Lozynska M., lozynskyy Y., Рinyazhko R., Рrokopchuk N., Fedota O.

MEDICAL GENETICS

Scentific article

According to the literature data in some monogenic and polygenic diseases, including cancer, observed the earlier age manifestation and increasing severity of symptoms of disorders in successive generations of pedigrees, called anticipation. In the basis of this phenomenon is a dynamic mutation in DNA with the trinucleotide repeat expansion. Trinucleotide repeats consist of a pattern of three nucleotides which is repeated a number of times. During meiosis, unstable repeats can undergo triplet expansion; in this case, the germ cells produced have a greater number of repeats than are found in the somatic tissues. The mechanism behind the expansion of the triplet repeats is not well understood. There are controversial results regarding effects of anticipation in Lynch syndrome, one of the most common among monogenic cancer diseases of intestine, which is inherited with an autosomal dominant mode with penetrance of 80-90%. The aim of this research is to study the peculiarity of the age manifestation of colorectal cancer, associated with Lynch syndrome I and II, in parents and offsprings with different gender, residents of western regions of Ukraine. Results. The analyses of medical records and genealogical information in 182 patients with colorectal cancer was carried out. Lynch syndrome was confirmed in 9 (5.0%) patients whose family meets the Amsterdam criteria. Age manifestation of CRC, associated to Lynch syndrome, in 42 patients (9 probands and 33 relatives) ranged from 32 to 68 years. The average age of CRC manifestation in patients with Lynch syndrome was 40.35 ± 6.84 years for males, and 50.27 ± 9.41 years for females (p > 0.05). Pedigree analysis of probands families showed the earlier age manifestation of the disease in successive generations of pedigrees, called anticipation. According to some authors, the anticipation in Lynch syndrome was not confirmed (Tsai et al., 1997), but other results statistically proven phenomenon in the group of patients for almost the same period (Westphalen et al., 2005). The average difference between age of CRC manifestation in parents and descendants was 11.2 ± 2.36 years. The largest average difference at age manifestation of disease, nearly 15 years, was observed in the pairs mother-son, father-son, and parents-sons, respectively. These data varied in different pairs: from 10.7% in the pairs parents-daughter to 15.6% in the pairs father-son. The average meaning of relative anticipation sign is 13.0%. Number of mother-offspring pairs was in three times higher than the number of parent-offspring pairs. The possible cause of phenomenon is considered the dinamic mutation during gametogenesis. The calculation of a correlation coefficient between relatives by the age manifestation of CRC, associated to Lynch syndrome, showed the strongest correlation (r ± sr) in the pairs parent-daughter (0.63 ± 0.29, p < 0.01) and in the same-sex pairs: father-son – 1, and mother-daughter (0.64 ± 0.32, p < 0.001). The correlation connection (r ± sr) of the average closeness was observed in the pairs parents-descendants. The negative correlation was found in a pair of mother-son and father-son. The positive correlation (r = 0,48) between the age manifestation of cancer was found in the parents and offsprings. The registration of anticipation is important in prognostic meaning, because it helps to estimate the age of probable manifestation of the disease taking into account the gender of patients, and, therefore, it will be possible to carry out the purposive prevention. During the genetic counseling of patients with Lynch syndrome is necessary to accent attention on high penetration of the disease and 50% risk of the disease occurrence in the first degree relatives of the probands.

anticipation, Amsterdam diagnostic criteria, colorectal cancer, age manifestation, gender, Lynch syndrome

• 1. Атраментова Л. А. Корреляция между родственниками по возрасту манифестации рака легкого и рака толстого кишечника / Л. А. Атраментова, Л. В. Беляева // Генетика. – 2003. – Т. 39, № 12. – С. 1702-1709.
• 2. Атраментова Л. А. Статистические методы в биологии: учебн. [для студ. высш. учеб. зав.] / Л. А. Атраментова, О. М. Утевская. – Горловка: Ліхтар, 2008. – 248 с.
• 3. Carethers J. M. Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer / J. M. Carethers, E. M. Stoffel // World J. Gastroenterol. – 2015, Vol. 21 (31). – P. 9253-9261.
• 4. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset / H. Hampel, J. A. Stephens, E. Pukkala [et al.] // Gastroenterol. – 2005. − Vol. 129 (2). – P. 415-421.
• 5. Iwama T. Anticipation phenomenon in familial adenomatous polyposis: an analysis of its origin / T. Iwama, J. Utsunomiya / World J. Gastroenterol. – 2000. – Vol. 6 (3). – P. 335-338.
• 6. An update of HNPCC (Lynch syndrome) / H. T. Lynch, T. Smyrk, J. Lynch [et al.] // Cancer Genet Cytogenet. – 1997. – Vol. 93 (1). – P. 84-99.
• 7.Lindor M. Familial colorectal cancer type X: the other half of hereditary nonpolyposis colon cancer syndrome / M. Lindor // Surg. Oncol. Clin. N. Amer. – 2009. – 18 (4). – P. 637-645.
• 8. van Lier M. G. F. A review of molecular diagnostic of Lynch syndrome: a central role of pathology laboratory / M. G. F. van Lier, A. Vagner, M. E. van Leerdam // J. Cell Mol. Med. – 2010. – Vol. 14 (1-2). – P. 181-197.
• 9. McFaul C. D. Anticipation in familial pancreatic cancer / C. D. McFaul, W. Greenhalf, J. Earl [et al.] // Gut. – 2006. – Vol. 55. – P. 252-258.
• 10. McInnis Melvin G. Anticipation: an old idea in new genes / G. McInnis Melvin // Am. J. Hum. Genet. – 1996. – Vol. 59 (5). – P. 973-979.
• 11. Pogosean A. A study of anticipation in families with hereditary nonpolyposis colorectal cancer. Degree project in biology / A. Pogosean // Bachelor of science. — 2009. — Uppsala universitet, och Karolinska Institute. – 23 р.
• 12. Tsai Y. Y. Evidence Against Genetic Anticipation in Familial Colorectal Cancer / Y. Y. Tsai, G. M. Petersen, S. V. Booker [et al.] // Genet Epidemiol. – 1997. – Vol. 14. – P. 435-446.
• 13.The International Collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC) / H. F. Vasen, J. P. Mecklin, P. M. Khan., H. T. Lynch //Dis. Colon Rectum. – 1991. – Vol. 34 (5). – P. 424-425.
• 14. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC / H. F. Vasen, P. Watson, J. P. Mecklin, H. T. Lynch // Gastroenterol. –1999. – Vol. 116 (6). – P. 1453-1456.
• 15. Westphalen А. Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer / A. A. Westphalen, A. M. Russell, M. Buser [et al.] // Hum. Genet. – 2005. – Vol. 116. – P. 461-465.
• 16. Yacoub G. Oncologic management of hereditary colorectal cancer / G. Yacoub, S. Nagalla, M. Aklilu // Clin. Colon Rectal. Surg. – 2012. – Vol. 25 (2). – P. 118-122.

«Bulletin of problems biology and medicine» Issue 1 part 1 (126), 2016 year, 218-221 pages, index UDK [575.224.2: 616.34-056.7- 006]-037