Lynch syndrome since the diagnoses of some families are based on women with endometrial cancers. Therefore, gynecologists play an important role in the identification of Lynch syndrome. In women with Lynch syndrome demonstrating metachronous diagnoses of colorectal and endometrial cancers, half were diagnosed with colorectal cancer first, and the remaining were diagnosed with endometrial cancer first. These findings suggest that women with Lynch syndrome should be offered information on both colorectal and endometrial cancers. It has been reported that endometrial cancer arising solely in the lower uterine segment is associated with Lynch syndrome, and hMSH6 mutations play an important role in Lynch syndrome-associated endometrial cancer. There is room for further investigation of the molecular characteristics of familial endometrial cancer.

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We started active observation of Japanese hereditary (≧ 3 subjects) and familial (non-hereditary) (2 subjects) prostate cancer in 1994. Two hundred and sixty one families, including 42 hereditary (group H) and 219 familial prostate cancer families (group F）, were included in this study. The sporadic group (group S) included 11,664 subjects who were diagnosed in our prefecture and surrounding areas between 1986 and 2010. Members of group H and group F were significantly younger than those of group S at the time of diagnosis (p ＜ 0.01, p ＜ 0.01) ;, furthermore, the members of group H were younger than those group F (p ＜ 0.05）. Prostate cancer-specific survival rate, in group H and group F was lower than that in group S (p ＜ 0.01, p ＜ 0.05）;, there was no significant difference between the prostate cancer-specific survival rate of group H and group F (p ＝ 0.84）. In 1997, we reported the prostate-specific antigen (PSA) levels in 20 healthy males who had at least two family members with prostate cancer. The PSA Levels in five of these 20 subjects was above the cut off level (4.0 ng/ml）. All family members with PSA levels above the cut off level in 1997 were diagnosed with prostate cancer within 3 years. The final prostate cancer detection rate was 25 ％ (5/20）. We emphasized the importance of PSA screening for healthy male family members in familial prostate cancer lines. We confirmed pathologically the accuracy of family histories of prostate cancer obtained by interviewing prostate cancer patients. Only 195 of the total 259 cases (75.3 ％) had provided correct information. Confirmation of pathological findings is important in the assessment of family history of prostate cancer.

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Neuroblastoma (NB) originates in the adrenal medulla or the sympathetic neural chains and accounts for 9–10 ％ of all pediatric tumors. The familial form of NB is rare, accounting for 1 ％ of all NB. Wilms tumor (WT) is an embryonic kidney cancer and constitutes 5 ％ of all pediatric tumors. The incidence of hereditary cases is suggested to be about 1–3 ％. The hereditary form in both tumors is supposed to be autosomal dominant with inconsistent penetrance. The first candidate gene found in an American NB family pedigree was 16p12–13, and 4p16 or 4p12 was later suggested in an Italian NB family. Recently, the synergic action of 2p and 12p abnormality was also suggested to be the cause of familial occurrence. In WT, two types of cancer suppressor genes, WT1 and WT2, were identified. Congenital absence of WT1 is characterized by the association of aniridia or urogenital abnormalities. However, cases of WT familial occurrence are not always associated with such somatic abnormalities. Recently, new loci of 17q12–21 or 19q13 have been also suggested as causes of familial occurrence but these genes are not considered tumor suppressor genes. These findings suggest that tumor occurrence is a multifactorial event and tumor heterogeneity is apparent from the study of hereditary occurrence in NB or WT.

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Nevoid basal cell carcinoma syndrome (NBCCS), also called Gorlin syndrome, is an autosomal dominant disorder characterized by minor anomalies and predisposition toward cancer. It is caused by mutations in the PTCH1 gene encoding a suppressor component of a receptor complex for a secreted protein, sonic hedgehog. We performed a nation-wide surveillance of NBCCS and reviewed the findings of 311 affected individuals. The major criteria were met at frequencies ranging form 36–86％ and 60％ of cases were expected to have novel mutations. Of note, compared with reports from Western countries, the frequency of basal cell carcinoma (BCC) was much smaller in Japanese (38％) and the mean age of onset of BCC was much younger (37.5 years). Mutational analyses demonstreted that 91％ of the NBCCS families carried PTCH1 mutations including large deletions. Clinical diagnosis of NBCCS is not always easy because some of the NBCCS phenotypes develop with age. Therefore, early genetic testing is advisable for the early detection of tumors and for the protection of BCCs.

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Familial cancer is not commonly in encountered routine clinical practice. However, it is important for physicians to pay close attention to familial history and recognize typical symptoms for diagnosis of familial cancer syndrome. Moreover, counseling for familial cancers has great significance for both the proband and carrier, especially for screening to find early cancers in carriers. We provide some examples to illustrate the importance to knowledge regarding familial cancer syndrome.

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Lynch syndrome is an inherited disease caused by a pathological mutation in one of the mismatch repair genes and is characterized by the development of colorectal cancer, endometrial cancer, gastric cancer and various other cancers. We report a man with a family history of colonic, gastric, and bile duct cancer, who underwent proximal gastrectomy for stage I gastric adenocarcinomas at age 54. Eight years later, metachronous gastric cancer was detected in the remnant stomach by surveillance gastroscopy. Total gastrectomy was performed uneventfully. The main lesion was an elevated and well differentiated adenocarcinoma measuring 20 mm in diameter. Histological examination demonstrated two other independent small gastric carcinoma in situ. In conclusion, multiple cancers in various organs are common in Lynch syndrome, lifelong endoscopic surveillance for new cancer in the remnant stomach is essential. Moreover, total gastrectomy may be a choice for any gastric carcinomas for Japanese patients Lynch syndrome, since gastric carcinoma remains one of the main causes of cancer death in the Japanese population.

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